Popular Science Monthly/Volume 58/February 1901/Malaria
SURGEON-GENERAL, U. S. ARMY.
IN my address as president of the Biological Society, in 1896, the subject chosen was 'The Malarial Parasite and other Pathogenic Protozoa.' This address was published in March, 1897, in the Popular Science Monthly, and I must refer you to this illustrated paper for a detailed account of the morphological characters of the malarial parasite. It is my intention at the present time to speak of 'Malaria' in a more general way and of the recent experimental evidence in support of Manson's suggestion, first made in 1894, that the mosquito serves as an intermediate host for the parasite. The discovery of this parasite may justly be considered one of the greatest achievements of scientific research during the nineteenth century. Twenty-five years ago the best-informed physicians entertained erroneous ideas with reference to the nature of malaria and the etiology of the malarial fevers. Observation had taught them that there was something in the air in the vicinity of marshes in tropical regions, and during the summer and autumn in semi-tropical and temperate regions, which gave rise to periodic fevers in those exposed in such localities, and the usual inference was that this something was of gaseous form—that it was a special kind of bad air generated in swampy localities under favorable meteorological conditions. It was recognized at the same time that there are other kinds of bad air, such as the offensive emanations from sewers and the products of respiration of man and animals, but the term malaria was reserved especially for the kind of bad air which was supposed to give rise to the so-called malarial fevers. In the light of our present knowledge it is evident that this term is a misnomer. There is no good reason for believing that the air of swamps is any more deleterious to those who breathe it than the air of the sea coast or that in the vicinity of inland lakes and ponds. Moreover, the stagnant pools, which are covered with a 'green scum' and from which bubbles of gas are given off, have lost all terrors for the well informed man, except in so far as they serve as breeding places for mosquitoes of the genus Anopheles. The green scum is made up of harmless algæ such as Spirogyra, Zygnema Protococcus, Euglena, etc.; and the gas which is given off from the mud at the bottom of such stagnant pools is for the most part a well-known and comparatively harmless compound of hydrogen and carbon—methane or 'marsh-gas.' In short, we now know that the air in the vicinity of marshes is not deleterious because of any special kind of bad air present in such localities, but because it contains mosquitoes infected with a parasite known to be the specific cause of the so-called malarial fevers. This parasite was discovered in the blood of patients suffering from intermittent fevers by Laveran, a surgeon in the French army, whose investigations were conducted in Algiers. This famous discovery was made toward the end of the year 1880, but it was several years later before the profession generally began to attach much importance to the alleged discovery. It was first confirmed by Richard in 1882; then by the Italian investigators, Marchiafava, Celli, Golgi and Bignami; by Councilman, Osier and Thayer in this country, and by many other competent observers in various parts of the world. The Italian investigators named not only confirmed the presence of the parasite discovered by Laveran in the blood of those suffering from malarial fevers, but they demonstrated its etiological rôle by inoculation experiments and added greatly to our knowledge of its life history (1883-1898). The fact that the life history of the parasite includes a period of existence in the body of the mosquito, as an intermediate host, has recently been demonstrated by the English army surgeons Manson and Ross, and confirmed by numerous observers, including the famous German bacteriologist, Koch.
The discoveries referred to, as is usual, have had to withstand the criticism of conservative physicians, who, having adopted the prevailing theories with reference to the etiology of periodic fevers, were naturally skeptical as to the reliability of the observations made by Laveran and those who claimed to have confirmed his discovery. The first contention was that the bodies described as present in the blood were not parasites, but deformed blood corpuscles. This objection was soon set at rest by the demonstration, repeatedly made, that the intra-corpuscular forms underwent distinct amœboid movements. No one witnessing these movements could doubt that he was observing a living microorganism. The same was true of the extra-corpuscular flagellate bodies, which may be seen to undergo very active movements, as a result of which the red blood corpuscles are violently displaced and the flagellate body itself dashes about in the field of view.
