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Obituary - A. Laveran1922

LAVERAN, Alphonse Charles Louis:"Nature parasitaire des accidents de l'impaludisme, description d'un nouveau parasite trouvé dans le sang des malades atteints de fièvre palustre", Paris 1881

Original document at BIUM-Bibliothèque Interuniversitaire de Médecine

CONTENTS: CHAPTER I OBSERVATIONS I-IV CHAPTER II CHAPTER III CHAPTER IV OBSERVATION V-XXV CHAPTER V CHAPTER VI CONCLUSIONS PLATE I:Explanation of Plate I PLATE II:Explanation of Plate II

English Translation:

LAVERAN, Alphonse Charles Louis: The parasitic nature of the mishaps of paludism : description of a new parasite found in the blood of people stricken by marsh fever.

PREFACE

In the month of August, 1878, I left Paris in order to serve in the province of Constantine; I was naturally obliged to consider utilising my stay in the province in a study of the palustrine fevers which, moreover, by their frequency, and their seriousness, impressed themselves on the attention of any doctor arriving in Algeria. As the histology of the changes produced in the various organs by impaludism had been a little neglected hitherto, I made a resolution to apply my principal effort to this particular part of the problem. This study, pursued for two years at Bone, Biskra, and at Constantine, demonstrated to me that the only lesion characteristic of impaludism consisted of pigmented rudiments in the blood.

What was the nature of these pigmented elements? How did they come into being in the blood? An examination of lesions in the cadaver not providing an answer to this question, I decided to examine these pigmented elements in fresh blood. It did not take me long to realise that in the blood of some patients subject to obstinate, intermittent fever, one found, aside from the pigmented elements already described by different observers as melanin-bearing leucocytes, other elements, round or elongated, pigmented, highly regular, which bore not the slightest resemblance to leucocytes loaded with pigment. I had suspected for some time that these elements were of parasitic origin when, on the 6th. of November, 1880, while examining one of these rounded, pigmented bodies in a preparation made from fresh blood, I established with astonishment that at the periphery of this element there existed a series of slender, extremely transparent filaments which were moving with a great agility, of an incontestably animal nature. Soon, I recovered these elements in the blood of other patients, and I abandoned all doubts as to their parasitic nature.

I have already described these new blood parasites in two notes presented to the Academy of Medicine by Professor L. Colin (sessions of 23rd November and of 28th December 1880), and in another note sent to the Medical Society of Hospitals.

These communications have not aroused, I know, much attention from the medical public. So often has an announcement been made that someone has discovered the live germ of marsh fever, and the hopes raised by these promises have been dashed so often, that the scepticism of the medical public is explicable. On the other hand, one finds oneself, in Paris, in very poor conditions, especially in the climate in which we are, to verify the facts which I observed at Constantine.

In publishing this work, I have entertained, therefore, the hope that it will reach at least as far as colleagues who labour in locations where marsh fever is endemic, and that it will serve to guide them in finding the blood parasites which I have described.

Paludism manifests itself in all countries with such uniformity and constancy of character, with near enough the same intensity, that it is not possible to admit that it might be due to different causes depending on the locality. If the parasites that I discovered in the blood of patients attacked by marsh fever at Constantine were truly responsible for the mishap of paludism, in keeping with the conviction I have acquired, these parasites ought to be recoverable with the same characteristics among patients who have contracted the fever, whether in the Indies or in Senegal, for example.

In this work I shall present, initially, a very short summary of the lesions of paludism. Next, I shall describe the parasite elements which I discovered in the blood of patients attacked by marsh fever, and it will be easy to establish that the pigmented bodies which are found in such great numbers in the blood of subjects who have died of pernicious fever are none other than the remains of these parasites. Finally, I shall look into what might be the nature, and what the pathologic rôle of these new blood parasites.

Constantine, 20 February 1881.

CHAPTER I:

[Résumé of anatomic lesions in paludism - Importance of the pigmented particles which are found in the blood.]

The most constant, and most characteristic lesion of paludism is the presence of pigmented elements in the blood which have until now been thought of as melanin-bearing leucocytes.

These pigmented elements circulate in the blood; one can, therefore, find them in all organs, and all tissues, which receive blood vessels. It must be said, however, that they have a predilection for certain organs.

In individuals who have died of pernicious fevers, these pigmented elements exist in such large numbers in the vessels of the spleen, and of the liver, that these viscera take on a slaty coloration, indicated by all authors; the abundance of the pigmented elements in the capillary vessels of the brain, and of the spinal cord, often gives to these nervous centres a grey hue far deeper than in the normal situation or, equally, a violaceous colour, hydrangea-like, no less characteristic than the slaty colouring of the spleen and the liver.

The pigmented elements which have been found in cadavers has been ascribed hitherto to leucocytes enclosing pigmentary granules, and the deposition of this pigment, which is not seen in any other illness, to the rapid destruction suffered by the red blood cells during febrile fits.These so-called leucocytes often acquire in the spleen, and in the liver, a diameter three to four times greater than those of normal leucocytes. In other respects, the pigment does not happen to be deposited by chance inside these elements, as it also enters within when a coloured and pulverulent material is injected into the veins of an animal. The grains of pigment in variable amounts appear, in elements which have not undergone any alteration, in the form of rounded grains, blackish, or a very deep fiery-red, regularly disposed around the periphery of these elements. Figure 1 of Plate 1 shows some of these bodies found in the middle of dissociated elements in the spleen.

One encounters, sometimes, in blood collected from a cadaver, elongated bodies, with enfiled extremities, pigmented in their middle parts (a, a', fig. 2, pl.1); nearly always pigmented elements originating from a cadaver have a more or less regularly spherical form (b, b', b", fig.2, pl. 1). When the cadavers have begun to undergo putrefaction, the pigmented granules often come together in a single, blackish mass. The pigment can also be liberated following the disorganisation of the elements which contained it.

Figures 3,4 and 5 of Plate 1 portray histological sections of the liver, of the spleen, and of the grey matter of the brain of an individual who died of pernicious fever. It can be seen that the capillary vessels of the spleen and of the liver include a large number of pigmented elements.

In the liver, these bodies are all situated inside the vessels; not a single pigmented granule is encountered in the trabeculae of the hepatic parenchyma or amid the connective tissue.

In the spleen, the pigmented bodies show up equally well in the splenic pulp, as in the vessels. This exception to the general rule, which would have the pigmented bodies be found in the blood, is more apparent than real. In point of fact, the splenic pulp is traversed by capillary vessels, the rudimentary walls of which are very difficult to detect, even if, as Frey thinks, the blood does not circulate freely within the splenic pulp. It must be remarked at the outset, however, that in pernicious fever the spleen is so altered that it is often difficult to distinguish vascular orifices from splenic pulp in histological cuts, while lymphoid elements appear to be scattered in the venules, the epithelium of which is desquamated, and in many spots it is clear that the blood has invaded the splenic pulp. Therefore, very probably, the pigmented bodies which are located in the middle of lymphoid elements are bathed in blood, similar to those which are found within the splenic veins, during life.

The coverings of lymphoid tissue which accompany splenic arterioles, and which have become known by the highly improper name of Malpighian corpuscles(1), are generally very poor in pigmented elements, or even containing none at all, whereas the surrounding splenic parenchyma is literally riddled. This is doubtless due to the few, hardly noteworthy number of blood capillaries which penetrate these coverings of lymphoid tissues. Thanks to this absence of pigment, Malpighian corpuscles can be easily distinguished from neighbouring areas in histologic sections of the spleen from individuals who have died of pernicious fever; carmine imparts to them a much more lively rose colour than to the splenic pulp properly speaking, where the abundance of pigmented elements and of red blood cells communicates a brownish tint.

In sections of cerebral convolutions, dyed in carmine and mounted in Canada balsam, it can be recorded that the capillaries include a large number of pigment granules, rounded, equal to each other, and forming black knobs, often highly regular. Here, the grains appear free in the interior of the vessels, which would be in keeping with the elements, of which they form part, being left uncoloured by carmine and, therefore, perfectly transparent in the balsam.

The capillaries of the bulb and the medulla present a view similar to the cerebral capillaries, with their trajectories marked by a series of black spots forming a peglet, more or less regular, or united in a mass, more or less voluminous. If the pigmentation is more evident in the grey substance of the nervous centres than in the white matter, this can be attributed to the relative rarity of capillaries in this latter substance.

This black peglet, which marks the trajectory of the capillaries of the cerebrum and of the medulla in individuals who have died of pernicious fever, is not seen in any other malady, and the regularly rounded grains of pigment which it gives rise to barely resembles, to mention it in passing, the blood pigment which might be deposited by chance.

The capillary vessels in muscle and, in particular, those of the heart contain the pigmented elements in a more or less large number.

Outside the existence of these pigmented elements in the blood, among subjects that have died from pernicious fever one does not find any other constant lesion; apart from these elements, it can be said that the liver, the kidneys, the brain, the spinal medulla, the bulb, and the muscles, are all in a healthy state in the great majority of cases; as for the softening of the spleen, it is probably only consequential to the presence of pigmented bodies in very large numbers in this organ which, in any case, is insufficient to account for death.

Among those individuals who die of a palustral cachexia, the same pigmented elements can be discovered in the blood which occur in those who succumb following a pernicious mishap, save that these elements are far fewer in number, and instead of being disseminated in all the organs and all the tissues of the economy, they are localised, in general, in the vessels of the spleen and the liver. In addition, inflammatory lesions are encountered in these cases involving the spleen, and often, the liver and the kidneys.

Hypertrophic cirrhosis of the spleen is always present. The spleen often reaches a size of enormous proportions, above all among individuals who have lived for a long time in unhealthy locations, and who have taken little, or no, quinine sulphate. In Algeria, it is overall among the Arabs coming from unwholesome places, and never having taken cinchona, that I have observed these monstrous spleens which occupy all of half the abdomen. The surface of the spleen is covered over by thick, fibrous plaques with a pearly appearance. The splenic parenchyma is indurated and the microscope reveals, as one might have expected, a considerable thickening of the connective web.

The liver shows sometimes lesions of an atrophic cirrhosis, sometimes those of a hypertrophic cirrhosis.

Changes which are most common in the kidneys, changes less common, moreover, than those of the liver and the spleen, are those of a mixed chronic nephritis.

The lungs are at times affected by a partial cirrhosis. I drew attention recently to this form of chronic pneumonia, especially remarkable in showing transformation of the alveolar endothelium into an epithelium of cylindrical cells at the level of the diseased parts (Société médicale des hospitaux, 26 décembre 1879).

These inflammatory lesions are, to be sure, very interesting in themselves, but are secondary lesions, a consequence of repeated congestion from irritation brought about by paludism in different organs. Therefore, since the propositum is of one to research the alterations which relate directly to paludism, they must be given less importance than the lesions which can be observed following a pernicious fit.

As proof of the uniformity of lesions present in acute forms of paludism, and of the importance of the rôle played by these pigmented elements in the blood, I have thought it necessary to publish the following observations that it might be easier for me to generalise.

Observation I:

M...., soldier with the 3rd African battalion, enters the military hospital at Biskra on 6th October 1878. The sick person had had several well-characterised fits of fever prior to his entry into hospital. The 6th. October, a very strong attack, prostration marked. I prescribe 1gramme of quinine sulfate, then, the sick man having vomited the solution of quinine sulphate, a quart of enema with 4 grammes of quinine sulfate. Until the 19th October, the patient takes 0.80 grammes of quinine sulfate per day, the fever does not reproduce itself. On October 14th., the patient leaves at his own behest.
On 19th. October, M..... re-enters the hospital; he complains of diarrhoea. The sick man is wasted, markedly anaemic; oedema of his lower limbs; an anaemic murmur in the heart and in the vessels, Apyrexial.
The days following, the diarrhoea persists.
12th November. A febrile fit. The patient takes 0.80gr of quinine sulfate.
13th November. The morning, apyrexia. Another visit, I find the patient in a coma. The axillary temperature is 39.2°, the pulse, very strong, beat 112 times a minute. I call to the patient in vain, I get no response; strongly pricking and pinching the skin of the limbs, one evokes a few withdrawal movements which are probably no more than reflex movements.
At 3 o'clock in the evening, I inject subcutaneously into the cellular tissues 1 gramme of quinine chlorohydrate.
At 5.30 o'clock in the evening, the patient has regained consciousness, he is very feeble, very down.
14th November. At the morning visit, the patient has fully conscious, apyrexial, Quinine sulphate, 1 gramme.
At 10 o'clock in the morning, the patient is taxed by shudders, and at 3 o'clock I come across him, like the day before, in a coma. The axillary temperature is only 38.7°, the pulse variable;respiration stertorous. Complete insensibility.
Like the day before, I inject 1 gramme of quinine chlorohydrate, but this time the coma does not disperse, the patient dies 15th November, at 5 o'clock in the morning.

Autopsy made the 15th. November, at 2 o'clock in the evening.

The skin has a polished pallor; oedema of lower limbs.
Abdomen: The peritoneal cavity contains about one litre of citrine serous fluid, without trace, moreover, of any peritonitis.
The spleen is very enlarged, it weighs 730 grammes, its firmness is reduced; its colour markedly slatey.
The liver is normal in size, and presnts a deep brown colour; the gall bladder contains a very small quantity of very pale yellow bile.
Kidneys: they are of normal size; the cortical substance is very pale.
Intestines: The large intestine presents lesions testifying the existence of previous dysentery, on the way to being healed; At various distances, it shows shrinkage from adhesive strips of fibrous scarring; the colonic mucosa presents, besides, along its entire length, black spots which appear to correspond to isolated follicles, previously ulcerated. One also finds some small ulcerations, in the process of reparation.
The small intestine is perfectly healthy, without any change in the Peyer's patches.
The stomach is small, retracted; the gastric mucosa presents several areas of very marked hyperaemia.
Thorax - A small amount of citrine fluid in the pericardium, which is otherwise healthy.
The myocardium does not appear altered, the right heart includes some soft clots; the cardiac orifices are in a healthy state.
Some pleural adhesions which permit easy peeling. The lungs present, to a very marked degree, the lesions of hypostatic congestion.
Cranium - No alteration of the meninges. The grey substance of the cerebral gyri are of a grey slate much darker than in the normal state; this colouration is uniformly distributed, found equally at the base as in the convexity of the cerebrum. However, the cerebral substance has its normal consistency. No abundant effusion present in the ventricles.
The bulb appears to be in a healthy state.
The muscles (rectus abdominis *, psoas, etc.) have a normal colour and constituency.

Histological Examination:

A. Spleen: - The fragments of spleen are hardened by ordinary methods (alcohol, acid picric, solution of gum and alcohol), then are cut into sections, dyed with picrocarmine and mounted in glycerine. One can distinguish in the sections of spleen, a large number of pigmented elements which are lodged either at the vascular orifices, or the splenic pulp; it is quite difficult, moreover, in many places, to define the boundaries between the blood vessels and the splenic pulp; the endothelium appears to have become detached and the lumen of the vessels appears to have been invaded by lymphoid elements, whereas in the middle of the splenic pulp, one can find red cells of blood. The pigmented elements have respected nearly everywhere the lymphoid tissue which surrounds the splenic arterioles; it is easy to reassure oneself , in examining longitudinal cuts of the arterioles, that the tissue is disposed in the form of a 'sleeve' along the whole length of the arterioles. The pigmented elements have a very variable size, a good number approaching the dimensions of the leucocytes, others three or four times less than the size of leucocytes. The grains of pigment that they contain are regularly rounded, well separated from each other, or quite close and mingled into one and the same black mass.
B. Liver (examined using the same procedure as the spleen): - The slightly dilated blood capillaries include, amid the normal blood constituents, a large number of pigmented bodies, similar to those in the spleen. Outside the vessels, one finds none of these pigmented bodies.
The liver cells do not appear to be altered, no more than the connective tissue.
C. Brain. - Pieces of the frontal and parietal ascending convolutions, are hardened in a weak solution of chromic acid, then cut into sections, dyed with picrocarmine, and mounted in Canada balsam. The small vessels contain pigmented elements in rather large numbers; in sections mounted in Canada balsam, one can only see pigmented grains, which are rounded, and of almost equal size, disseminated in the form of a black, highly regular peg or, more rarely, grouped to form a heap. No grain of pigment is encountered outside the vessels. The other constituents of the brain do not present any other notable change. D. Myocardium. - Cuts made after hardening by ordinary methods. The sections are dyed using picrocarmine, and mounted in glycerine. The cardiac fibres are regularly striated. The sole alteration consists of the presence of pigmented elements in the small vessels.
E. Muscles (rectus abdominis and psoas). - Fibres dissociated in their fresh state or after being placed in alcohol for some hours. Some fibres have suffered a vitreo-granular degeneration; the diseased fibres are, furthermore, in very small numbers relative to healthy fibres, presenting regular striations. The small vessels which are found among the dissociated fibres include pigmented elements in large number.

Observation II:

B...detainee employed in a workshop of public works, aged twenty one years, enters the military hospital at Constantine on the 13th. September 1880. He dies on the 20th. September at 6 o'clock in the morning, after having presented all the symptoms of a pernicious fever up to becoming comatose.

Autopsy performed on 21st. September 1880, at 8.30 in the morning.

Abdomen. - Healthy peritoneum, without effusion. The intestines are small, retracted, and almost completely empty; three lumbrici are discovered there. No alteration of the mucosa, Peyers plaques, notably, are intact.
The spleen is enlarged, it weighs 850 grammes; it is diffluent and presents a characteristic slaty hue. no perisplenitis, no adherence.
The liver weighs 1900 grammes, and has a diminished consistency; characteristic slaty coloration.
The kidneys do not appear to be altered, they present their normal coloration.
Thorax. - Healthy pericardium, The myocardium consists of its normal colour and consistency. Healthy endocardium, with no valvular lesions. The right ventricle and auricle contain some soft red or amber clots.
Pleurae intact, with no adhesions.The lungs have only incompletely collapsed after having retracted from the thoracic cage; hypostatic congestion.
Cranium. - Healthy meninges. The circumvolutions have a violaceus, hydrangea-like, very characteristic tint. The central nuclei do not appear altered; no effusion in the ventricles.
The bulb has a normal form.
The muscles abdominal great recti, psoas, etc, do not appear to show any change to the naked eye.

Histological Examination:

A. Spleen. - The fragments of spleen are hardened by ordinary procedures (alcohol, picric acid, gum and alcohol), after which sections are made, dyed with picrocarmine and mounted in glycerine. One confirms in the sections a large number of pigmented elements of which it is difficult to appreciate their exact form and dimensions. The pigment presents itself in the form of black, rounded granules, of rather variable volume. The pigmented elements are found just as well in the middle of the splenic pulp as inside the venules, but only observed very rarely in the sleeves of lymphoid tissue which accompany the arterioles (Malpighian corpuscles). The connective tissue of the spleen is not thickened.
B. Liver (prepared using the same procedure as the spleen). - One finds a large number of pigmented elements in the blood capillaries; these elements, the form of which is very irregular, are half the size of leucocytes, but some are more voluminous; the pigment grains are disposed most often at the periphery. Outside the blood vessels, one does not detect any grains of pigment. The hepatic cells do not appear altered. At the level of the triangular spaces, there are often small foci of embryonic elements.
C. Kidneys (prepared using the same procedure as the spleen and the liver). - One finds in the small vessels, especially at the level of the glomeruli, pigmented elements, but in far fewer numbers than in the spleen and the liver.
D. Lungs (same method of preparation). - All the vessels are distended by blood; in the middle of the red corpuscles one distinguishes the pigmented elements in small numbers. A certain number of alveoli contain blood more or less altered, often reduced to the state of a granular magma. No traces of inflammation.
E. Heart. - Fragments of the ventricles are hardened using ordinary methods, then cut into sections, coloured with picrocarmine and mounted in glycerine. The muscular fibres are regularly striated, with no alteration of connective tissue. One only detects, here and there in the small vessels, some pigmented elements.
F. Brain. - Fragments of cerebrum, taken especially from the convolutions of motor cortex, are hardened slowly in a weak solution of chromic acid, then cut into sections, dyed with carmine, and mounted in Canada balsam.The grey matter of the convolutions presents a very remarkable view in these cuts : all the small vessels are highlighted by a black peglet, rather regular, formed by rounded granulations, nearly all equal to each other; one might say that the vessels had been injected with a transparent substance holding a large number of grains of a black substance in suspension ( Fig. 5, pl. I). In some spots, the black grains are closed in, one against the other, to form heaps more or less large. In some vessels of larger calibre, in which the Canada balsam has produced a transparence less complete than in the capillaries, one can assure oneself that the grains of pigment are not free, but enclosed inside rounded elements analagous to those which are encountered in the other organs : spleen, liver, etc. As these elements are not dyed by carmine and their transparence in Canada balsam is perfect, one can only distinguish, especially in the capillaries, the grains of pigment, and not the elements which include them.
The small vessels of the white matter contain, equally, grains of pigment in large number; but these vessels are far less numerous than in the grey matter, with the result that the views from these cuts is less remarkable than in the grey matter. The cerebrum, moreover, shows no alteration; the large neurones of the convolutions of the motor cortex are in a healthy state. One detects no pigment outside the vessels.
G.Bulb, medullary (prepared using the same procedure as the cerebrum), - The small vessels present the same aspect as in the cerebrum, and are marked by a black peglet, rather regular, very remarkable. There exists no other change in the bulb or in the medulla.
H. - Fragments of the psoas and great recti muscles of the abdomen are dissociated in the fresh state or after a few hours stay in alcohol. The muscle fibres are regularly striated. The small vessels which are found in the middle of dissociated fibres contain pigmented elements analogous to those in the spleen and the liver.

Observation II:

D...., aged twenty- two years, military detainee employed in a workshop of public works, enters the military hospital at Constantine on the 18th. September 1880. The sick man dies on the 20th. September at 7 o'clock in the evening during a pernicious fit leading to a comatose form.

Autopsy made on the 21st. September at 8.30 hours in the morning.

The cadaver is of a man still vigorous, well-muscled, but very anaemic. No oedema of the lower limbs.
Abdomen. - Healthy peritoneum. No ascites.
Intestines: Nothing abnormal, Peyer's patches, especially, are not altered.
Spleen. - The spleen, noticeably increased in volume and in weight (it weighs 600 grammes), has a brownish colour, slaty; it is softened to a point where it can hardly be removed from the abdomen, the fingers sinking into the splenic pulp with the least pressure.
The liver is increased in volume, it weighs 2150 grammes; it has a diminished consistency; it presents a characteristic slaty colour.
The kidneys do not appear noticeably altered.
Thorax. - Healthy pericardium. The myocardium has a normal colour and consistency. The left ventricle is a little hypertrophic. No lesions of the endocardium or of the valves. The right heart contains some soft clots.
The lungs are voluminous, and collapse only very incompletely at the time of the opening of the thorax; there is a hypostatic congestion present.
Cranium. - The meninges do not present anything abnormal. The grey substance in the cerebral convolutions has a violaceous tint, hydrangea-like; the cerebrum appears more anaemic than hyperaemic. No effusion in the ventricles.
The bulb presents no notable change.
Muscles. - The grand recti muscles of the abdomen, psoas, etc., do not appear altered to the naked eye.

Histological Examination:

The procedures adopted for examination are the same as in the previous observations. A. Spleen. - a. Examination of fresh elements, dissociated. The dissolution was spontaneous and it was sufficient merely to take a little of the splenic deposit and mix it with a few drops of picrocarmine; the picrocarmine was next replaced by glycerine. One found in the preparations so made : a great number of lymphoid cells, red globules of blood, elongated endothelial cells characteristic of the endothelium of splenic veins, and lastly, a number of more or less deformed pigmented elements, and free pigment.
b. Examination of sections of the spleen after hardening. The existence of a large number of pigmented elements is confirmed, whether at the level of the vascular orifices, or in the splenic pulp. The spleen is highly congested and, even in the middle of the splenic pulp, trails of red blood corpuscles can be found. The sleeves of lymphoid tissue which accompany the arterioles only contain a very small number of pigmented elements.
B. Liver. - The blood capillaries contain a great number of pigmented elements concerning which it is very difficult to determine the form in the sections made after hardening. Outside the vessels, which are dilated, no pigmented elements exist, no grains of pigment. The hepatic cells are not altered ; the connective tissue of the liver and the triangular spaces are in a normal state.
C. Kidneys. - In the small vessels, especially at the level of the glomerulus, one can distinguish pigmented elements in far smaller numbers than in the liver. No alteration of the tubular epithelium, nor of the connective tissue.
D. Lungs - At the points examined corresponding to the congested areas, one ascertains a great number of alveoli to contain granular masses, in the middle of which one distinguishes red blood corpuscles, desquamated endothelial cells and, finally, some pigmented elements; in other alveoli one finds young cells and fibrinous tracts which evidently indicate an inflammatory process. The interalveolar walls are a little thickened following the engorgement of capillaries which include pigmented elements in rather large numbers.
The presence of some of these elements in the interior of the alveoli raises the possibility of detecting them during life in the spittle.
E. Heart. - The cardiac muscle fibres are regularly striated; nothing abnormal.
F. Cerebrum. - Cuts made at the level of the gyri of the motor cortex. The small vessels contain a great number of pigment grains, blackish, almost equal to each other, forming a highly regular, black peglet. At certain points, the pigment grains are agglomerated in more or less considerable numbers. Outside the blood vessels, one does not finds a trace of pigmented bodies. The cerebral cells do not appear altered, still less the other elements constituting the brain.
G. Bulb, medulla. - The small vessels of the bulb and of the medulla contain, like those of the cerebrum, a large number of pigment grains; there exists no other alteration; the nerve cells, and the neuroglia are in a healthy state.
H. The grand recti of the abdomen, psoas. - The muscle fibres are regularly striated; the small vessels which are found in the middle of the dissociated muscle fibres contain pigmented elements.

Observation IV:

D..., aged 27 years, gendarme, is brought to the military hospital at Constantine on the 27th. September 1880. The sick man falls into a deep coma from the moment of his arrival at the hospital, and one has no information on the onset, nor the progress of the disease. A diagnosis of pernicious fever in comatose form is made, and quinine sulphate in a high dose is administered internally, and on several occasions, he is given hypodermic injections of quinine chlorohydrate, The patient does not regain consciousness, he dies in a coma on the 28th September at 6 o'clock in the morning.

Autopsy performed on the 28th of September at 3.30 o'clock in the evening.

The cadaver is that of a well-formed man, a little wasted. A suggestion of an icteric tinge of the skin and the sclera; no oedema.
Abdomen. - No effusion in the peritoneum. The intestines are in a healthy state; notably, there is no alteration in Peyer's patches present.
The spleen is very enlarged, it weighs 700 grammes approximately; the splenic pulp is softened but not reduced to porridge, as often happens in these cases; it has a characteristic,slaty colour.
The liver is highly enlarged, it weighs 2125 grammes; the hepatic parenchyma, more friable than in its usual state, has a characteristic slaty hue. The gall bladder contains a thick bile, very dark in colour, similar to raisins.
The kidneys do not appear altered.
Thorax - The pericardium is healthy, and includes a small quantity of a citron, serous fluid. The myocardium and the endocardium do not appear altered. In the heart are found a few soft clots.The pleurae are healthy; the lungs present lesions of a hypostatic congestion.
Cranium - The meninges are healthy. The cortical substance presents a violaceous tint, hydrangea-like, very characteristic. This violaceous tint also shows up in the central grey nuclei, although to a lesser degree. The white matter of the cerebrum is of its normal appearance. There is no other alteration of the cerebrum or of the bulb.
Grand recti muscles of the abdomen, psoas, etc. - These muscles are of normal appearance.

Histological Examination:

The same methods of examination are employed as in the preceding observations.
A. Blood taken from the heart examined in the fresh state. - Amid the normal constituents of the blood, free pigment, rounded, pigmented elements, more or less deformed (b, b', b", fig.2, pl.1), and also some elongated elements, narrowed at their extremities, pigmented in their middle part (a, a', same figure) can be seen.
B. Spleen. - In sections made after hardening, the existence of numerous pigmented elements can be confirmed, either situated in the vessels, or in the middle of the splenic pulp; only the parts corresponding to the arteriolar cuff of lymphoid tissue is spared this infiltration of pigmented elements, and as a result, they stand out a lot more than in the normal state. The pigmented elements are in general spherical; the pigment is disposed at the circumference of these elements in the form of blackish grains, rounded, and of a rather variable size. In a certain number of elements the pigment grains are so large that they touch and appear, at first glance, to form a single mass.
C. Liver. - The capillaries include these pigmented elements in fairly large numbers; the hepatic cells do not appear to be noticeably altered. At the level of the triangular spaces, small heaps of embryonic elements are found frequently.
D. Kidneys. - The small vessels, especially those of the glomeruli, contain rather large numbers of pigmented elements. The tubular epithelium does not seem sick, nor does the connective tissue.
E. Heart. - The muscle fibres are regularly striated; the small vessels include pigmented elements.
F. Brain - Cuts made at the level of the convolutions of the motor cortex. The capillaries include a large number of pigment grains which are disseminated either in a rather regular fashion, or well agglomerated. The neuronal cells and the neuroglia are in a healthy state.
G. Bulb. - The capillaries contain, as those of the brain, a large number of pigmented elements; the pigment grains are only visible in sections mounted in Canada balsam. The other elements of the bulb are in a healthy state.
H. Grand recti muscles of the abdomen, psoas, etc. - The muscle fibres present regular striation .