The first confirmation in this country of Laveran's discovery of amœboid parasites in the blood of malarial-fever patients was made by myself in the pathological laboratory of the Johns Hopkins University in March, 1886. In May, 1885, 1 had visited Eome as a delegate to the International Sanitary Conference, convened in that city under the auspices of the Italian Government, and while there I visited the Santo Spirito Hospital for the purpose of witnessing a demonstration, by Drs. Marchiafava and Celli, of that city, of the presence of the plasmodium malariæ in the blood of persons suffering from intermittent fever. Blood was drawn from the finger during the febrile attack and from individuals to whom quinine had not been administered. The demonstration was entirely satisfactory, and no doubt was left in my mind that I saw living parasitic micro-organisms in the interior of red blood corpuscles obtained from the circulation of malarial-fever patients. The motions were quite slow and were manifested by a gradual change of outline rather than by visible movement. After a period of amœboid activity of greater or less duration, the body again assumed an oval or spherical form and remained quiescent for a time. While in this form it was easily recognized, as the spherical shape caused the light passing through it to be refracted and gave the impression of a body having a dark contour and a central vacuole; but when it was flattened out and undergoing amœboid changes in form, it was necessary to focus very carefully and to have a good illumination in order to see it. The objective used was a Zeiss's one-twelfth inch homogeneous oil immersion.
But, very properly, skepticism with reference to the causal relation of these bodies to the disease with which they are associated was not removed by the demonstration that they are in fact blood-parasites, that they are present in considerable numbers during the febrile paroxysms and that they disappear during the interval between these paroxysms. These facts, however, give strong support to the inference that they are indeed the cause of the disease. This inference is further supported by the evident destruction of red blood corpuscles by the parasite, as shown by the presence of grains of black pigment in the amœba-like microorganisms observed in these corpuscles and the accumulation of this insoluble blood pigment in the liver and spleen of those who have suffered repeated attacks of intermittent fever. The enormous loss of red blood corpuscles as a result of such attacks is shown by the anæmic condition of the patient and also by actual enumeration. According to Kelsch, a patient of vigorous constitution in the first four days of a quotidian intermittent fever, or a remittent of first invasion, may suffer a loss of 2,000,000 of red blood corpuscles per cubic millimeter of blood, and in certain cases a loss of 1,000,000 has been verified at the end of twenty-four hours. In cases of intermittent fever having a duration of twenty to thirty days the number of red blood cells may be reduced from the normal, which is about 5,000,000 per cubic millimeter to 1,000,000 or even less. In view of this destruction of the red blood cells and the demonstrated fact that a certain number, at least, are destroyed during the febrile paroxysms by a blood parasite, which invades the cells and grows at the expense of the continued hæmoglobin, it may be thought that the etiological rôle of the parasite should be conceded. But scientific conservatism demands more than this, and the final proof has been afforded by the experiments of Gerhardt and of Marchiafava and Celli— since confirmed by many others. This proof consists in the experimental inoculation of healthy individuals with blood containing the parasite and the development of a typical attack of periodic fever as a result of such inoculation. Marchiafava and Bignami, in their elaborate article upon 'Malaria' published in the 'Twentieth Century Practice of Medicine' say:
"In order that the disease be reproduced in the inoculated subject it is not necessary to inject the malarial blood into a vein of the recipient, as has been done in most of the experiments; a subcutaneous injection is all-sufficient. Nor is it necessary to inject several cubic centimeters, as was done especially in the earlier experiments; a fraction of a cubic centimeter will suffice and even less than one drop, as Bignami has shown."
After the inoculation of a healthy individual with blood containing the parasite a period varying from four to twenty-one days elapses before the occurrence of a febrile paroxysm. This is the so-called period of incubation, during which, no doubt, the parasite is undergoing multiplication in the blood of the inoculated individual. The duration of this period depends to some extent upon the quantity of blood used for the inoculation and its richness in parasites. It also depends upon the particular variety of the parasite present, for it has been ascertained that there are at least three distinct varieties of the malarial parasite—one which produces the quartan type of fever, in which there is a paroxysm every third day and in which, in experimental inoculations made, the period of incubation has varied from eleven to eighteen days; in the tertian type, or second day fever, the period of incubation noted has been from nine to twelve days; and in the æstivo-autumnal type the duration has usually not exceeded five days. The parasite associated with each of these types of fever may be recognized by an expert, and there is no longer any doubt that the difference in type is due to the fact that different varieties or 'species' of the malarial parasite exist, each having a different period of development. Blood drawn during a febrile paroxysm shows the parasite in its different stages of intra-corpuscular development. The final result of this development is a segmenting body, having pigment granules at its center, which occupies the greater part of the interior of the red corpuscle. The number of segments into which this body divides differs in the different types of fever, and there are other points of difference by which the several varieties may be distinguished one from the other, but which it is not necessary to mention at the present time. The important point is that the result of the segmentation of the adult parasites contained in the red corpuscles is the formation of a large number of spore-like bodies, which are set free by the disintegration of the remains of the blood corpuscles and which constitute a new brood of reproductive elements, which in their turn invade healthy blood corpuscles and effect their destruction. This cycle of development, without doubt, accounts for the periodicity of the characteristic febrile paroxysms; and, as stated, the different varieties complete their cycle of development in different periods of time, thus accounting for the recurrence of the paroxysms at intervals of forty-eight hours, in one type of fever and of three days in another type. When a daily paroxysm occurs, this is believed to be due to the alternate development of two groups of parasites of the tertian variety, as it has not been possible to distinguish the parasite found in the blood of persons suffering from a quotidian form of intermittent fever from that of the tertian form. Very often, also, the daily paroxysm occurs on succeeding days at a different hour, while the paroxysm every alternate day is at the same hour, a fact which sustains the view that we have to deal, in such cases, with two broods of the tertian parasite which mature on alternate days. In other cases there may be two distinct paroxysms on the same day, and none on the following day, indicating the presence of two broods of tertian parasites maturing at different hours every second day.
Manson, in his work on tropical diseases, recently published, accounts for the febrile paroxysm as follows:
"The periodicity of the clinical phenomena is accounted for by the periodicity of the parasite. How are we to account for the periodicity of the parasite? It is true that it has a life of twenty-four hours, or of a multiple of twenty-four hours; but why should the individual parasites of the countless swarm all conspire to mature at or about the same time? That they do so—not perhaps exactly at the same moment, but within a very short time of each other—is a fact, and it is one which can be easily demonstrated. If we wish to see the sporulating forms of the Plasmodium in a pure intermittent, it is practically useless to look for them in the blood during the latter stages of fever, or during the interval, or during any time but just before, during, or soon after rigor. If we wish to see the early and unpigmented forms, we must look for them during the later stage of rigor or the earlier part of the stage of pyrexia. And so with the other stages of the parasite; each has its appropriate relationship to the fever cycle."
There are numerous cases of malarial fever in which there is no distinct intermission and in which the course of the fever is either continued or remittent in character. Fevers of this type usually occur in the late summer or in the autumn (æstivo-autumnal) and are believed to be due to infection by two distinct varieties of the parasite; one, the tertian æstivo-autumnal, causes a fever characterized by a marked rise in the temperature every second day; the other, a fever in which there is a daily elevation of temperature. There are certain peculiarities relating to the intra-corpuscular development of these parasites which enable us to differentiate them from the tertian and quartan parasites of intermittent fever, but a more striking difference to be observed in their life cycle of development in the blood of man is the presence of peculiar crescentic-shaped bodies, which play an important part in their further development in the body of an intermediate host—the mosquito. Associated with these 'crescents' fusiform and ovoid bodies are often seen which are no doubt similar in their origin and function. The crescents are a little longer than the diameter of a red blood corpuscle and are about three times as long as broad. They contain in the central portion grains of pigment (melanin) derived from the hæmoglobin of the infected corpuscle which has been changed into a crescentic body as a result of the development of the malarial parasite in its interior. When a fresh preparation of malarial blood containing these crescents is observed under the microscope, while a majority of them retain the crescentic form, others may be seen, after an interval of ten minutes or more, to change in form, first becoming oval and then round; then, in the interior of these round bodies an active movement of the pigment granules occurs; this is followed by the thrusting forth from the periphery of several filaments—usually four, which have flagella-like movements. These, as a rule, become detached and continue to move rapidly among the blood corpuscles. With reference to the function of these motile filaments, Marchiafava says:
"In these later days there is increasing belief in the theory, which we uphold, that the crescents and the flagellata are sexual forms of the malarial parasite, and that a reproductive act (in which the flagellum represents the male element and an adult crescent the female cell) gives rise to the new being which begins its existence in the tissues of the mosquito.