Notes: Chapter 1.
1. It is easy to assure oneself, by examining longitudinal cuts of splenic arterioles, that this lymphoid tissue surrounds the arterioles along their entire length, and that this does not constitute corpuscles, properly speaking, and still less the man.

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CHAPTER II:

[Description of the pigmented particles found in the blood of patients attacked by marsh fever. Different aspects of the elements - Bodies nos.1, 2 and 3. - Method of blood examination.]

The pathological anatomy demonstrates, as we have just observed, the importance of the rôle played by the pigmented elements in paludism, but there the information comes to an end; in order to understand the true nature of the pigmented elements, it becomes necessary to study these bodies not in the cadavers, but also in the living, in the blood of those individuals stricken by marsh fever.

When the blood of a sick person attacked by marsh fever, and one who has not taken any quinine sulphate for a certain time, at least in a strong dose, is examined under the microscope using sufficient magnification (400 - 500 diameters), very characteristic, pigmented elements are frequently discovered which I shall describe under the names of bodies no.1, no.2, and no. 3.

Bodies No. 1. - These are elongated elements, more or less tapered at their extremities, often crescentically curved inwards (A, A', fig.1, pl. II) ; sometimes in an oval shape (B, same figure) . The length of these bodies is 8 to 9 thousandth of a millimetre, their width 3 thousandth of a millimetre on average. The contours are indicated by a very fine line; the body is transparent, colourless, except in the middle part where there is a blackish speck made up of a row of rounded granules, blackish or, rather, a very dark fiery red. Exceptionally, the pigmentary speck is situated at one end of the extremities of bodies no. 1, and not in the middle part. The pigment grains are quite often disposed in a fairly regular arrangement, crown-like, which we shall find again in bodies no. 2. On those bodies no. 1 which are incurved, a pale, curved line can be frequently detected on the concave side, which connects the extremities of the crescent; this line is indicated for body A (fig. 1, pl. II).

In preparations of blood treated with osmic acid (in a 1:300 solution), and preserved in glycerine picrocarminate, it can be ascertained that the bodies no. 1 exhibit a double contour (C, fig. 1, pl. II), and that the central part shows up as a much paler rosy tint than that shown by leucocytes in the same preparation.

Bodies no.1 do not appear to be endowed with movement; when their form undergoes change, it is in a very slow fashion.

Bodies No. 2. - These bodies present themselves in many aspects, according to whether they are in a state of rest or movement.

At rest, a spherical body can be distinguished, transparent, and with a fine contour, the diameter of which is 6 thousandths of a millimetre on average, sometimes a little larger, and with a diameter greater than even of red blood cells. In the interior of this body (A, fig. 2, pl. II) rounded grains of pigment can be found, similar to each other, which affect ordinarily a fairly regular crown-like disposition, one might say like a necklace of black pearls, or rather, of a very dark red.

In a state of movement, around the spherical and pigmented body, very fine and transparent filaments can be discerned, which are animated by rapid movements in every sense; the movements cannot be better compared, than to those of eels of which one extremity has been fixed to within the interior of the spherical element. These filaments impress the nearest red blood cells with highly varied, and easily detectable movements. The length of the filaments, or mobile appendages, of bodies no. 2 can be evaluated as three to four times the diameter of a red blood cell; their number, for each body no. 2 appeared to me to be three or four; it is perhaps greater, since only those filaments which are agitated can be perceived, and even so, among these, only those which are in exact focus can be seen. At times, the mobile filaments are displayed in a fairly symmetric fashion (B,fig. 2, pl. II), at times they are grouped to one side alone (B', same figure). The free extremity of these mobile filaments is swollen, as is indicated for the appendages of bodies B and B' (fig. 2, pl. II); The terminal swellings are only visible when exactly in focus, and it hardly ever comes about that they are all so at the same time.

While these filaments are agitated, the spherical body into which they appear inserted undergoes a more or less rapid, oscillatory movement, sometimes, the same, it is animated by a translational movement; almost always, body no. 2 waves about in one place, and it can be examined for hours on end without needing to move the preparation in order to maintain it in the same field.

At times the pigment granules remain immobile in the inside of bodies no. 2, while the filaments are agitated; at other times, the granules are animated themselves in very lively movements in the interior of bodies no. 2.

I have seen, several times, the mobile filaments persist in their movements for three or four hours; in general, they disappear much more rapidly. The same instant when the movements of the filaments stop, the filaments become invisible; the pigment particles are often agitated at this time by movements more or less lively, and their disposition becomes very irregular.

Bodies no. 2 often change their form while under observation: they become elongated, they spread out, then revert back to their spherical form. Figure 7 of plate II portrays the different aspects of a body no. 2 with mobile filaments, drawn on the 1st. December 1880 : 1. at 3 o'clock in the evening (A), 2. at 3.15 (B), 3. at 3.30 (C), 4. at 3.35 (D); one sees that these last movements greatly resemble amoeboid movements, and that they are generated without it being necessary to use a warm plate, that is to say, in conditions where one does not observe amoeboid movements of leucocytes in human blood.

It has happened to me several times, while I examined bodies no.2 in movement, to see one of these peripheral filaments detach itself from the pigmented body and continue to move itself among the red blood cells and imparting to them movements which are very easily recorded; one of these free filaments is represented in C (fig. 2, pl. II).

I have also encountered many times, in preparations of blood from patients stricken by marsh fever, spherical bodies much larger than bodies no. 2, in the interior of which can be distinguished pigment granules moving in a very brisk way, fairly similar to brownian movement; these bodies do not present peripheral filaments (D, fig. 2, pl. II).

In preparations of blood treated with a solution of osmic acid 1:300 and preserved in glycerine picrocarminate, it can be established that bodies no. 2 present a double contour (E, fig. 2, pl.II) and a central portion very lightly rose-coloured, whereas the leucocytes are dyed a vivid rose; the peripheral filaments are not visible.

Bodies No. 3 - The primitive form of these bodies is spherical, but they are capable of suffering extremely varied deformations; figure 3 (plate II) shows some of the forms in which these elements present themselves. Bodies no. 3 are slightly granular, immobile, and without any apparent peripheral filaments; their diameter is larger to that of bodies no. 2 (8 to 10 thousandths of a millimetre). Inside these bodies grains of pigment can be seen, the disposition of which recalls that of pigment in bodies no. 2 (a, fig. 3). Frequently also, these grains of pigment are disposed seemingly without order and in very variable number.

Bodies no. 3 sometimes include grains of fiery red pigment, regularly rounded, much bigger than those of bodies no. 2; these large grains of pigment can also be found in the blood in a free state. It is probable that here it is the breakdown product of bodies analogous to bodies no. 2, but that they have undergone an increase in the spleen or in the liver which does not permit them to circulate freely in the blood in a state of integrity.

Bodies no.3 are not coloured by carmine or, at least, they take up colour with much greater difficulty than leucocytes.

Outside bodies nos. 1,2 and 3, in preparations of blood taken from patients attacked by marsh fever, small shining bodies, rounded, mobile and without specific characteristics, can often be found, as can free pigment, fiery red or clear blue.

The blue pigment appears to result from a transformation of the fiery red pigment; I have happened to encounter bodies no. 3 in which one of the grains of pigment was blue, whereas the others had retained their normal tint. When the blue pigment has lost its form of a regular, spherical grain, it is very difficult to distinguish it from the blue particles coming from surrounding objects, which often make their way into the preparations.

I researched bodies nos. 1,2 and 3 in the blood of a large number of patients affected by various conditions, but not of paludism, and have never found any of these bodies in the blood of these patients.

Method of examination of the blood. - During the entire pursuit of these researches I conformed to the following rules for examination of the blood:

The ground slide and the cover slip are washed in alcohol the same as the patient's finger which got ready to apply a prick, and the pin which serves to perform the puncture. The blood which emerges from the puncture, which ought to be of a medium quantity, is deposited on the carrier slide (it is sufficient for this to invert the hand of the patient and to bring to it the slide and to make contact with the drop of blood), followed immediately by covering it with the cover slip prepared for this purpose. In order to get good spread of the blood, without the interpositioning of bubbles of air, it is as well to deposit a light vapour with the breath on the surface of the cover slip at the moment when it is applied to the drop of blood.

The preparation is mounted in paraffin.

A magnification of 400 to 500 diameters suffices in order to observe all the details of bodies nos. 1,2 and 3 indicated above; I have generally found ocular no.2 and objective no. 7 of Verick to be useful; I have also used the objective 10 in immersion which is not indispensable for this study.

The blood was always examined pure, without being mixed with any other liquid.

Upon proceeding with the examination of blood when its preparation has been completed, in general, the peripheral filaments of bodies no. 2 are not observed; these movements stop, probably from the influence of cooling suffered by the blood in passing from the vessels to the glass slide; perhaps this inconvenience might be avoided in making use of warm plate. At the end of a quarter of an hour or half an hour the movements of the filaments reappear; at this moment the bodies nos. 1,2, and 3 become much easier to examine, their adherence to the red blood cells appears less great than at first, and they isolate themselves more. With a little practice one can get to discover bodies nos. 1 and 2 even in the middle of the red blood cells; the pigment granules serve as reference points.

The preparations made according to what has just been said do not last, some drying out despite the paraffin, and others becoming filled with mould. The preparations with desiccated blood become very transparent; pigment granules are always seen, but the bodies which enclose them are unrecognisable.

The following procedure gives rather good results: a drop of blood is mixed on the carrier slide with a drop of a 1:300 osmic acid solution, and covered with a cover slip. Next, glycerine mixed with a little picrocarmine is gently brought to the lamellae. Bodies nos. 1,2 and 3 maintain fairly well the form which they have in fresh blood; it can be verified however that in these conditions there exists a double contour which is not visible on elements in the fresh state, and that the central part situated inside the double contour takes on a very pale, rosy colour, quite different moreover, to the vivid rose adopted by the leucocytes in the same preparation. Unfortunately, the mobile filaments of bodies no. 2 do not become apparent.

I have tried without success to colour the pigmented elements with the aid of purpurine. The colouring matter precipitates with the albumin in blood which is coagulated by alcohol and this precipitate hinders the examination considerably. Iodine solution, equally, only gives less satisfactory results; bodies nos. 1 and 2 are not coloured and, consequently, the peripheral filaments of bodies no.2 do not become visible.

Eosin in an aqueous solution dyes bodies nos.1 and 2 poorly, and the peripheral filaments of bodies no. 2 do not become visible; red blood corpuscles, however, take on a fine rose tint in these preparations.

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CHAPTER III:

[Reports of bodies nos. 1,2 and 3, in relation to each other and with the pigmented elements found in the cadaver.]

Despite the different appearances of dimension and form which characterise them, bodies nos. 1, 2 and 3 have a certain familial look, if I may so term it, which makes one think, a priori, that it is simply a matter of the same elements existing in different states. The presence of pigmentary granules in bodies nos. 1, 2 and 3, and the coexistence of these three species in the blood of the same patient argue strongly in favour of this interpretation; it is moreover easy to establish directly that bodies no. 2 with mobile filaments are only another state of bodies no. 2, and that bodies no. 3 result from a transformation of bodies no. 2.

Taking a preparation freshly made of blood, a well-isolated, immobile body no. 2, without apparent, peripheral filaments is found; the preparation is fixed upon the plate of the microscope in such a manner that the body no. 2 is seen at the centre of the field, and this body is, for instance, examined for all of five minutes. In general, it does not take long to verify that the element becomes mobile and, sometimes one is indeed happy to observe body no. 2 at the very moment when it passes from a state of rest to a state of movement; at the same time the peripheral filaments become apparent. If these filaments are not apparent at rest, this can be attributed to their being very fine and transparent; their refringence differs very little from that of blood serum; it is like when a glass rod becomes invisible when plunged into Canada balsam. In the state of movement, the refringence of the mobile filaments is probably slightly modified; in addition, the displacements which these filaments impress upon the pigmented body into which they are inserted and to the nearest blood corpuscles make their ascertainment very easy.

One can assure oneself by the same procedure that bodies no. 3 result from a transformation of bodies no.2. In a preparation of fresh blood a body no. 2 is looked for which is furnished with its mobile filaments and is very alive; the preparation is fixed upon the microscope plate and one proceeds to examine, for all of five or ten minutes, the body placed under observation. At the end of the space varying from a few minutes to a few hours, one can establish that the movements of the filaments become less lively, that they subsequently come to a halt, and that at the same instant, it becomes impossible to distinguish the filaments. At the same time, the pigmented body appears to spread out, its diameter augmented; The pigment grains become agitated sometimes for a few moments in the interior, next they too become immobile and dispose themselves at times irregularly, at times in a fashion that recalls the crown-like disposition which they have in bodies no. 2; only, the pigment grains are more varied. If the examination is prolonged yet further, it can be ascertained that the element becomes more and more deformed and that it becomes lightly granular; the pigment grains accumulate at a point and end up sometimes by disappearing except for a grain or two.

Figure 4 (pl. II) represents body no. 2 viewed : 1° at 9 o'clock in the morning (A), when the filaments can be recorded; 2° at 9.30 in the morning (B), the filaments having become invisible, the pigment grains have been displaced, one from the other, while keeping to their coronary disposition, and the aspect is one of body no. 3; 3° at 2.30 in the evening (C), the aspect is that of a deformed body no. 3.

Figure 7 (pl. II) shows likewise the successive transformations of a body no. 2. At the end of 35 minutes, body A equipped with mobile filaments has taken on the aspect shown in D, which is to say that the body no. 2 has transformed itself under the eyes of the observer into body no. 3.

On every occasion in which I have repeated this experience, I arrived at the same result, and thus able to conclude that bodies no 3 are none other than the cadavers of bodies no. 2.