These crescentic bodies may be found in the blood of man long after all febrile symptoms have disappeared, and it is generally recognized that they are not directly concerned in the production of the phenomena which constitute a malarial attack and that the administration of quinine has no influence in causing them to disappear from the blood. On the other hand, the febrile phenomena are directly associated with the appearance of the amœboid form of the parasite in the interior of the red blood corpuscles and the administration of suitable doses of quinine has a marked effect in causing these amœba-like micro-organisms to disappear from the blood.
These crescentic bodies are not found in the benign tertian and quartan intermittent fevers, but are characteristic of the malignant forms of malarial infection, including the so-called æstivo-autumnal fever. In these forms of fever they are not seen at the outset of the attack, and they have no direct influence upon the course of the fever. A week usually elapses between the first appearance of the amœboid form of the parasite and that of these crescentic bodies. They are often found in the blood some time after all symptoms of fever have disappeared, and are associated with the malarial cachexia which follows an attack of æstivo-autumnal fever. When blood containing these crescents is ingested by a mosquito of the genus Anopheles the following very remarkable transformations occur: Some of the crescents are transformed into hyaline flagellate bodies having active movements; others are changed into granular spheres. The flagella break away from the hyaline bodies and, approaching the granular spheres, appear to seek energetically to enter these bodies. A minute papilla is given off from the surface of the sphere, seeming to be projected to meet the attacking flagellum. At this point, one of the flagella succeeds in entering the sphere, causing an active movement of its contents for a brief time, after which the flagella disappear from view, and the contents become quiescent. This is no doubt an act of impregnation. After a time the impregnated granular sphere alters its shape, becoming oval, and later vermicular in form. The pigment granules are now seen at the posterior part of this body, which, after the changes mentioned, exhibits active movements. It is believed that this motile vermicular body penetrates the wall of the mosquito's stomach. Here it grows rapidly and, after a few days, may be seen projecting from the surface as a spherical mass. In the meantime the contents are transformed into spindle-shaped bodies (sporozoites) which are subsequently set free by the rupture of the capsule of the mother cell. According to Manson, these spindle-shaped bodies pass from the body cavity of the mosquito, probably by way of the blood, to the three-lobed veneno-salivary glands, lying on each side of the fore part of the thorax of the insect. "These glands communicate with the base of the mosquito's proboscis by means of a long duct along the radicles of which the clear, plump cells of the gland are arranged. The sporozoites can be readily recognized in many, though not in all, of the cells, especially in those of the middle lobe, and also free in the ducts. So numerous are they in some of the cells that the appearance they present is suggestive of a bacillus-laden lepra-cell."
The hypothesis that malarial infection results from the bites of mosquitoes was advanced and ably supported by Dr. A. F. A. King, of Washington, D. C, in a paper read before the Philosophical Society on February 10, 1883, and published in the Popular Science Monthly in September of the same year. In 1894, Manson supported the same hypothesis in a paper published in the 'British Medical Journal' (December 8), and the following year (1895) Ross made the important discovery that when blood containing the crescentic bodies was ingested by the mosquito, these crescents rapidly underwent changes similar to those heretofore described, resulting in the formation of motile filaments, which become detached from the parent body and continue to exhibit active movements. In 1897, Ross ascertained, further, that when blood containing crescents was fed to a particular species of mosquito, living pigmented parasites could be found in the stomach walls of the insect. Continuing his researches with a parasite of the same class which is found in birds, and in which the mosquito also serves as an intermediate host, Ross found that this parasite enters the stomach wall of the insect, and, as a result of its development in that locality, forms reproductive bodies (sporozoites), which subsequently find their way to the veneno-salivary glands of the insect which is now capable of infecting other birds of the same species as that from which the blood was obtained in the first instance. Ross further showed that the mosquito which served as an intermediate host for this parasite could not transmit the malarial parasite of man or another similar parasite of birds (halteridium). These discoveries of Ross have been confirmed by Grassi, Koch and others, and it has been shown that the mosquitoes which serve as intermediate host for the malarial parasites of man belong to the genus Anopheles and especially to the species known as Anopheles claviger.
The question whether mosquitoes infected with the malarial parasite invariably become infected as a result of the ingestion of human blood containing this parasite has not been settled in a definite manner, but certain facts indicate that this is not the case. Thus there are localities noted for being extremely dangerous on account of the malarial fevers contracted by those who visit them, which on this very account are rarely visited by man. Yet there must be a great abundance of infected mosquitoes in these localities, and especially in low, swampy regions in the tropics. If man and the mosquitoes are alone concerned in the propagation of this parasite, how shall we account for the abundance of infected mosquitoes in uninhabited marshes? It appears probable that some other vertebrate animal serves in place of man to maintain the life cycle of the parasite, or that it may be propagated through successive generations of mosquitoes.
It is well known that persons engaged in digging canals, railroad cuts, etc., in malarious regions are especially liable to be attacked with one or the other of the forms of malarial fever. This may be due to the fact that the digging operations result in the formation of little pools suitable for the development of the eggs of Anopheles, but another explanation has been offered. Ross and others have found in infected mosquitoes certain bodies, described by Ross as 'black spores/ which resist decomposition and which may be resting spores capable of retaining their vitality for a long time. The suggestion is that these 'black spores' or other encysted reproductive bodies may have been deposited in the soil by mosquitoes long since defunct 'and that in moving the soil these dormant parasites are set at liberty and so in air, in water or otherwise, gain access to the workmen engaged' (Manson). This hypothesis is not supported by recent observations, which indicate that infection in man occurs only as a result of inoculation through the bite of an infected mosquito. The question is whether malarial fevers can be contracted in marshy localities independently of the mosquito, which has been demonstrated to be an intermediate host of the malarial parasite? Is this parasite present in the air or water in such localities as well as in the bodies of infected mosquitoes? Its presence has never been demonstrated by the microscope; but this fact has little value in view of the great variety of micro-organisms present in marsh water or suspended in the air everywhere near the surface of the ground, and the difficulty of recognizing the elementary reproductive bodies by which the various species are maintained through successive generations. It would appear that a crucial experiment for the determination of this question would be to expose healthy individuals in a malarious region and to exclude the mosquito by some appropriate means. This experiment has been made during the past summer and the result, up to the present time, has been reported by Manson in the London 'Lancet' of September 29. Five healthy individuals have lived in a hut on the Roman Campagna since early in the month of July. They have been protected against mosquito bites by mosquito-netting screens in the doors and windows and by mosquito bars over the beds. They go about freely during the daytime, but remain in their protected hut from sunset to sunrise. At the time Manson made his report all these individuals remained in perfect health. It has long been known that laborers could come from the villages in the mountainous regions near the Roman Campagna and work during the day, returning to their homes at night, without great danger of contracting the fever, while those who remained on the Campagna at night ran great risk of falling sick with fever, as a result of 'exposure to the night air.' What has already been said makes it appear extremely probable that the 'night air,' per se, is no more dangerous than the day air, but that the real danger consists in the presence of infected mosquitoes of a species which seeks its food at night. As pointed out by King, in his paper already referred to, it has repeatedly been claimed by travelers in malarious regions that sleeping under a mosquito bar is an effectual method of prophylaxis against intermittent fevers.