We have seen in the chapter devoted to the description of bodies nos. 1, 2 and 3 that the spherical elements filled with mobile granular pigment which, moreover ,were observed much more rarely than the other elements, were probably only aspects of bodies no. 2; we also saw that the mobile elements which were encountered at times in a free state in the preparations were detached from bodies no. 2.

There remain bodies no.1, the relationship of which to bodies nos. 2 and 3 has not been established in a certain fashion. Bodies no. 1 contained in preparations of fresh blood become deformed after a while, always less rapidly than bodies no. 2. They become at first oval, then they take on a spherical form, more or less regular, and their appearance then recalls that of bodies no. 3. Figure 5 (pl. II) represents three bodies no. 1 observed on the 29th. November, 1880 at 2.15 in the evening. These three bodies were found in one field at the same time; the blood preparation was fixed on the microscope plate and on the morning of the 30th. November the three bodies a, a', a", had the aspect of bodies b, b', b" (fig.6, pl. II).

Often, in preparations of oval, pigmented bodies, there appear to be intermediary forms of bodies no. 1 and no. 2; I believe that bodies no. 2 represent nothing other than in a more advanced stage of evolution bodies no. 1; I must say, however, that I have not hitherto succeeded in seeing a body no. 1 transform itself into a body no. 2 furnished with mobile filaments, although in many attempts, the observation of the same body had been prolonged for a period of 36 to 48 hours. It is probable that bodies no.1 die too quickly in blood preparations for them to be able to continue to develop and transform themselves into bodies no.2.

Bodies no.3, such as the ones which result from transformation of bodies no.2 after death of these latter elements, have an obvious resemblance to the pigmented elements which are found in the blood and in all the organs of individuals who have succumbed to a fatal attack. It is enough to convince oneself of this similarity or, rather, this identity, by comparing the elements represented in figure 3 of plate II to the elements represented in figure 1 of plate I; there is no important difference between the elements which had been found in the blood during life, and which result manifestly from a transformation of bodies no. 2, and the elements dissociated from the spleen (a, b, c, d, e, f, fig. 1, pl. I) or the blood gathered from the cadaver (b, b', b", fig. 2, pl.I). The pigmented elements found in the spleen or the liver frequently have, it is true, a larger volume than those of bodies no.3 in live blood, while the grains of pigment which they contain are often also more voluminous than the latter; but as it is a question of living bodies capable of growth, these differences which relate only to size do not have any importance; it is probable that bodies no. 2 which have reached their full development do not circulate as easily in the blood and that they are stemmed in the small vessels, notably those of the spleen and the liver. Account should also be taken of the deformations suffered by bodies nos. 1,2 and 3 in the cadaver; the death of the patient rapidly entails that of those parasitic elements contained in the vessels, probably consequential to defective oxygenation of the blood. It thus explains why it is rare to find in the cadaver elements analogous to bodies no.1 and no.2; these elements have had time to adopt a spherical form, more or less regular, which does not permit them to be differentiated from bodies no. 3. I have on occasions, nevertheless, succeeded in discovering elongated elements (a,a', fig.2, pl.I) in the blood taken from a cadaver analogous to bodies no. 1. When the cadavers have undergone the beginning of putrefaction, the grains of pigment go into solution, get mixed up, and often give a uniform, black tint to the elements which they contain; the elements thus transformed do not appear to have any form of resemblance to bodies no.2 or no.3.

To sum up, the elements which I have signalled under the names of bodies nos. 1,2 and 3, and which have been described above, appear to represent merely different phases in the evolution of the same parasitic elements; the transformation of bodies no. 2 into bodies no. 3 is not in doubt, the transformation of bodies no. 1into bodies no. 2 is very probable; these latter elements equipped with their mobile filaments probably represent the parasite in a state of complete development; as for bodies no. 3, they are only the residues, cadavers of the parasitic elements, and their identity with pigmented elements which are found in such great numbers in all the organs of individuals who have died from deadly fever does not appear doubtful.

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CHAPTER IV:

[Conditions which lead to variation in the number and nature of parasitic elements in the blood of patients stricken by marsh fever - Action of quinine sulphate - Observations.]

In the 60 patients attacked by different degrees of paludism whom I examined during the months of November and of December 1880, and during the month of January 1881, at the military hospital in Constantine, I recorded 42 times the existence of bodies nos. 1, 2 and 3 in the blood.

The figure for negative findings appears at first sight to be rather large: 18 out of 60, but an attentive examination of the facts greatly reduces the significance of this figure. Of these 18 patients, 14 had undertaken a prolonged treatment using quinine sulphate at the time when the examination of the blood had been made, and we shall see a little later that quinine sulphate exerts an incontestably toxic action on the parasitic elements of the blood; three of the patients had had a fever previously, but had not experienced a fit for some time, and they had entered the hospital for a condition other than the fever; with regard to one sole patient who came to experience a febrile fit and who had not taken any quinine sulphate for many days, one could say that the examination was truly negative; again, consideration must be given in this case to the examination which was only made the once and which was conducted on just one drop of blood; it is probable that if it had been repeated, it would have revealed the presence of some parasitic elements. The patients who served me for this research had not been chosen; I examined all the patients attacked by marsh fever who had entered in the period of my service during the months of November and December 1880, and January 1881, and all those who my colleagues at the military hospital had wished to refer to me; it so happened, however, that because of the period in which these observations were made, all the patients fell into the same category, that of 'récidivistes'; in the months of November, December and January, it is quite rare for someone to be affected by marsh fever in Algeria, but recidivism is rather frequent during this period and, actually, all the patients whom I observed had had one or more febrile fits before, the which, perhaps, had an influence on the results I arrived at.

The presence of pigmented elements in the blood of patients stricken by marsh fever has had attention drawn to it , as one knows, for a long time, notably, by Frerichs; according to Dr. Kelsch, these elements are recoverable from the blood of all the patients attacked by marsh fever at the time of the paroxysms, and the fact of their presence or absence in the blood can equally well serve as a diagnostic basis for cases in doubt. (Kelsch, Contribution à l'histoire des maladies palustres; de la mélanémie, in Arch. gén. de médicine, 1880.) The pigmented elements described by Frerichs and Kelsch as melanin-bearing leucocytes correspond most certainly, at least for most of the large numbers, to the elements designated in this work with the name of bodies no. 3; the facts cited by these authors lend their support then to those which I have observed, in witnessing, like the latter, the very common, if not constant, presence of pigmented elements in the blood of patients stricken by marsh fever.

The number of the pigmented elements in the blood varies a lot amongst patients, and even in the same patient during different periods of the disease. Sometimes, in an entire preparation made according to what has been said above, one is at pains to discover some of the bodies nos. 1,2 and 3; at other times the bodies exist in such huge numbers in the blood that one can find three or four of them at the same time in the field of the microscope and their research in this case presents no difficulty.

Most often, bodies nos. 1, 2 and 3 co-exist in variable proportions in the blood of the same patients; sometimes, however, just bodies belonging to one of these types is found; it is rare to encounter only bodies no.1 or no.2; it happens frequently that the blood contains only bodies no. 3.

The following table, a summary of 92 blood examinations, indicates the relative frequency of different combinations of bodies no.1, no. 2, and no. 3, which can be encountered.

It can be seen that the most frequent combinations are: that of bodies nos. 1,2 and 3, which was encountered 26 times, and that of bodies nos. 1, and 2, which was encountered 21 times.

It was of interest to know what changes were produced in the number and the relations of the parasitic elements before, during, and after febrile paroxysms, and what the action of quinine sulphate on these elements was.

In 28 patients in whom the blood was examined during a febrile fit, or a short time afterwards, I found :

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That which stands out most obviously in this table is the frequency of bodies no. 3 in these conditions; these bodies were encountered in point of fact, 21 times out of 28, and on 9 occasions were found alone, to the exclusion of bodies nos. 1 and 2. The observations XII and XIV are very interesting from this point of view; we see in effect that, whether during a deadly attack or immediately afterwards, while it was impossible to find any trace in the blood of bodies nos. 1 and 2, there were only bodies no. 3 there. It must be taken into account, it is true, the fact that the patients almost always took quinine sulphate at the time of their paroxysms of fever, and that they took a dose as much stronger again as their fit was more severe, more disquieting. I sought to avoid this cause of error by examining blood as much as possible before the quinine sulphate was administered, and I found equally, in these conditions, the relative rarity of bodies nos.1 and 2 during febrile paroxysms and a frequency of bodies no.3.

The patients in whom I found bodies nos. 1 and 2 in large numbers were all stricken by an obstinate, intermittent fever, and for some time had not had a fit or taken quinine sulphate, at least in a strong dosage and in a continuous fashion. It is then during the intervals of apyrexia which separate the febrile relapses, and among patients who had not been submitted to quinine for some time, that one had the best chance of finding bodies no.1 and bodies no.2 armed with their mobile filaments.

When the blood examination reveals the existence of numerous bodies no. 2 furnished with their mobile filaments, one can predict almost in one fell swoop the imminence of a relapse. Observations V, XXI, XXII, and XXIV are very convincing in this respect. It is also among patients threatened by a relapse of fever that I have encountered free, mobile filaments, and spherical bodies much larger than bodies no.2 filled with grains of mobile pigment.

Observation V:

The blood examination made on the 25th. November reveals the existence of bodies no. 1 and less numerous bodies no. 2, but much larger than at the time of the preceding examinations; pigment granules shake very briskly in the interior of bodies no. 2 furnished with mobile filaments; I confirm the presence of free mobile elements, and of spherical bodies much larger than bodies no. 2 without apparent mobile filaments. The 26th November, the patient has a fit of fever.

Observation XXI:

The blood examination made on the 28th. November, in the morning, reveals the presence of the following elements: bodies no. 1 in rather great numbers; bodies no. 2 furnished with filaments in large number; spherical bodies larger than ordinary bodies no. 2, filled with mobile grains of pigment; bodies no. 3. The 29th. November, the patient has a very violent febrile fit, the axillary temperature mounts to 41.2°.

Observation XXII:

The examination of blood made on the 12th. December, in the morning, reveals the existence of bodies no. 1 in large number, and of bodies no. 2 in equally large number, furnished with mobile filaments; many of these mobile filaments have become detached from bodies no. 2 and circulate freely among the red blood cells. The 16th. and the 17th. December, the patient has febrile fits.

Observation XXIV:

The blood examination made on the 24th. January reveals the existence of the following elements : bodies no. 1 in great number; bodies no. 2 in equally great number, furnished with mobile filaments; spherical bodies much larger than the ordinary bodies no. 2, containing pigment grains agitated by a very rapid movement. The 25th January, the patient has a fit of fever.

While there remain only bodies no. 1 in the blood without any bodies no. 2, one can predict again that there will be a relapse, but after a lapse of an undetermined period of time, sometimes fairly long.

The action of quinine sulphate on the parasitic elements of the blood is not to be doubted; one can formulate a general rule that these elements diminish rapidly in number and finish by disappearing completely in all the patients who are submitted to a regular and prolonged treatment of quinine sulphate.

The experiment is easy to conduct: a patient is chosen whose blood includes bodies no. 1 and bodies no. 2 with mobile filaments in sufficiently large numbers so as to make it easy to record their presence; the patient is made to take quinine sulphate in weak or strong dose, and the effects of the medication are followed day by day as far as possible.

The weak doses of quinine sulphate have, in general, little effect on the parasitic elements of blood, many of the patients in whom I found bodies no. 1 and no. 2 armed with mobile filaments had taken quinine sulphate for some days. It seemed to me that feeble doses of quinine sulphate acted to suspend the movements of the mobile filaments only. Example:

Observation XXIV:

The 24th. January, blood examination revealed the presence of bodies no. 1 and of bodies no. 2 with mobile filaments; the patient took a dose of quinine sulphate on the 26th January; the blood examination carried out on the same day revealed again the existence of bodies no.1 and no. 2, but the latter bodies were immobile, and despite prolonged observation it proved impossible for me to establish the existence of mobile filaments in any of them. The 31st January, a fresh blood examination on the same patient who had no longer taken quinine sulphate allowed me to observe anew bodies no. 1 and bodies no. 2 which presented mobile peripheral filaments.

When the medication is prolonged yet further, bodies no. 2 become more and more scarce and end up by disappearing completely; bodies no.1 and bodies no. 3 resist, in general, much longer; finally, all traces of the parasitic elements disappear and the disappearance of bodies nos. 1,2 and 3 in the blood always coincides with the return of strength, the diminution of anaemia, and a general well-being. I have already had occasion to remark that among fourteen patients who had been submitted to a prolonged treatment of quinine sulphate from the moment the blood examination had been conducted, I never found any trace of pigmented bodies.

To look for parasitic elements in the blood of a patient who has been subjected for some time to quinine medication is, if I might be so bold as to say it, like when Sarcoptes are sought on the skin of a scabietic while treated with rubbing down of sulphur ointment; one can certainly find in these two cases some parasites which have escaped death, one can above all find more or less deformed cadavers of the parasites, but in order to conduct this pursuit in ideal conditions it should be carried out before all treatment.

It is, moreover, impossible to formulate absolute rules and to say: such a dose of quinine sulphate administered during so long a period suffices to cause disappearance of the parasitic elements. I have happened to find a body no. 2 with mobile filaments in a patient who had taken quinine sulphate for eight days, but this was an exceptional occurrence; it is commoner to find bodies no. 1 and no. 2 in these conditions. In a patient whose blood is very rich in bodies no. 1 and no. 2, treatment by quinine sulphate for fifteen days is often necessary to make all traces of these bodies to disappear.

Two other factors appear to me to act on the abundance of parasitic elements in the blood: the general state and the race.

The elements abound especially in individuals who are profoundly anaemic and weakened; their numbers diminish under the influence of a tonic and restorative regimen to which patients are subjected at the hospital, as also, independently, from quinine medication.

The blood of Arabs and of Negroes attacked by intermittent fever is ordinarily much less rich in parasites than that of Europeans, that which is in keeping, moreover, with the strength of resistance presented by these men to impaludism.

It is easy to verify directly the toxic action of quinine sulphate upon the parasitic elements in blood. A 1:1000 and a 1:10,000 solution of quinine sulphate is prepared, for example. Next, a patient is selected in whose blood has been recorded recently the presence of parasitic elements, notably those of bodies no. 2 which by their motility lend themselves readily to this experiment, and the blood is collected on to three glass slides. One of the drops of blood is examined pure with a view to assuring oneself that mobile bodies no.2 still exist; to the other preparations a drop of a thousandth, and a ten-thousandth solution of quinine sulphate is added, followed by an inspection. It is thus established that bodies no.1 and no. 2 rapidly become deformed in the preparations mixed with solutions of quinine, even at the ten-thousandth, and that in these conditions it is impossible to observe movements of the peripheral filaments. I prefer to this experiment, a little blunt, that which can be made naturally on the patients to whom quinine sulphate has been administered.

I believe it to be unnecessary to reproduce here the blood observations on the 60 patients in which I researched the presence of parasitic elements; I shall content myself in choosing among the positive findings, that is to say among those in which the existence of parasites had been established, those which appear to me to be of most interest. I shall not recapitulate with every observation the mode of examination of the blood, having conformed in all these cases to the rules outlined further above (Chapter II); I shall designate the pigmented elements found in the blood by the names of bodies no.1,bodies no.2 and bodies no. 3, the explanations for these denominations having been provided in Chapter II; it would be tiresome to repeat at the instance of each patient, and of each blood examination, the description of these elements which always present the same characteristics, or which at least are little removed from the types that I have described and portrayed.

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OBSERVATION V-XXV

Observation V:

D...., 48 years old, soldier with the 8th. training squadron, in Algeria since the 5th. December 1879, enters the military hospital at Constantine the 4th. November 1880.
The sick man is barracked at Bardo, which is to say a notoriously insalubrious district on the edges of Rummel; the previous October he had caught fever for the first time: no violent shudders, malaise, heat, cephalalgia, general weakness; he was admitted to hospital the 12th. of October, the fever yielded easily to quinine sulphate. Having left the hospital the 24th. October, the patient caught fever again from the 26th; the fever presented this time a well-marked, intermittent character; the fits recurring everyday towards ten o'clock in the morning.
The patient is wasted, profoundly anaemic, the mucous membranes are colourless, the skin has an pasty colour. The 4th. November, at the follow-up visit, the temperature is 39.5°. Tongue white, moist; avid thirst. Splenic dullness measures 12 centimetres in height, and 11 in width.
I prescribe 0.80gm. of quinine sulphate.
5th. November. The morning temperature is 38.5°, the evening 37.2°. Quinine sulphate, 0.80.
6th. November. Apyrexia; 36.8°, morning, 37.2°, evening.
Quinine sulphate 0.60.
Blood examination made on the 5th. November at 8.30 in the morning: bodies no. 1 in large number.
Blood examination made on the 6th. November at 2.30 in the evening: bodies no.1in large number; bodies no. 2 armed with peripheral, mobile filaments of which a record the existence for the first time.
7th. November. Apyrexia; The patient eats with appetite half a portion.
Quinine sulphate 0.60gm, morning and evening.
Blood examination made on the 7th. November at 2.30 in the evening: bodies no.1in large number; bodies no. 2 armed with mobile filaments.
The days following, the apyrexia persists, the quinine sulphate suppressed. The patient eats a portion. Cinchona wine, coffee.
Blood examination made on the 9th. November in the morning : bodies no.1; bodies no. 2 armed with mobile filaments. Mr. Aron, principal physician, and Mr. Petit and Mr Troussaint, medical assistant-majors, confirm the existence of movements of bodies no.2.
10-25th. November. Apyrexia persists. The anaemia is still very profound, nevertheless the patient finds himself stronger, he eats a portion, and gets up for a part of the day. Cinchona wine, Black coffee.
Blood examination made on the 25th. November: bodies no. 1, bodies no. 2 less numerous, but much larger than in the preceding examinations. The pigment granules move about very briskly in the interior of the bodies no. 2 armed with filaments; I ascertain the presence of free, mobile filaments, of bodies no.2, and of spherical bodies no. 2 much larger than those of bodies no. 2 without apparent peripheral filaments, filled with pigmentary granules; the mobile filaments, after their separation from bodies no. 2, continue to wave about among the red blood corpuscles upon which they impress highly variable movements, easy to record.
The 26th. November, at 10.30 in the morning, the patient has a febrile fit. Quinine sulphate, 0.80gm.
The fever does not recur. From the 27th. to the 30th. November, the patient takes 0.60gm twice daily of quinine sulphate, and from the 1st. to the 8th. December 0.80gm of quinine sulphate every day.
Blood examination made on the 10th. December : nothing abnormal. The patient leaves the hospital on the 12th. December; he goes away on leave of convalescence.

Observation VI:

F.......soldier with the 3rd. infantrymen, aged 21 years, enters the military hospital at Constantinople the 10th. November 1880.
No prior illness to incorporate. The sick man, having arrived in Algeria three years ago, had been successively garrisoned at Philippeville, Constantine, Tébessa and at Djijelli from whence he came.
The first attack of fever goes back to the month of September 1879, the patient had stayed eighteen days in hospital at Philippeville; the fever had given way easily to quinine sulphate.
In the month of September 1880, second attack of fever; the patient was at the time detailed out to guard the forests: well-characterised quotidian, intermittent fever; forty eight days of treatment at the hospital in Djijelli.
The patient left the hospital at Djijelli the 3rd. November; from the next day, the fever re-appeared. The last fit the 9th. November.
10th. November. The patient is wasted, profoundly anaemic; the mucous membranes are colourless, the skin has a pasty hue. No oedema of the lower limbs. Apyrexia.
Insomnia, a very great sense of fatigue; the patient could hardly get himself up on his feet, he reeled like a drunk man.
Anorexia. Belly soft, neither diarrhoea nor constipation; splenic dullness measures 10 centimetres in height and 9 and a half centimetres in width.
Prescriptions: one half-portion, two portions of wine. Cinchona wine, black coffee.
Blood examination made the morning of 10th. November: bodies no.1in large number; bodies no. 2 immobile or armed with peripheral, mobile filaments; bodies no.3; free granules of pigment.
New examination of the blood the 10th. November at 2.30 in the evening: bodies no.1in large number; bodies no. 2 immobile or armed with peripheral, mobile filaments; bodies no.3;
From the 11th. to 16th. November, apyrexia persists; strength returns gradually.
16th. November in the morning the patient has an attack of fever.
In the evening, he takes 0.80gm. quinine sulphate.
The 17th. November the fever does not recur; the patient takes 0.80gm. quinine sulphate morning and evening.
Blood examination made on the morning of 17th. November ; no bodies no. 1 or 2; bodies no. 3 in fairly large number, bright mobile corpuscles; free pigment.
Quinine sulphate is continued further for eight days at a dose of 1.60gm. to start with, then 0.80gm.
Blood examination made on the evening of 3rd.December; I again find some bodies no. 1, no bodies no. 2 or 3.
7th. December the patient leaves the hospital; he goes on leave of convalescence.

Observation VII:

M......., soldier with the 3rd. Chasseurs d'Afrique, twenty -three years of age, enters the military hospital at Constantine the 31st. October 1880. M...., in Algeria for four years, has been successively garrisoned at Biskra, Guelma, Tébessa and at Constantine.
First attack of fever in the month of August, 1880, at Tébessa : intermittent, quotidian fever, well-characterised, which yielded to quinine sulphate at the end of eight days. In the month of September 1880, there was a relapse which necessitated a new admission by ambulance. During the course of October, the patient had been seized by sharp pains in the left hypochondrium, he had been treated at the infirmary where he had had applied in the region of the spleen dry cupping-glasses, followed by a vesicatory.
31st. October. The patient is wasted, anaemic; the mucous membranes are colourless, the skin a pasty hue. No vascular murmurs, fever rather acute.
Dark spots on the anterior abdominal wall; pediculi pubis in great number.
Tongue moist, whitish; normal stools.
The patient complains above all of a sharp pain in the left hypochondrium, pressure is very painful below the false ribs on the left side; the spleen extends outwards notably, the splenic dullness measures 13cm. in height against 12 of width.
Prescriptions: soup, wine : quinine sulphate, 0.80gm.; a vesicatory is applied at the level of the spleen.
1st.-3rd. November. - The pain is less keen in the left hypochondrium. Febrile motion without frank fit, regular. Quinine sulphate is continued until 3rd. November.
4th.-10th. November. Fairly satisfactory state. Apyrexia. The tip of the spleen has disappeared. The appetite returns; the patient eats a portion. Cinchona wine, black coffee.
Blood examination made the 11th. November in the evening: bodies no. 1 in large number; bodies no. 2 immobile or armed with peripheral, mobile filaments; bodies no.3; free fiery red or clear blue granules of pigment.
Blood examination made the 13th. November in the evening: bodies no. 1 in large number; bodies no. 2 immobile or armed with peripheral, mobile filaments. Mr. Petit and Mr. Vacher, medical assistant majors, verify the existence of mobile filaments; bodies no.3; free pigment.
A new examination of the blood made 18th. November gives the same results as the preceding two. As the patient had to leave the hospital shortly, and the abundance of bodies no. 2 armed with mobile filaments made foreseeable a relapse with a short delay, I prescribed quinine sulphate. From the 19th. to the 22nd. November the patient took 1.60gm. at first, followed by 0.80gm of quinine sulphate.
Blood examination made the 22nd. November: I find again in the preparations bodies no.1, but in very small number. Bodies no. 2 or no. 3 are not there any more.
The patient departs on the 24th. November on leave of convalescence.

Observation VIII:

B.........,soldier with the 3rd. Chasseurs d'Afrique, aged twenty-three years, enters the military hospital at Constantine the 18th. September, 1880.
B arrived in Algeria i the month of November 1878; in December of 1878 he had had a first attack of intermittent fever; the fever had reappeared in the month of July 1879. Since the beginning of the month of September 1880 the sick man had caught the fever again, the attacks of a medium intensity returning irregularly, as and when thwarted by the doses of quinine sulphate taken by the sick man.
10th. November. The patient is wasted, anaemic; The last fit of fever goes back to 8th. November. The spleen extends beyond the false ribs notably. The patient takes quinine sulphate 0.50 to 0.60gm per day.
Blood examination made on the 10th. November: bodies no. 1 in small number; no bodies no.2 or no. 3.
22nd. November. The patient has not had any new fits.
Blood examination made on the 22nd. November: bodies no. 1, bodies no. 2 armed with mobile filaments, bodies no. 3.
Some days after this examination, the patient left the hospital.

Observation IX:

S........, aged twenty one years, in Algeria for three years, enters the military hospital at Constantinople the 12th. November 1880.
The patient had caught fever for the first time in July 1880; he had spent thirty days at the Djijelli hospital. The last febrile fit, the 8th. November; following on from this fit, the patient had taken three doses of quinine sulphate.
12th. November. Apyrexia. The patient is wasted, anaemic; the spleen extends a little below the false ribs.
Blood examination made on the morning of 13th. November : no bodies no.1, no.2, nor no. 3; a little free pigment.
The 13th. November, during the day, the patient has a fit of fever. Quinine sulphate, 0.80gm.
The 14th. November, new fit; the temperature taken at the morning visit is 40.9°.
Blood examination made the 14th. November in the evening: bodies no.3; no bodies no.1, or no.2; free deep red and clear blue pigment.
From the 14th. to the 25th. November the patient takes quinine sulphate at a dose of 1.60gm. daily at first, then 1.20gm., and finally 0.60gm.
2nd. December. The patient has had no new fits; the strength has returned, the anaemia is dissipated little by little.
Blood examination made the 2nd. December: nothing abnormal. A few days after this last examination the patient leaves the hospital.

Observation X:

D......., soldier with the 3rd. zouaves, enters the military hospital at Constantine the 29th. October 1880.
For a month, the patient has been attacked by an intermittent, quotidian fever. The day of admission to the hospital I record a febrile fit. The patient is wasted, anaemic; the skin presents a pasty hue, the mucous membranes are colourless. Splenic dullness measures 9 cm. of height by 8.5 of width. The 29th. October, the patient takes 0.80gm of quinine sulphate.
The fever does not re-appear the days following. The quinine sulphate is continued until the 6th. November.
14th. November. The patient finds himself better, the fever has not re-appeared; the strength has returned. Cinchona wine, black coffee.
Blood examination made the 15th. November: no bodies no. 1; immobile bodies no. 2 without obvious peripheral filaments; bodies no. 3. In one of these bodies no. 3 I ascertain that one of the fiery-red pigment grains is replaced by a grain of blue pigment; fiery-red or clear blue free pigment.
28th. November. The patient has had no new fits; the general state is most satisfactory, the anaemia dissipates little by little under the influence of a tonic and fortifying regimen to which the patient is subjected.
Blood examination made the 28th. November: no bodies no.1, or no.2; few bodies no.3.
The 29th. of November the patient departs on leave of convalescence.

Observation XI:

L......., soldier with the 3rd. African battalion, enters the military hospital at Constantinople the 13th. November 1880.
For two years the patient suffers from either dysentery, or intermittent fever, he is wasted, profoundly anaemic; colourless mucosae, pasty tint of the skin; enormous weakness. Last fit of fever the 12th. November; for fifteen days the patient has not taken any quinine sulphate.
Blood examination made on the morning of 14th. November: no bodies no. 1; immobile bodies no. 2 , or armed with peripheral filaments; no bodies no. 3. A little free pigment.
22nd. November. The patient has had no new febrile fits, he took quinine sulphate all the while from the 13th. November at a dose of 0.80gm. initially, then of 0.50gm.
Blood examination made the 22nd. November : there is no trace of parasitic elements anymore.
A few days after this last examination the patient left the hospital.