That malarial fevers may be transmitted by mosquitoes of the genus Anopheles was first demonstrated by the Italian physician Bignami, whose experiments were made in the Santo Spirito Hospital in Home. The subjects of the experiment, with their full consent, were placed in a suitable room and exposed to the bites of mosquitoes brought from Maccarese, 'a, marshy place with an evil but deserved reputation for the intensity of its fevers.' It has been objected to these experiments that they were made in Rome, at a season of the year when malarial fevers prevail to a greater or less extent in that city, but Marchiafava and Bignami say:
In view of the objection made, a crucial experiment has recently been made in the city of London. The result is reported by Manson, as follows:
We have still to consider the question of the transmission of malarial fevers by the ingestion of water from malarious localities. Numerous medical authors have recorded facts which they deemed convincing as showing that malarial fevers may be contracted in this way. I have long been of the opinion that while the observed facts may, for the most part, be authentic, the inference is based upon a mistake in diagnosis. That, in truth, the fevers which can justly be ascribed to the ingestion of a contaminated water supply are not true malarial fevers—i. e., they are not due to the presence of the malarial parasite in the blood. This view was sustained by me in my work on 'Malaria and Malarial Diseases,' published in 1883. The fevers supposed to have been contracted in this way are, as a rule, continued or remittent in character and they are known under a variety of names. Thus we have 'Roman fever' 'Naples fever' 'Remittent fever' 'Mountain fever' 'Typho-malarial fever' etc. The leading physicians and pathologists, in regions where these fevers prevail, are now convinced that they are not malarial fevers, but are simply more or less typical varieties of typhoid fever—a disease due to a specific bacillus and which is commonly contracted as a result of the ingestion of contaminated water or food. The error in diagnosis, upon which the inference has been based that malarial fevers may be contracted through drinking water, has been widespread, in this country, in Europe and in the British possessions in India. It vitiated our medical statistics of the Civil War and of the recent war with Spain. In my work already referred to, I say:
I have already mentioned the fact that Marchiafava denies that malarial fevers prevail in the city of Rome, yet every one knows how frequently travelers contract the so-called 'Roman fever' as a result of a temporary residence in that city. In our own cities numerous cases of so-called 'remittent' or 'typho-malarial' fevers are reported in localities where typical malarial fevers (intermittents) are unknown, and at seasons of the year when these fevers do not prevail even in the marshy regions where they are of annual occurrence—during the mosquito season. Malarial fevers may, of course, occur in cities as a result of exposure elsewhere to the bites of infected mosquitoes of the genus Anopheles, either as primary attacks or as a relapse, or in urban localities in the vicinity of marshy places or pools of water suitable as breeding places for Anopheles. But when a previously healthy individual, living in a well-paved city, in a locality remote from all swampy places is taken sick with a 'remittent fever,' and especially when the attack occurs during the winter months, it is pretty safe to say that he is not suffering from malarial infection, and the chances are greatly in favor of the view that he has typhoid fever. It must be remembered that a remittent or intermittent course is not peculiar to malarial fevers. Typhoid commonly presents a more or less remittent character, especially at the outset of an attack; the hectic fever of tuberculosis is intermittent in character. The formation of an abscess, an attack of tonsilitis, etc., are usually attended by chills and fever, which may recur at more or less regular intervals. Indeed, in certain cases of pyæmia the febrile phenomena are so similar to those of a malarial attack that a mistake in diagnosis is no unusual occurrence. Finally, I may say that it is the fashion with many persons and with some physicians to ascribe a variety of symptoms, due to various causes, to 'malaria' and to prescribe quinine as a general panacea. Thus a gentleman who has been at the club until one or two o'clock at night and has smoked half a dozen cigars—not to mention beer and cheese sandwiches as possible factors—reports to his doctor the next morning with a dull headache, a furred tongue and a loss of appetite which he is unable to account for except upon the supposition that he has 'malaria' Again the symptoms arising from indigestion, from crowd-poisoning, from sewer-gas-poisoning, from ptomaine-poisoning (auto-infection), etc., are often ascribed to 'malaria' and quinine is prescribed, frequently with more or less benefit, for the usefulness of this drug is not limited to its specific action in the destruction of the malarial parasite.
As stated at the outset, it is evident, in the present state of our knowledge, that the term 'malaria' is a misnomer, either as applied to the cause of the periodic fevers or as used to designate this class of fevers. It would be more logical to use the name plasmodium fever and to speak of a plasmodium intermittent or remittent, rather than of a malarial intermittent. But it will, no doubt, be difficult to displace a term which has been so long in use, which up to the present time has had the sanction of the medical profession, and which expresses the popular idea as to the origin of that class of fevers which we now know to be due to a blood-parasite, introduced through the agency of mosquitoes of the genus Anopheles.
- Annual address of the president of the Philosophical Society of Washington. Delivered under the auspices of the Washington Academy of Sciences, on December 8, 1900.
- Quoted from an editorial in the 'New York Medical Journal' of October 20, 1900.