Observation XII:

V......, aged twenty-eight years, soldier with the 11th. training squadron, enters the military hospital at Constantinople the 14th. November 1880.
The patient has been in Algeria for eight years, he spent two years at the military penitentiary in Bone, next garrisoned in succession at Biskra, Batna, Kenchela and, lastly, Constantine.
No illness prior to conscription. The first attack of intermittent fever goes back to the month of November 1872; 26 days of hospital treatment.
Second attack of fever in the month of August; 15 to 20 days treatment at the hospital.
In the month of May 1875, the patient is admitted to the hospital at Guelma for a deadly attack characterised by restlessness, delirium, and then, coma; the patient remained for five days without consciousness. Four months of treatment at Guelma hospital; following the pernicious attack he was left, it seems, by a right-sided, facial hemiplegia which disappeared at the end of one month.
On the 12th. November, while at M'lila, the patient had been seized by tremor, then by bilious vomiting which persisted until the next day. The patient was evacuated to the hospital at Constantine.
The evening of the 14th. November, the axillary temperature is 39.2°, the vomiting has ceased, there are no pernicious symptoms. The patient is wasted, anaemic; Splenic dullness measures 11 cm. of height by 15 of width. Tongue white, moist. Quinine sulphate, 0.80gm.
15th. November. 37.3° morning, 39.7° evening. In the evening of the 15th. November, the patient responds very poorly to my questions, he contradicts himself endlessly and when I point this out to him, he responds by saying that he does not know too well what he is saying. Quinine sulphate, 1.20gm. twice.
Blood examination made the 15th. November at 2 o'clock in the evening: no bodies no.1, or no.2; bodies no.3.
16th. November. Fever persists: morning, 39.3°, evening, 39.5°. Agitation, delirium. The patient does not recognise me, and does not respond to any of my questions; he tries ceaselessly to lift himself up, I am obliged to post an orderly at his bedside. 1.20gm of quinine sulphate in solution; at 3 o'clock in the evening, 1gm of quinine hydrochlorate injected with a hypodermic.
17th. November. Apyrexia, morning and evening, 36.7°; The patient has regained consciousness, he responds well to my questions, only he has the astonished look of a who is woken up.
Quinine sulphate, 1.60gm. twice.
Blood examination made on the morning of 17th. November ; no bodies no. 1 or 2; bodies no. 3 in fairly large number, bright mobile corpuscles; free pigment.
The apyrexia persists in the days following. Quinine sulphate is prescribed from the 18th. to the 23rd. November at a dose of 1.20gm initially, then 0.60gm.
24th. November. The strength returns, the patient eats a portion; four portions of wine. Cinchona wine, black coffee.
Blood examination made the 14th. November : bodies no. 1 in small number; no bodies no. 2 nor bodies no. 3. Brilliant mobile corpuscles, a little free pigment.
The patient leaves the hospital the 19th. December.

Observation XIII:

J......, aged twenty-six years, soldier with the 3rd. African battalion, enters the military hospital at Constantine the 26th. October 1880.
The patient caught intermittent fever for the first time in 1873 in Algeria. Went home to France in 1874, and came back to Algeria in the month of September 1879.
For three months the patient has had intermittent fever; the fits recur in an irregular manner, disturbed as they are by the doses of quinine sulphate taken by the sick man from time to time.
16th. November. The patient is wasted, anaemic; the skin has a pasty complexion. The spleen extends below the false ribs.
Last fit of fever the 14th. November; following this attack, the patient took two doses of quinine sulphate daily.
Blood examination made on the morning of 16th. November; bodies no.1; immobile bodies no.2; bodies no. 3; brilliant mobile corpuscles, grains of free pigment.
Some days after this examination the patient left the hospital.

Observation XIV:

L....., soldier with the 3rd training squadron, enters the military hospital at Constantine on the 7th. October 1880. It is the third time that the periodic fever has led him to the hospital; intermittent, quotidian fever, very marked anaemia, colourless mucosae, pasty-coloured skin; the spleen extends below the false ribs. The fever yields easily to quinine sulphate.
The 1st. November, at the time when the patient finding himself feeling much better was preparing himself to leave the hospital, he was gripped by a very intense fit of fever. Quinine sulphate was prescribed over eight days in a dose of 1.60gm per day initially, then of 0.80gm.
On the evening of 15th. November a fresh relapse, the temperature climbs to 40.5°, vomiting. Quinine sulphate, 0.80gm.
16th. November. Apyrexia in the morning, 37.3°; new fit in the evening, at the time of the second visit the temperature is 40.2°, repetitive bilious vomiting, the patient also vomits a little blood. Quinine sulphate, 0.80gm., morning and evening.
Blood examination made on the morning of 16th. November at 1.30 hrs. in the evening at the beginning of the fit: no bodies no. 1 or 2; bodies no. 3; bright mobile corpuscles; a little free pigment.
17th. November. Apyrexia which persists in the days following. The quinine sulphate is continued until the 24th. November at a dose of 1.20gm. to start with, then 0.60gm.
Blood examination made the 27th. November in the evening : bodies no. 2 very rare; bodies no.3.
Some days after this examination, the patient quits the hospital.

Observation XV:

P......, aged twenty-eight years, in Algeria for two years, enters the military hospital at Constantine on the 20th. October 1880.
The sick man had caught the fever in 1872 in Senegal; from 1872 to 1875, there were several relapses; from 1875 to 1880, the fever had not reappeared.
In the month of July 1880, a new attack of fever; the patient had been working at the time at a mine in the surroundings of Philippeville; a month of treatment at the military hospital in Philippeville.
The 12th. of October the fever had re-appeared; the 20th. October, the patient was admitted to the hospital at Constantine.
18th. November. The patient had once again had day before yesterday a fit of fever, he is weakened, anaemic; spleen enlarged. The 17th. November, the patient took 1gm of quinine sulphate.
Blood examination made on the morning of 18th. November: bodies no. 1; bodies no. 2 , armed with mobile filaments; brilliant mobile corpuscles; a little free pigment.
29th. November. The patient has not had any fresh fits, he has not taken quinine sulphate since the 18th. November.
Blood examination made on the morning of 29th. November: bodies no. 1; bodies no. 2 , armed with mobile filaments; Mr. Boppe, medical-major, and Mr. Langue, assistant medical-major, confirm the existence of mobile filaments.
7th. December, the patient has a fit of fever at the end of which he takes a single dose of quinine sulphate.
Blood examination made on the 9th. and the 12th. December: bodies no. 1 and bodies no. 2 in great number armed with mobile filaments; bodies no.3. Mr. Hattute, principal physician, and Mr. Mounier, medical-major, confirm the existence of mobile filaments.
18th. December. There have not been any new fits, the patient had not taken any quinine sulphate.
Blood examination made on the 18th. December: bodies no. 1, bodies no. 2 armed with mobile filaments, bodies no. 3.
The patient goes out of the hospital the 19th. December, 1880.

Observation XVI:

L....., aged twenty-two years, enters the military hospital at Constantine the 15th. November 1880.
In Algeria for two years, the patient caught the fever for the first time in the month of August 1879; the fever had disappeared at the end of eighteen days; it had re-appeared in the month of August 1880 and since that time it had recurred ceaselessly. Since the 1st. November daily fits, the last fit on the 13th. November. The patient had taken for several days 0.80gm. of quinine sulphate. Very pronounced anaemia; the spleen is notably increased in size.
Blood examination made the 18th. November: bodies no. 1; no bodies no.2; bodies no. 3 in small number; brilliant, mobile corpuscles; a little free pigment.
The 23rd. November, the patient, who had not taken any quinine sulphate since his admission to the hospital has a very powerful fit; at the second visit, the temperature is 41.5°; I prescribe: 0.80gm. quinine sulphate.
24th. November. fever persists : 38.7° in the morning, 39.3° in the evening. Quinine sulphate 0.80gm morning and evening.
Blood examination made on the morning of 24th. November: bodies no.1 in small number, immobile bodies no.2, rare; bodies no.3.
Quinine sulphate is continued from 25th to the 30th of November at the dose of 1.20gm to start with, then 0.60gm per day.
The 23rd. November, there is complete apyrexia.
The patient leaves the hospital in the first days of the month of December.

Observation XVII:

B......, soldier with the 3rd. training squadron, admitted to the military hospital at Constantine, the 18th. November 1880, for intermittent fever; it is the third time this year that the patient comes into hospital for the same complaint. Mild anaemia, splenic dullness measures 11centimetres in height by 10 in width. The evening of the 18th., the patient is at the end of a fit, the axillary temperature is 38.3° Quinine sulphate 0.80gm.
19th. November. Apyrexia. Quinine sulphate, 0.80gm morning and evening.
Blood examination made on the morning of 19th. November: bodies no. 1in small number; bodies no. 2 armed with well-characterised, mobile filaments; bodies no.3; brilliant mobile corpuscles; a little free pigment.
2nd. December. There have not been any new fits; the patient has taken quinine sulphate everyday since the 20th. November at a dose of 1.20gm initially, then 0.60gm.
Blood examination made the 2nd. December : bodies no.1 in very small number; no bodies no. 2, some bodies no. 3.
The patient leaves the hospital a few days after this examination.

Observation XVIII:

M......, soldier with the 3rd. African chasseurs, aged twenty-two years, entered into the military hospital at Constantine the 6th. November, 1880.
In Algeria for a year, M...... had always felt well until the 22nd. September last; on that day he was seized by a fever and was admitted to hospital on the 24th. where he stayed for forty-one days. Having left the hospital on the 5th. November, he was seized again by the fever from the following day and sent back to hospital.
7th. November. Brisk fever : morning, 40.7°, evening, 39.8°; Cephalalgia, general malaise, lively thirst. Tongue red and extremely dry; otherwise, no abdominal symptoms; no diarrhoea, no pain in the right iliac fossa; no rose spots. Splenic dullness measures 10 centimetres in height by 12 in width. The diagnosis of intermittent quotidian fever is made. Quinine sulphate, 0.80gm morning and evening.
Blood examination made the morning of the 7th. November: nothing abnormal.
8th. November. The fever persists: morning, 40.6°, evening,39.6°; the pulse is strong, regular, it beats 104 times per minute in the morning. The patient has slept very little at night, the cephalalgia has increased in intensity. Quinine sulphate, 0.80gm. morning and evening.
9th. November. The fever is not as strong: morning, 38.6°, evening, 38.9°; The pulse rate is 92 times a minute in the morning, The cephalalgia is less severe, the general malaise not so great. Marked deafness, humming of the ears. Quinine sulphate, 0.80gm. morning and evening.
10th. November. Diminishing fever: morning, 38.4°, evening, 37.5°. The patient slept a little at night. Cephalalgia less severe. Tongue moist, whitish. Quinine sulphate, 0.80gm. morning and evening.
11th. November. Defervescence persists: morning, 36.7°, evening, 37°. The pulse rate only 55 times per minute at 11 in the morning. The patient slept during the night. The cephalalgia has disappeared, but the deafness persists. Quinine sulphate is discontinued. The patient takes a liquid medicament containing extract of cinchona 4 gm. Soups; wine, two portions.
12th. November. Apyrexia persists. The patient asks to eat . A half-portion, two portions of wine, cinchona wine, black coffee.
The days following, the amelioration becomes marked; the fever does not re-appear. The patient soon eats a portion, then two and three. Cinchona wine.
Blood examination made the 19th. November in the evening : few bodies no.1, no bodies no.2,nor 3.
The patient goes out of the hospital the 14th. December 1880 without the fever having re-appeared.

Observation XIX:

B....., aged twenty-two, in Algeria for a year, caught the fever in the month of August 1880, at Bardo, the fever gave way rapidly to quinine sulphate. The 16th. September, the fever had reappeared and there had been, since that time, many relapses.
I see the patient for the first time on the 23rd. November 1880; he is anaemic, the spleen extends notably below the false ribs. Apyrexia.
Blood examination made the 23rd. November: bodies no. 1 and no. 2 in small number. Brilliant mobile corpuscles, a little free pigment.
The 6th. December, in the morning, the patient had a fit of fever; at the visit the axillary temperature is 39.5°.
Blood examination made the 6th. December during the fit: few bodies no. 1; bodies no. 2 armed with mobile filaments; bodies no.3; brilliant mobile corpuscles; fiery-red or clear blue free pigment.
The 6th. December, in the evening, the patient takes quinine sulphate 0.80gm. The fever has died down.
7-8th. December. Apyrexia.Quinine sulphate, 0.80gm. morning and evening.
Blood examination made the 8th. December in the evening: bodies no.1 and no.3 very rare ; no bodies no.2.
The 9th. and the 10th. December, the patient takes again 0.60gm of quinine sulphate. Then, from the 11th., the quinine sulphate is replaced by wine of cinchona.
18th. December. There have not been any new fits; the strength has returned, the anaemia has disappeared little by little.
Blood examination made the 18th. December : bodies no.1 and no.3 very rare ; no bodies no.2.
The 19th. December the patient departs on leave of convalescence.

Observation XX:

S......., aged forty-five years, soldier with the 21st artillery regiment, enters into the military hospital at Constantine on the 26th. November 1880.
In Algeria since 1873, S...... caught intermittent fever for the first time in the month of September 1880; he was admitted to the hospital at Constantine for the first time on the 16th. October; he came out of it on the 30th. October. For twelve days the fever had re-appeared; intermittent, quotidian fever, well-characterised. The last fit had been on the 26th. November. Very pronounced anaemia, colourless mucosae, the skin a pasty hue; very great general feebleness. Spleen enlarged.
The 26th. December, in the evening, the patient takes 0.80gm. of quinine sulphate.
Blood examination made the morning of the 7th. November: bodies no. 1; bodies no. 2 , immobile or armed with mobile filaments; brilliant mobile corpuscles; a little free pigment.
5th. December. Since the 27th. November has taken quinine sulphate at a dose of 1.20gm initially, then 0.60gm. There have been no fresh fits; the strength returns.
Blood examination made the 5th. December: no bodies no.1, I again find bodies no. 2 armed with mobile filaments; no bodies no. 3.
The quinine sulphate is continued until 12th. December.
The patient goes out on the 12th. December. The general state is very satisfactory; there have been no new febrile fits.

Observation XXI:

Br....., aged twenty-two years, soldier with the 3rd. Zouaves, enters the military hospital at Constantine on the 28th. November 1880.
In Algeria for a year, Br......caught the fever in the surroundings of Djijelli on the 16th. September 1880; he was treated at the hospital at Djijelli from which he came out on 4th. November last (44 days of treatment). From sixteen days ago the fever had re-appeared; intermittent, quotidian fever, well-characterised; the last fit had been on the 27th. November at 9.30 in the morning. Profound anaemia. Splenic dullness measures 0.10m. in height by 0.14m. in width.
Blood examination made the morning of the 28th. November: bodies no.1 in rather large numbers; bodies no.2 in large number armed with mobile filaments; spherical bodies filled with mobile pigment granules; bodies no.3.
The 29th. November, the patient, who had not taken any quinine sulphate since his entry into hospital, had a violent fit of fever; the axillary temperature rose at the follow-up visit on the 29th.to 41.2°. Abundant sweating at night. Quinine sulphate, 0.80gm.
30th. November. Apyrexia. 36.6° in the morning. Quinine sulphate, 0.80gm. morning and evening.
Blood examination made on the 30th. November in the morning: bodies no.1 again in rather large numbers; immobile bodies no.2; some spherical bodies filled with mobile pigment granules; bodies no.3; brilliant mobile corpuscles; a little free pigment.
Quinine sulphate is prescribed from the 1st. to the10th. December at a dose of 1.20gm. per day at first, then of 0.60gm.
24th. December. The patient is doing well, there have been no new fits, the strength returns.
Blood examination made on the 24th. December in the morning: nothing abnormal.
A few days after this examination the patient quits the hospital.

Observation XXII:

P......., of twenty-four years, in Algeria since the 8th. November 1880, caught the intermittent fever in Corsica fifteen months ago. Continual relapses; last fit the 28th. November.
I see the patient for the first time on the 29th. November 1880; he is wasted, anaemic; the spleen extends beyond the false ribs. 1gm. quinine sulphate in the morning of the 29th. November.
Blood examination made the 29th. November: bodies no.3; no bodies no. 1 or 2.
6th. December. The patient had had a fit this morning, and had been made to take 1gm. of quinine sulphate at the end of this fit.
Blood examination made the 6th. December in the evening: bodies no. 1 in rather large numbers; bodies no.2 immobile or armed with mobile filaments; no bodies no.3; a little free pigment.
The 11th. December, a febrile fit, the temperature climbs to 40°. At the end of the fit, the patient takes a single dose of quinine sulphate.
Blood examination made on the 12th. December in the morning: bodies no. 1 in great number; bodies no. 2 armed with mobile filaments, in great number : several filaments have become detached from the bodies no. 2 and circulate amid the red blood cells.
24th. December. The patient had had a fit on the 16th. and 17th. December; at the end of these fits took two doses of quinine sulphate.
Blood examination made on the 24th. December in the morning: bodies no. 1 in great number; bodies no. 2 armed with mobile filaments; Mr. Maupetit, medical assistant-major, confirms the existence of mobile filaments.
The patient, who does not belong to my department, quits the hospital some days after the last examination.

Observation XXIII:

D......, twenty-six years old, soldier with the third African battalion, enters the military hospital at Constantine the 30th. November 1880.
D...... arrived in Algeria in the month of June 1877, he caught the fever for the first time in 1877 at Biskra, he kept it for fifteen days only. The fever did not re-appear in 1878, or in 1879. A month ago, the patient had been taken afresh by fever at Akbou, he had spent fifteen days at the ambulance of this station. The last fit, the morning of the 30th. November, which is to say the same day as the hospital admission.
1st. December. Apyrexia. The patient is wasted, profoundly anaemic, the mucosae are colourless, the skin presents a pasty colour. Splenic dullness measures 15 centimetres in height by 14 in width. The patient has only had one dose of quinine sulphate before entering the hospital.
Blood examination made the 1st. December at 2 o'clock in the evening: bodies no. 1 in rather large numbers; bodies no.2 in armed with their mobile filaments; I record on several of these bodies no.2 the very remarkable changes of form which recall amoeboid movements; bodies no. 3 in fairly large numbers;
10th. December. The patient has taken quinine sulphate for 6 days (from the 1st. to the 6th. December) at a dose of 0.80gm, then of 0.60gm. There have been no new febrile fits, the general condition has improved markedly.
Blood examination made the 10th. December: bodies no. 1 in small number; bodies no. 2 also rare: I record on several of these bodies the existence of mobile filaments; some bodies no. 3.
20th. December. There have not been any new fits of fever; the patient regains his strength, the anaemia dissipates little by little. Wine of cinchona, black coffee.
Blood examination made the 20th. December: small number of bodies no.1, no bodies no.2, or 3.
The patient leaves the hospital the 31st. December.

Observation XXIV:

L......, aged twenty-seven years, detailed to the workshop of public works, enters the military hospital at Constantine the 27th. December 1880.
L......, caught the fever at Martinique in 1878; since this time, there have been successive relapses; the patient has been in Algeria for a year. Last fit the 26th. December; 3 doses of quinine sulphate made up of 0.6gm for each of the 24th., 25th., and 26th. December.
I see the patient for the first time the 29th. December: The patient is wasted, anaemic, the spleen extends a little below the false ribs. Apyrexia.
Blood examination made the 29th. December: bodies no. 1 in great number ; bodies no.2 rather numerous, armed with mobile filaments; bodies no.3 in small number; a little blue pigment.
9th. January 1881. The patient has had a fit of fever on the 3rd.,the 5th., the 6th., and the 7th. January; he took four doses of quinine sulphate 0.60gm each.
Blood examination made the 9th. January: bodies no. 1 in less great number than during the preceding examination ; immobile bodies no.2, I could not establish the presence of peripheral mobile filaments; bodies no. 3 in rather large number.
12th. January, the patient had a febrile fit, at the end of which he took two doses of quinine sulphate of 0.50gm. each.
Blood examination made the 24th. January: bodies no. 1 in great number; bodies no. 2 in great number, armed with mobile filaments, spherical bodies much larger than bodies no.2 containing mobile pigmentary granulations.
The 25th. of January, the patient had a violent febrile fit at the end of which he took 0.50gm.of quinine sulphate.
Blood examination made the 26th. January: bodies no. 1 less numerous than the 24th.; immobile bodies no. 2; it is impossible for me to establish the existence of mobile filaments upon a single one of these bodies; no bodies no.3.
31st.January. There have not been any new fits of fever. The patient has not taken any quinine sulphate since the 26th. January.
Blood examination made the 31st. January: bodies no. 1 in rather large number; bodies no. 2 rare, but furnished with mobile filaments; free, deep-red and clear blue pigment.
The 2nd. February, in the evening the patient has a fit of fever.
Blood examination made on the 3rd. February in the morning : (one dose of quinine sulphate had been prescribed for this morning, but the patient had not yet had it yet by the time I made the blood examination) bodies no. 1 in rather large number; bodies no. 2 armed with mobile filaments; no bodies no. 3; brilliant mobile corpuscles.
The 4th. February, a new fit of fever, following which the patient took two doses of quinine sulphate of 0.50gm. each.
Blood examination made on the 6th. February: bodies no. 1 in less great number than on the 3rd. February; bodies no. 2 in small number, immobile : I did not observe mobile peripheral filaments on any of these bodies; bodies no. 3.
10th. February. There have been no new fits, the patient finds himself better.
Blood examination made on the 10th. February: bodies no. 1 in small number; immobile bodies no.2, very rare; no bodies no. 3; some mobile, brilliant corpuscles.

Observation XXV:

C......., soldier with the 8th. training squadron, enters the military hospital at Constantine on the 3rd. October 1880, complaining of being ill for just one day.
C......., is barracked at Bardo, which is to say one of the more unhealthy spots of Constantine. I record the existence of a continuous fever, inflammatory, which gives way rapidly to quinine sulphate.
The 5th. November, the fever re-appears, and is accompanied by gastralgia, bilious vomiting, and a very great exhaustion of strength, This pernicious gastralgia yields to hypodermic injections of quinine chlorohydrate, and to quinine sulphate administered internally when the vomiting had ceased. 16th. November. The fever has disappeared completely since the 7th. November, the patient has not had any more quinine sulphate since the 8th. November.
Blood examination made on the 16th. November in the morning: bodies no.1 in rather large numbers; bodies no.2 armed with mobile filaments; no bodies no. 3; brilliant, mobile, small, rounded bodies; a little free pigment.
From the 17th. to the 23rd. November I prescribe quinine sulphate: 1.60gm per day at first, twice, then 0.80gm.
Blood examination made the 20th. November in the evening: the number of parasitic elements in the blood have diminished considerably, but I find, nevertheless, some bodies no. 1 again; and also bodies no. 2 armed with filaments; bodies no. 3 in small number; brilliant mobile corpuscles; a little free pigment.
Fresh examination of the blood made the 23rd. November: bodies no. 1, but in very small number; no bodies no. 2, nor no.3.
The 24th. November, the patient departs on leave of convalescence.

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CHAPTER V:

[The nature of bodies no.1, no.2, and no.3 found in the blood of patients attacked by marsh fever. Their parasitic origin. The new parasite discovered in these patients is a haematozoite, similar to the oscillaria]

I shall not delay any longer in order to demonstrate that bodies no.1, no.2, and no.3 described above can be found most effectively in the blood; one saw earlier the minute precautions which were taken to prevent the introduction of foreign bodies in the preparations. The glass slides, carrier, and cover-slip, were carefully washed in alcohol, as was the patient's finger, the blood examined pure, without mixing with any liquid and, lastly, the preparations were mounted in paraffin. These precautions did not impede, it is true, the introduction of some particles in a state of suspension in the air; but how then can it be admitted that the pigmented bodies were to be found in the air only when I examined the blood of patients stricken by marsh fever? How can it be supposed that the bodies no. 2, with their delicate mobile filaments, were to be found in a state of desiccation in the air, and that they regained their form and their movements when they happened to fall into the drop of blood being prepared? How might the relation be explained, finally, which I established many times, between the abundance or rarity of these elements and the state of illness or of recovery of individuals attacked by marsh fever, if their introduction into the blood was nothing but a chance effect? Moreover, I took the care of making the preparations, at times in rooms by the bedsides of the patients, at times in my laboratory, and the results were the same.

I believe I can affirm that the bodies no.1, no.2, and no.3 originate, very truly, from blood.

Is it possible to confuse these bodies with the normal elements of blood, more or less altered? Evidently, not. Bodies no. 2 with their pigment grains arranged crown-like, and their peripheral, mobile filaments, do not bear resemblance to any normal or pathological element in blood; the black grains of pigment cannot be mistaken for the granulous state of leucocytes, and it is hardly necessary to state that the very lively and very rapid movements of the peripheral filaments in no way resemble the amoeboïd movements of leucocytes; furthermore, the amoeboïd movements of leucocytes cannot be observed in human blood except when laid out on a warm plate, which was never employed in these researches. None of the colleagues to whom I was able to show bodies no. 2 hesitated even for a single instant in recognising that it moved about just like an animate being, a parasite. It is enough to glance at figure 2 (plate II) in order to understand that bodies similar to those depicted in B and B' could not possibly be confused with leucocytes, however deformed or pigmented one might suppose them to be. When one has noted de visu the movements, so vivid and remarkable, of the peripheral filaments, it is impossible to retain the shadow of a doubt in this respect; this curious spectacle converts the most incredulous. Even in a state of rest, bodies no. 2 are easy to distinguish from leucocytes : their diameters are smaller than those of the latter, the grains of pigment which they contain are arrayed, most often, in a regular fashion; one cannot record the existence of nuclei in the interior; under the influence of osmic acid, and of glycerine, one can see appear a double contour; finally, carmine colours these bodies with great difficulty and imparts only a rosy tint, very pale, to the central part; the part contained within the two lines of the double contour do not become coloured.

The red blod cells appear sometimes to the observer with a form that recalls that of bodies no. 1, but it is only an appearance; as soon as the red blood cells become displaced, one observes that they have a characteristic discoid shape, whereas bodies no.1, even when they are dragged by a current in the preparation, and they come out, in rolling over themselves, under their differing faces, retain the aspect of a cylindrical element, more or less enfiled at its extremities, and lightly incurved; bodies no. 1 are always pigmented, whereas the red blood cells are never so; treated by osmic acid and glycerine picrocarminate, they show a double contour and the central part takes on a very pale, rosy tinge; it is futile to add that one never observes anything analogous with red blood cells.

Bodies no. 3, it is true, bear a great resemblance to leucocytes laden with pigmentary granulations; the form, the dimensions, are somewhat the same. Nevertheless, these two types of elements yet present certain distinctive characteristics: the pigment grains frequently adopt a fairly regular disposition inside bodies no.3, they seem equal to each other, regularly rounded, no internal nucleus can be found and, lastly, these bodies do not take on a colour, or at least, do so with great difficulty using carmine, contrary to what occurs with leucocytes. We have seen that it is easy to be directly re-assured that bodies no.3 result from a transformation of bodies no.2, since in leaving a body no.2 under the objective of the microscope, at the end of a certain time one rediscovers a body no. 3 there; with a little patience, one can just as well come to see this transformation brought into effect at the time when the movements of the mobile filaments cease, that is to say, when bodies no.2 die.

Moreover, I do not dispute the possibility of finding in the blood of a patient stricken by marsh fever true leucocytes containing pigment granulations. The pigment which is liberated after destruction of bodies no.2 and no.3 must have a great tendency to becoming incorporated into leucocytes, just as pulverulent material does when injected into the blood of animals.

The parasitic nature of bodies no.1, no.2, and no.3 appears to me to be indisputable.

Is it a question of the parasite belonging to the animal kingdom or the vegetable kingdom?

The fact that these parasitic elements live in an alkaline milieu like the blood already indicates that it belongs to the animal kingdom. The toxic effect exerted upon them by quinine sulphate is also excellent proof of their animality. One knows that it is enough to add a little quinine sulphate to a vegetal infusion in order to impede the development of infusoria in the liquid. Contrariwise, fungi thrive very well in solutions of quinine sulphate. In military hospitals there is at one's disposal a fiftieth solution of quinine sulphate which is contained in ordinary bottles; when these bottles have been used for some time without having been rigorously cleaned, their internal wall gets covered in brownish patches which end up by uniting with each other and forming a continuous coat; it is easy to assure oneself that these patches are formed by a mould which lives, therefore, in a concentrated solution of quinine sulphate.

The very lively and very varied movements of the mobile filaments of bodies no.2 give, moreover, the impression of an animalcule, bordering on the infusoria, to the observer.

To which species does this new haematozoite belong? Here, I must confess my embarrassment and call upon the naturalists. I had thought, at first, it was a question of an amoeba which, in its full state of development is equipped with mobile filaments; we have seen, in effect, that the bodies no.2, apart from the oscillatory movements which are impressed upon them by mobile filaments, present very often slow movements, analogous to those of amoebae; but I was right to abandon this idea when I established that the mobile filaments could become detached from bodies no.2 and live in a free state in the blood. Today I suppose that the mobile filaments lightly swollen at their extremities represent the perfect state of the blood parasite, and that the bodies no.1, no.2, and no.3 are only types of pockets in which the parasites live for a certain period in a state of agglomeration, or encystment.

The brilliant, rounded, mobile corpuscles that are found almost always in the preparations of blood derived from patients attacked by marsh fever represent, perhaps, the first phase of development of parasitic elements. These corpuscles, moreover, have no specific characteristics.

The mobile filaments of bodies no. 2 have a great similarity with the 'oscillaria'. It is note-worthy that several observers, who never suspected the existence of these animalcules in the blood of patients attacked by marsh fever, have already attributed a major rôle to the oscillaria in the pathogenesis of impaludism. Hallier, the first I believe, has expressed this opinion, totally theoretically besides.

Dr. Schurtz ( of Zwickau) cites the case of a man taken by intermittent fever in apparently very good, healthy conditions; this patient had given himself up to the study of cryptogams, and he had in his bedroom twenty-four saucers containing oscillaria (Arch.d.Heilk., 1868, p.69). If it was demonstrated that the mobile filaments of bodies no.2 were really of the same species as oscillaria, the name of 'Oscillaria malariæ' would agree well the new haematozoite.

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CHAPTER VI:

[Pathological rôle of the parasitic elements found in the blood of patients attacked by marsh fever. The nature of impaludism]

What is the pathological importance of the parasitic elements found in the blood of patients attacked by marsh fever? Are these elements the direct cause of the mishaps of impaludism, or is it that their rôle is merely accessory, and that their development in the blood depends only on the general enfeeblement produced by the fever? One knows that an organism is easily invaded by parasites when a previous illness has diminished its power of resistance: thrush, pityriasis versicolor, ascariasis thrive, in preference, among cachectic individuals; to take a recent example, there is still a discussion going on to define whether Stronglyoides stercorale is the cause of the chronic diarrhoea of Cochinchine, or whether, indeed, this parasite simply finds in individuals affected by this malady a milieu which is favourable to its development.

It appears obvious to me that the parasitic elements which have been described in Chapter II of this work under the names of bodies no.1, no.2, and no.3, play the principal rôle in the pathogenesis of the mishaps that occur in impaludism. The following propositions seem to me to leave no doubt in this respect:

1. These elements are not found except in the blood of patients stricken by marsh fever. I have searched for them in vain in the blood of individuals attacked by diarrhoea or chronic dysentery, typhoid fever, tuberculosis, etc.; nevertheless these last patients were as profoundly anaemic as those which had contracted fevers, and the blood of which contained the parasitic elements, and they had lived in the same environment. It is true that the presence of pigmented bodies cannot always be recorded in the blood of patients attacked by marsh fever; but with an examination conducted on merely one or two drops of blood it can be imagined without trouble how difficult it might be to discover the parasites when they are in small numbers; it is probable, besides, that the parasites of their own accord become settled in certain organs, in the spleen in particular, and that they are not swept off by the circulatory stream until they have multiplied many times over.
2. At autopsy, in individuals who have died from pernicious fever, a large number of pigmented elements can be found in the blood and in the vessels of all the organs, notably the spleen and the liver, identical to bodies no. 3, which here are an absolutely constant characteristic of acute impaludism, and one not observed in any other illness. Among patients who have succumbed to chronic impaludism, there exist, equally, pigmented elements in the blood, but these elements localise themselves in general in the liver and the spleen.
3. The haematozoites, numerous in the blood of individuals, who have had the fever for a long time and who have not been treated in a regular manner, disappear rapidly when these patients are subjected to quinine medication. It is most probably because quinine sulphate kills these blood parasites that quinine cures patients attacked by marsh fever.

It has indeed been a long time that the idea was expressed for the first time that impaludism was caused by a parasite, by an animated germ; in order to find the father of the parasitic theory of marsh fever, it is necessary to go as far back as Lancisi, and in truth, as far as Lucretius.

In the last twenty years, the question has come out of a speculative phase and entered into an experimental phase, and a large number of distinguished observers have set about on all sides to seek out the animated germ of marsh fevers. To give an idea of the importance of this scientific current, it will be enough for me to cite the works of J. Lemaire (Comptes rendus de l'Académie des sciences, 1864, p.426), of Massy (Army med. Report, 1865, t. VII, p.539), of Salisbury (American Journ. of the med. sc., 1866, and Revue des cours scientifiques 6th. November 1869), of Balestra (Congrès med. de Florence, in Union médicale, 1869, p.645 and Acad. des sciences, 18th. July 1870), of Lanzi and Terrigi (1875), of Magnin (thesis, Paris, 1876), of Corre (Archives de médecine navale, 1877), of Frédéric Eklund (same collection, 1878), of Klebs and Tommasi Crudeli (Reale Accademia dei Lincei, series 4, t. III, anal. in Revue d'hygiène 1879, p. 760).

It is to be noted that the principal, if not unique, goal pursued by these investigators has been to find the germs of fevers in the air, in water, and in the soil of these marshy localities, and that the search for these germs in the blood of patients stricken by different forms of impaludism has not been made except in a secondary, and somewhat accessory, manner. It is thus that Salisbury and Eklund speak of having found in the blood and in the urine of patients attacked by marsh fever the fungi which they consider to be the cause of the fever, Palmelles (Salisbury), Limnophysalis hyalina (Eklund). The air, the water, and the soil of these marshy localities contain a very large number of microscopic entities belonging either to the animal or vegetable kingdoms; therefore one understands how difficult it is to say which are those entities responsible for the fever from among those one had been led to describe as the parasite or germ of intermittent fever, at times one fungus, at times another, according to the varieties that prevail in the localities where the observations were made.

Mr. Lanzi and Mr. Terrigi found melanoid pigment in the liver and the spleen of guinea-pigs which had breathed the air in marshes; in cultivating the pigmentary granules contained in the spleen and liver of individuals who had died from palustral cachexia, the same observers talk of having obtained a vegetation comparable to Zooglia, to which they gave the name of Bacteridium brunneum

Mr. Klebs and Mr. Tommasi Crudeli inoculated into animals, especially rabbits, liquid derived from washing the earth from marshlands; they succeeded in producing thus periodic fevers among inoculated animals; the spleen of these animals swelled up, and became filled with pigment, as in man attacked by palustral fever. Mr. Klebs and Mr. Tommasi Crudeli come to this conclusion, that the symptoms of paludism are produced by a fungus to which they propose to give the name of Bacillus malariae; the Bacillus malariae will develop in the bodies of animals in the form of long filaments which, at first homogenous, becomes partitioned eventually in a manner to represent the articles in the interior from which the spores will be formed.

Bacteridium brunneum and Bacillus malariae in no way resemble the pigmented elements which exist in the blood of patients attacked by marsh fever, and I believe that these would-be parasites of paludal fever are no more authentic than the palmelles; the experimental attempts which I have just described are not, however, any the less interesting. The fact that Mr. Klebs and Mr. Tommasi Crudeli succeeded in reproducing in the spleen and in the liver of animals inoculated with the water derived from lavage of marshy earth the pigmented granules analagous to those which can be found in the cadavers of patients stricken by marsh fever appears to indicate that it is possible to culture among animals the pigmented bodies which engender intermittent fever in man. As for the culture made by Lanzi and Terrigi of pigmented elements originating from the spleen and the liver of individuals who have died of palustral cachexia , I have great trouble in believing it; all the pigmented bodies which one recovers from the cadaver are dead; on the other hand, the vegetation, comparable to zooglia, which have been obtained under these conditions, appear to me to bear no relationship to the true parasites of marsh fever which are, as we have seen, animalcules related to the oscillaria.

The direct investigation of the parasites of marsh fever in the air, the water, and the soil in areas which are the most insalubrious thus far having provided only results not too satisfying, it was the obvious thing to change the method and follow an opposite course to that adopted by the preceding observers. Now that the nature of these elements is known, of which the presence in the blood gives birth to the symptoms of impaludism, it will be probably easy to retrieve these parasites in a perfect state, or in state of germs in the air, the water, or the soil of marshy locations.

I believe that impaludism ought to take place henceforth among parasitic ailments; impaludism is a parasitic disease of the blood, like trichinosis is a parasitic disease of the muscles, and scabies a parasitic affliction of the skin.

The haematozoites which develop in the blood of patients attacked by marsh fever are indeed parasites, they are non-fermenting, and actually impaludism behaves like parasitic diseases and not like miasmatic or virulent diseases; in impaludism, there is no period of incubation of a constant duration, no regular evolution of complications, no immunity conferred by a first attack, but rather the contrary, a tendency to relapse.

It readily explains why impaludism is not infectious, although produced by a parasite. The diseases brought about by parasites living on the surface of the body, such as scabies, or ring-worm, are contagious, because the parasite which causes them : sarcoptes, achorion, trichophyton, are easily transported from one individual to another; but those which are dependent on parasites living in the inside of the body, such as trichinella, echinococcus, helminths, are in no way contagious; one imagines that impaludism finds place among the latter, since the parasites which produce it develop in the blood.

If the blood of a patient stricken by marsh fever is inoculated into a healthy individual, it is more than probable that intermittent fever will not be seen to arise in the latter. In conceding all the same that the inoculated blood contained parasitic elements, these elements will not be take long to die in the connective tissue where they might have been deposited, and it would only be by chance that they might penetrate into the blood vessels. In proceeding along the following lines, however, it is to the contrary very probable that one would succeed in transplanting, so to speak, the parasitic elements of an ill individual into a healthy person: after having chosen a sick man whose blood was rich in parasitic elements, notably in bodies no. 2 with mobile filaments, a few drops of blood would be gathered from the sick man and injected immediately into the veins of a healthy individual. It is most probable that in placing oneself in these conditions one would see, at the end of a period impossible to specify, the accidents of impaludism develop in the inoculated individual. If it were simply a question of inoculating intermittent fever as one might inoculate a vaccine for example, subjects with good intentions would not be lacking for such an experiment, one would get off with some fits of fever easily arrested by quinine sulphate; but it is always a serious operation, that of pricking a vein, and I, for one, would not like to take on this responsibility. I propose, when we shall be in a more favourable climate, to try out the culture of parasitic elements in the blood of animals; the facts announced by Mr. Klebs and Mr. Tommasi Crudeli tend to make believe that such an experiment can succeed.

How, and by what mechanism, do the parasitic elements which I described under the names of bodies no.1, no.2 and no. 3 produce such a variety of mishaps in impaludism?

Once absorbed in a form and by a route which is yet unknown to us, the parasitic elements develop and multiply in the blood; during this period of incubation, the patient often does not experience any symptoms of disease. At the end of their growth and their multiplication, the parasites end up by bringing about an irritation of the different organs, which is when the fever appears, at times with the features of a continuous fever, inflammatory, at times with those of an intermittent one. The presence of trichinella in muscles often gives rise to a fever keen enough to make confusion with typhoid fever possible; one imagines also that the presence of numerous parasitic elements in the blood, and consequently in all the organs, could give birth to an inflammatory fever, more or less intense.

The intermittent fever is probably due to irritation which the parasites, reaching a certain stage in their development, produce in the marrow. It is known that frequently a permanent irritation of the nervous system is expressed in the form of intermittent symptoms; that cerebral tumours, for example, do not reveal themselves among some patients except by epileptiform attacks which reproduce themselves at intervals more or less distant; it is then easy to comprehend that the irritation of the marrow produced by the presence of parasitic elements in the blood gives birth to intermittent mishaps. Only the regularity of intermittence which is observed in marsh fever is difficult to explain. Perhaps it must be admitted that the irritability of the marrow is exhausted after each febrile paroxysm and that the interval which separates the fits of fever represents the time necessary for this exhaustion to disappear. One might thus explain to oneself that among vigorous individuals, recently arrived into countries where malaria prevails, the types persist and quotidian marsh fevers are the most common, whereas in men who have been weakened by previous illness and in particular among palustral cachectics, the most frequent types that are seen are the long, intermittent types, tertian, and quartan. It is logical to admit that in these latter patients the exhaustion of the nervous medullary influx which follows each fit dissipates less rapidly than in fully fit individuals who have not yet been affected by fevers.

The presence of parasitic elements in large number in the capillary vessels of the brain, which are truly obstructed by it in certain cases of pernicious fever, accounts very well indeed for the delirium and the coma which are the symptoms most frequently observed in patients attacked by pernicious mishaps. Frerichs had already accorded an important rôle to the accumulation of pigment in cerebral vessels in the pathogenesis of pernicious fits; but it was difficult to understand why these pigmentary thromboses could disappear so rapidly, and one always raised the objection to Frerichs because the rapidity with which the pernicious symptoms disappeared in certain patients in order to return sometimes at the end of a day or two; neither was the efficacy, so marvellous, of quinine sulphate, understandable in terms of this hypothesis.

The fact that the obstruction of cerebral vessels is wrought not by inert bodies but by parasitic elements answers these objections; it is easy to understand, in effect, that the parasitic elements which obstructed for an instant the small cerebral vessels could be swept away afresh in the circulatory torrent, especially if the quinine sulphate came to stun these parasites, or kill them.

The spleen, which is the seat of predilection of parasitic elements, undergoes, whether in the acute forms, or in the chronic forms of impaludism, profound alterations which certainly hamper its functions; that is, without doubt, one of the causes of the profound anaemia which is seen among all the patients stricken by marsh fever.

At length, the irritation produced by the parasitic elements in the different organs of the economy translates itself into lesions of chronic inflammation; the presence of sarcoptes brings about very varied inflammatory lesions of the skin; likewise the parasitic elements which are found in the capillary vessels of the spleen, the liver, etc., in patients attacked by marsh fever, leads to the congestion of these different organs, and gives rise in the end to inflammatory lesions which, once developed, can develop independently of palustral fever. The spleen, which is the seat of choice for these parasitic elements, constantly presents in individuals who have had the fevers for a long time, lesions of hypertrophic cirrhosis; inflammatory lesions of the liver come to follow next, in order of frequency, the inflammatory lesions of the kidneys and the lungs.

In the spleen and the liver of palustral cachectics, one finds most often, other than the lesions of chronic inflammation, pigmented elements which are contained within the small vessels and pigment in irregular masses outside the vessels. This pigment situated outside the vessels, ought it to be compared to that which shows up in all chronically inflamed organs, in the lungs of the tuberculous for example; or ought it to be admitted that the pigmentary granulations of parasitic elements contributes to its formation? When bodies no. 3 become disorganised, the pigment grains which they enclosed are shed into the blood where it is not unusual to encounter them in a liberated state; the leucocytes very probably take in this pigment and transport it to outside the vessels, just as they do with pulverulent material when injected into the veins of animals. Mr. L. Colin has drawn attention to this phenomenon, and has shown with reason that this was to be taken as proof of the diapedesis of white cells in man (Archives générales de médicine, 1875).

One understands without difficulty why recidivists of intermittent fever are so common : it would be sufficient for some parasitic elements situated in the spleen, for example, to have escaped the action of quinine sulphate for these elements to form the point of departure for new generations of parasites; the relapse prepares itself in silence, the patient enjoys good health meanwhile, but when the parasites have multiplied, and have reached a sufficient increase, the febrile paroxysms return.

CONCLUSIONS: