The traumatic[2] theory. There is much in favor of this. In a certain number of cases tumors do develop at the site of injuries. The coincidence of injury and tumor is apt to be overestimated because of the strong tendency to connect succeeding events. Tumors are not most common on those parts of the body which are most exposed to injury. They are rare, for instance, on the hands and feet, and very rarely do they appear at the site of wounds caused by surgical operations. For those tumors which develop in intra-uterine life it is difficult to assign injury as a cause. There does, however, seem to be a relation between tumors and injuries of a certain character. The natives of Cashmere use in winter for purposes of heat a small charcoal stove which they bind on the front of the body; burns often result and tumors not infrequently develop at the site of such burns. Injuries of tissue which are produced by the X-ray not infrequently result in tumor formation and years may elapse between the receipt of the injury and the development of the tumor. These X-ray injuries are of a peculiar character, their nature but imperfectly understood, and the injured tissues seem to have lost the capacity for perfect repair.

In regard to the possible action of both injuries and parasites in causing tumors, the possibility that their effects on different individuals may not be the same must be considered. In addition to the trauma or the parasite which may be considered as extrinsic factors, there may be conditions of the body, intrinsic factors, which favor their action in tumor development. The peculiar tissue growth within the uterus called decidua, which occurs normally in pregnancy and serves to fasten the developing ovum to the inner lining of the uterus, may be produced experimentally. This growth depends upon two factors, an internal secretion derived from the ovary and the introduction into the uterus of a foreign body of some sort; in the case of pregnancy the developing embryo acts as the foreign body. It is not impossible that some variation in the complex relations which determine normal growth may be one factor, possibly the most important, in tumor formation.

Another theory is that the tumor is the result of imperfect embryonic development. The development of the child from the ovum is the result of a continued formation and differentiation of cells. A cell mass is first produced, and the cells in this differentiate into three layers called ectoderm, entoderm and mesoderm, from which the external and internal surfaces and the enclosed tissues respectively develop, and the different organs are produced by growth of the cells of certain areas of these layers. The embryonic theory assumes that in the course of embryonic development not all the cell material destined for the formation of individual organs is used up for this purpose, that certain of the embryonic cells become enclosed in the developing organs, they retain the embryonic capacity for growth and tumors arise from them. There is no doubt that something like this does take place. There is a relation between malformations due to imperfect development of the embryo and tumors, the two conditions occurring together too frequently to be regarded as mere coincidence. Also tumors may occur in parts of the body in which there is no tissue capable of forming structures which may be present in the tumors. The theory, however, is not adequate, but it may be among the factors.

The problems concerned in the nature and cause of tumors are the most important in medicine at the present time. No other form of disease causes a similar amount of suffering and anxiety, which often extends over years and makes a terrible drain on the sympathy and resources of the family. The only efficient treatment for tumors at the present time is removal by surgical operation, and the success of the operation is in direct ratio to the age of the tumor, the time which elapses from its beginning development. It is of the utmost importance that this should be generally recognized, and the facts relating to tumors become general knowledge. Tumors form one of the most common causes of death (after the age of thirty-five one in every ten individuals dies of tumor); medical and surgical resources are, in many cases, powerless to afford relief and the tumor stands as a bar to the attainment of the utopia represented by a happy and comfortable old age, and a quiet passing. Every possible resource should be placed at the disposal of the scientific investigation of the subject, for with knowledge will come power to relieve.

FOOTNOTES: [1] By cachexia is understood a condition of malnutrition and emaciation which is usually accompanied by a pale sallow color of the skin.

[2] By trauma is understood a wound or injury of any sort.



CHAPTER IV

THE REACTIONS OF THE TISSUES OF THE BODY TO INJURIES.—INFLAMMATION.— THE CHANGES IN THE BLOOD IN THIS.—THE EMIGRATION OF THE CORPUSCLES OF THE BLOOD.—THE EVIDENT CHANGES IN THE INJURED PART AND THE MANNER IN WHICH THESE ARE PRODUCED.—HEAT, REDNESS, SWELLING AND PAIN.—THE PRODUCTION OF BLISTERS BY SUNBURN.—THE CHANGES IN THE CELLS OF AN INJURED PART.—THE CELLS WHICH MIGRATE FROM THE BLOOD-VESSELS ACT AS PHAGOCYTES.—THE MACROPHAGES.—THE MICROPHAGES.—CHEMOTROPISM.—THE HEALING OF INFLAMMATION.—THE REMOVAL OF THE CAUSE.—CELL REPAIR AND NEW FORMATION.—NEW FORMATION OF BLOOD-VESSELS.—ACUTE AND CHRONIC INFLAMMATION.—THE APPARENTLY PURPOSEFUL CHARACTER OF THE CHANGES IN INFLAMMATION.

Injury and repair have already been briefly considered in their relation to the normal body and to old age; there are, however, certain phenomena included under the term inflammation which follow the more extensive injuries and demand a closer consideration than was given in Chapter II. These phenomena differ in degree and character; they are affected by the nature of the injurious agent and the intensity of its action, by the character of the tissue which is affected and by variations in individual resistance to injury. A blow which would have no effect upon the general surface of the body may produce serious results if it fall upon the eye, and less serious results for a robust than for a weak individual.

Most of the changes which take place after an injury and their sequence can be followed under the microscope. If the thin membrane between the toes of a living frog be placed under the microscope the blood vessels and the circulating blood can be distinctly seen in the thin tissue between the transparent surfaces. The arteries, the capillaries and veins can be distinguished, the arteries by the changing rapidity of the blood stream within them, there being a quickening of the flow corresponding with each contraction of the heart; the veins appear as large vessels in which the blood flows regularly (Fig. 11). Between the veins and arteries is a large number of capillaries with thin transparent walls and a diameter no greater than that of the single blood corpuscles; they receive the blood from the arteries and the flow in them is continuous. The white and red blood corpuscles can be distinguished, the red appearing as oval discs and the white as colorless spheres. In the arteries and veins the red corpuscles remain in the centre of the vessels appearing as a rapidly moving red core, and between this core and the wall of the vessels is a layer of clear fluid in which the white corpuscles move more slowly, often turning over and over as a ball rolls along the table.

If, now, the web be injured by pricking it or placing some irritating substance upon it, a change takes place in the circulation. The arteries and the veins become dilated and the flow of blood more rapid, so rapid, indeed, that it is difficult to distinguish the single corpuscles. In a short while the rapidity of flow in the dilated vessels diminishes, becoming slower than the normal, and the separation between the red and white corpuscles is not so evident. In the slowly moving stream the white corpuscles move much more slowly than do the red, and hence accumulate in the vessels lining the inner surface and later become attached to this and cease to move forward. The attached corpuscles then begin to move as does an amoeba, sending out projections, some one of which penetrates the wall, and following this the corpuscles creep through. Red corpuscles also pass out of the vessels, this taking place in the capillaries; the white corpuscles, on the other hand, pass through the small veins. Not only do the white corpuscles pass through the vessels, but the blood fluid also passes out. The corpuscles which have passed into the tissue around the vessels are carried away by the outstreaming fluid, and the web becomes swollen from the increased amount of fluid which it contains. The injured area of the web is more sensitive than a corresponding uninjured area and the foot is more quickly moved if it be touched. If the injury has been very slight, observation of the area on the following day will show no change beyond a slight dilatation of the vessels and a great accumulation of cells in the tissue.

Everyone has experienced the effect of such changes as have been described in this simple experiment. An inflamed part on the surface of the body is redder than the normal, swollen, hot and painful. The usual red tinge of the skin is due to the red blood contained in the vessels, and the color is intensified when, owing to the dilatation, the vessels contain more blood. The inflamed area feels hot, and if the temperature be taken it may be two or three degrees warmer than a corresponding area. The increased heat is due to the richer circulation. Heat is produced in the interior of the body chiefly in the muscles and great glands, and the increased afflux of blood brings more heat to the surface. A certain degree of swelling of the tissue is due to the dilatation of the vessels; but this is a negligible factor as compared with the effect of the presence of the fluid and cells of the exudate.[1] The fluid distends the tissue spaces, and it may pass from the tissue and accumulate on surfaces or in the large cavities within the body. The greatly increased discharge from the nose in a "cold in the head" is due to the exudation formed in the acutely inflamed tissue, and which readily passes through the thin epithelial covering. Various degrees of inflammation of the skin may be produced by the action of the sun, the injury being due not to the heat but to the actinic rays. In a mild degree of exposure only redness and a strong sense of heat are produced, but in prolonged exposure an exudate is formed which causes the skin to swell and blisters to form, these being due to the exudate which passes through the lower layers of the cells of the epidermis and collects beneath the impervious upper layer, detaching this from its connections. If a small wad of cotton, soaked in strong ammonia, be placed on the skin and covered with a thimble and removed after two minutes, minute blisters of exudate slowly form at the spot.

The pain in an inflamed part is due to a number of factors, but chiefly to the increased pressure upon the sensory nerves caused by the exudate. The pain varies so greatly in degree and character that parts which ordinarily have little sensation may become exquisitely painful when inflamed. The pain is usually greater when the affected part is dense and unyielding, as the membranes around bones and teeth. The pain is often intermittent, there being acute paroxysms synchronous with the pulse, this being due to momentary increase of pressure when more blood is forced into the part at each contraction of the heart. The pain may also be due to the direct action of an injurious substance upon the sensory nerves, as in the case of the sting of an insect where the pain is immediate and most intense before the exudate has begun to appear.

When an inflamed area is examined, after twenty-four hours, by hardening the tissue in some of the fluids used for this purpose and cutting it into very thin slices by means of an instrument called a microtome, the microscope shows a series of changes which were not apparent on naked eye examination. The texture is looser, due to the exudate which has dilated all the spaces in the tissue. Red and white corpuscles in varying numbers and proportions infiltrate the tissue; all the cells which belong to the part, even those forming the walls of the vessels, are swollen, the nuclei contain more chromatin, and the changes in the nuclei which indicate that the cells are multiplying appear. The blood vessels are dilated, and the part in every way gives the indication of a more active life within it. There are also evidences of the tissue injury which has called forth all the changes which we have considered. (Fig. 15.)



The microscopic examination of any normal tissue of the body shows within it a variable number of cells which have no intimate association with the structure of the part and do not seem to participate in its function. They are found in situations which indicate that these cells have power of active independent motion. In the inflamed tissue a greatly increased number of these cells is found, but they do not appear until the height of the process has passed, usually not before thirty-six or forty-eight hours after the injury has been received. The numbers present depend much upon the character of the agent which has produced the injury, and they may be more numerous than the ordinary leucocytes which migrate from the blood vessels.

All these changes which an injured part undergoes are found when closely analyzed to be purposeful; that is, they are in accord with the conditions under which the living matter acts, and they seem to facilitate the operation of these conditions. It has been said that the life of the organism depends upon the cooerdinated activity of the living units or cells of which it is composed. The cells receive from the blood material for the purpose of function, for cell repair and renewal, and the products of waste must be removed. In the injury which has been produced in the tissue all the cells have suffered, some possibly displaced from their connections, others may have been completely destroyed, others have sustained varying degrees of injury. If the injury be of an infectious character, that is, produced by bacteria, these may be present in the part and continue to exert injury by the poisonous substances which they produce, or if the injury has been produced by the action of some other sort of poison, this may be present in concentrated form, or the injury may have been the result of the presence of a foreign body in the part. Under these conditions, since the usual activities of the cells in the injured part will not suffice to restore the integrity of the tissue, repair and cell formation must be more active than usual, any injurious substances must be removed or such changes must take place in the tissue that the cell life adapts itself to new conditions.



All life in the tissues depends upon the circulation of the blood. There is definite relation between the activity of cells and the blood supply; a part, for instance, which is in active function receives a greater supply of blood by means of dilatation of the arteries which supply it. If the body be exactly balanced longitudinally on a platform, reading or any exercise of the brain causes the head end to sink owing to the relatively greater amount of blood which the brain receives when in active function. The regulation of the blood supply is effected by means of nerves which act upon the muscular walls of the arteries causing, by the contraction or the relaxation of the muscle, diminution or dilatation of the calibre of the vessel. After injury the dilatation of the vessels with the greater afflux of blood to the part is the effect of the greatly increased cell activity, and is a necessity for this. In many forms of disease it has been found that by increasing the blood flow to a part and producing an active circulation in it, that recovery more readily takes place and many of the procedures which have been found useful in inflammation, such as hot applications, act by increasing the blood flow. So intimate is the association between cell activity, as shown in repair and new formation of cells, and the blood flow, that new blood vessels frequently develop by means of which the capacity for nutrition is still more increased. The cornea or transparent part of the eye contains no blood vessels, the cells which it contains being nourished by the tissue fluid which comes from the outside and circulates in small communicating spaces. If the centre of the cornea be injured, the cells of the blood vessels in the tissue around the cornea multiply and form new vessels which grow into the cornea and appear as a pink fringe around the periphery; when repair has taken place the newly formed vessels disappear.

The exudate from the blood vessels in various ways assists in repair. An injurious substance in the tissue may be so diluted by the fluid that its action is minimized. A small crystal of salt is irritating to the eye, but a much greater amount of the same substance in dilute solution causes no irritation. The poisonous substances produced by bacteria are diluted and washed away from the part by the exudate. Not only is there a greater amount of tissue fluid in the inflamed part, but the circulation of this is also increased, as is shown by comparing the outflow in the lymphatic vessels with the normal. The fluid exudate which has come from the blood and differs but slightly from the blood fluid exerts not only the purely physical action of removing and diluting injurious substances, but in many cases has a remarkable power, exercised particularly on bacterial poisons, of neutralizing poisons or so changing their character that they cease to be injurious.

We have learned, chiefly from the work of Metschnikoff, that those white corpuscles or leucocytes which migrate from the vessels in the greatest numbers have marked phagocytic properties, that is, they can devour other living things and thus destroy them just as do the amoebae. In inflammations produced by bacteria there is a very active migration of these cells from the vessels; they accumulate in the tissue and devour the bacteria. They may be present in such masses as to form a dense wall around the bacteria, thus acting as a physical bar to their further extension. The other form of amoeboid cell, which Metschnikoff calls the macrophage, has more feeble phagocytic action towards bacteria, and these are rarely found enclosed within them. It is chiefly by means of their activity that other sorts of substances are removed. They often contain dead cells or cell fragments, and when haemorrhage takes place in a tissue they enclose and remove the granules of blood pigment which result. They often join together, forming connected masses, and surround such a foreign body as a hair, or a thread which the surgeon places in a wound to close it. They may destroy living cells, and do this seemingly when certain cells are in too great numbers and superfluous in a part, their action tending to restore the cell equilibrium. The foreign cells do even more than this: they themselves may be devoured by the growing cells of the tissue, seemingly being actuated by the same supreme idea of sacrifice which led Buddha to give himself to the tigress.

The explanation of most of the changes which take place in inflammation is obvious. It is a definite property of all living things that repair takes place after injury, and certain of the changes are only an accentuation of those which take place in the usual life; but others, such as the formation of the exudate, are unusual; not only is the outpouring of fluid greatly increased, but its character is changed. In the normal transudation[2] the substances on which the coagulation of the blood depends pass through the vessel wall to a very slight extent, but the exudate may contain the coagulable material in such amounts that it easily clots. The interchange between the fluid outside the vessels and the blood fluid takes place by means of filtration and osmosis. There is a greater pressure in the vessels than in the fluid outside of them, and the fluid filters through the wall as fluid filters through a thin membrane outside of the body. Osmosis takes place when two fluids of different osmotic pressure are separated by animal membrane. Difference in osmotic pressure is due to differences in molecular concentration, the greater the number of molecules the greater is the pressure, and the greater rapidity of flow is from the fluid of less pressure to the fluid of greater pressure. The molecular concentration of tissue and blood fluid is constantly being equalized by the process of osmosis. In the injured tissue the conditions are more favorable for the fluid of the blood to pass from the vessels: by filtration, because owing to the dilatation of the arteries there is increased amount of blood and greater pressure within the vessels, and the filtering membrane is also thinner because the same amount of membrane (here the wall of the vessel) must cover the larger surface produced by the dilatation. It is, moreover, very generally believed that there are minute openings in the walls of the capillaries, and these would become larger in the dilated vessel just as openings in a sheet of rubber become larger when this is stretched. Osmosis towards the tissue is favored because, owing to destructive processes the molecular pressure in the injured area is increased; an injured tissue has been shown to take up fluid more readily outside of the body than a corresponding uninjured tissue. The slowing of the blood stream, in spite of the dilatation of the vessels, is due to the greater friction of the suspended corpuscles on the walls of the vessels. This is due to the loss from the blood of the outstreaming fluid and the relative increase in the number of corpuscles, added to by the unevenness of surface which the attached corpuscles produce.

The wonderful migration of the leucocytes, which seems to show a conscious protective action on their part, takes place under the action of conditions which influence the movement of cells. When an actively moving amoeba is observed it is seen that the motion is not the result of chance, for it is influenced by conditions external to the organism; certain substances are found to attract the amoebae towards them and other substances to repel them. These influences or forces affecting the movements of organisms are known as tropisms, and play a large part in nature; the attraction of various organisms towards a source of light is known as heliotropism, and there are many other instances of such attraction. The leucocytes as free moving cells also come under the influence of such tropisms. When a small capillary tube having one end sealed is partially filled with the bacteria which produce abscess and placed beneath the skin it quickly becomes filled with leucocytes, these being attracted by the bacteria it contains. Dead cells exert a similar attraction for the large phagocytes. Such attraction is called chemotropism and is supposed to be due in the cases mentioned, to the action of chemical substances such as are given off by the bacteria or the dead cells. The direction of motion is due to stimulation of that part of the body of the leucocyte which is towards the source of the stimulus. The presence in the injured part of bacteria or of injured and dead cells exerts an attraction for the leucocytes within the vessels causing their migration. When the centre of the cornea is injured, this tissue having no vessels, all the vascular phenomena take place in the white part of the eye immediately around the cornea, this becoming red and congested. The migration of leucocytes from the vessels takes place chiefly on the side towards the cornea, and the migrated cells make their way along the devious tracts of the communicating lymph spaces to the area of injury. The objection may be raised that it is difficult to think of a chemical substance produced in an injured area no larger than a millimeter, diffusing through the cornea and reaching the vessels outside this in such quantity and concentration as to affect their contents, nor has there been any evidence presented that definite chemical substances are produced in injured tissues; but there is no difficulty in view of the possibilities. It is not necessary to assume that an actual substance so diffuses itself, but the influence exerted may be thought of as a force, possibly some form of molecular motion, which is set in action at the area of injury and extends from this. No actual substance passes along a nerve when it conveys an impulse.

We have left the injured area with an increased amount of fluid and cells within it, with the blood vessels dilated and with both cells and fluid streaming through their walls, and the cells belonging to the area actively repairing damages and multiplying. The process will continue as long as the cause which produces the injury continues to act, and will gradually cease with the discontinuance of this action, and this may be brought about in various ways. A foreign body may be mechanically removed, as when a thorn is plucked out; or bacteria may be destroyed by the leucocytes; or a poison, such as the sting of an insect, may be diluted by the exudate until it be no longer injurious, or it may be neutralized. Even without the removal of the cause the power of adaptation will enable the life of the affected part to go on, less perfectly perhaps, in the new environment. The excess of fluid is removed by the outflow exceeding the inflow, or it may pass to some one of the surfaces of the body, or in other cases an incision favors its escape. The excess of cells is in part removed with the fluid, in part they disappear by undergoing solution and in part they are devoured by other cells. With the diminishing cell activity the blood vessels resume their usual calibre, and when the newly formed vessels become redundant they disappear by undergoing atrophy in the same way as other tissues which have become useless.

When these changes take place rapidly the inflammation is said to be acute, and chronic when they take place slowly. Chronic inflammation is more complex than is the acute, and there is more variation in the single conditions. The chronicity may be due to a number of conditions, as the persistence of a cause, or to incompleteness of repair which renders the part once affected more vulnerable, to such a degree even that the ordinary conditions to which it is subjected become injurious. A chronic inflammation may be little more than an almost continuous series of acute inflammations, with repair continuously less perfect. Chronic imflammations are a prerogative of the old as compared with the young, of the weak rather than the strong.

FOOTNOTES: [1] The term exudation is used to designate the passing of cells and fluid from the vessels in inflammation; the material is the exudate.

[2] By transudation is meant the constant interchange between the blood and the tissue fluid.



CHAPTER V

INFECTIOUS DISEASES.—THE HISTORICAL IMPORTANCE OF EPIDEMICS OF DISEASE.—THE LOSSES IN BATTLE CONTRASTED WITH THE LOSSES IN ARMIES PRODUCED BY—INFECTIOUS DISEASES.—THE DEVELOPMENT OF KNOWLEDGE OF EPIDEMICS.—THE VIEWS OF HIPPOCRATES AND ARISTOTLE.—SPORADIC AND EPIDEMIC DISEASES.—THE THEORY OF THE EPIDEMIC CONSTITUTION.—THEORY THAT THE CONTAGIOUS MATERIAL IS LIVING.—THE DISCOVERY OF BACTERIA BY LOEWENHOECK IN 1675.—THE RELATION OF CONTAGION TO THE THEORY OF SPONTANEOUS GENERATION.—NEEDHAM AND SPALLANZANI.—THE DISCOVERY OF THE COMPOUND MICROSCOPE IN 1605.—THE PROOF THAT A LIVING ORGANISM IS THE CAUSE OF A DISEASE.—ANTHRAX.—THE DISCOVERY OF THE ANTHRAX BACILLUS IN 1851.—THE CULTIVATION OF THE BACILLUS BY KOCH.—THE MODE OF INFECTION.—THE WORK OF PASTEUR ON ANTHRAX.—THE IMPORTANCE OF THE DISEASE.

These are diseases which are caused by living things which enter the tissues of the body and, living at the expense of the body, produce injury. Such diseases play an important part in the life of man; the majority of deaths are caused directly or indirectly by infection. No other diseases have been so much studied, and in no other department of science has knowledge been capable of such direct application in promoting the health, the efficiency and the happiness of man. This knowledge has added years to the average length of life, it has rendered possible such great engineering works as the Panama Canal, and has contributed to the food supply by making habitation possible over large and productive regions of the earth, formerly uninhabitable owing to the prevalence of disease. It is not too much to say that our modern civilization is dependent upon this knowledge. The massing of the people in large cities, the factory life, the much greater social life, which are all prominent features of modern civilization, would be difficult or impossible without control of the infectious diseases. The rapidity of communication and the increased general movement of people, which have developed in equal ratio with the massing, would serve to extend widely every local outbreak of infection. The principles underlying fermentation and putrefaction which have been applied with great economic advantage to the preservation of food were many of them developed in the course of the study of the infectious diseases. Whether the development of the present civilization is for the ultimate advantage of man may perhaps be disputed, but medicine has made it possible.

The infectious diseases appearing in the form of great epidemics have been important factors in determining historical events, for they have led to the defeat of armies, the fall of cities and of nations. War is properly regarded as one of the greatest evils that can afflict a nation, since it destroys men in the bloom of youth, at the age of greatest service, and brings sorrow and care and poverty to many. But the most potent factor in the losses of war is not the deaths in battle but the deaths from disease. If we designate the lives lost in battle, the killed and the wounded who die, as 1, the loss of the German army from disease in 1870-71 was 1.5, that of the Russians in 1877-78 was 2.7, that of the French in Mexico was 2.8, that of the French in the Crimea 3.7, that of the English in Egypt 4.2. The total loss of the German army in 1870-71 from wounds and disease was 43,182 officers and men, and this seems a small number compared with the 129,128 deaths from smallpox in the same period in Prussia alone. In the Spanish American war there were 20,178 cases of typhoid fever with 1,580 deaths. In the South African war there were in the British troops 31,118 cases of typhoid with 5,877 deaths, and 5,149 deaths from other diseases while the loss in battle was 7,582. The Athenian plague which prevailed during the Peloponnesian war, 431-405 B.C., not only caused the death of Pericles, but according to Thucydides a loss of 4,800 Athenian soldiers, and brought about the downfall of the Athenian hegemony in Greece. In the Crimean war between 1853-56, 16,000 English, 80,000 French and 800,000 Russians died of typhus fever. The plague contributed as much as did the arms of the Turks to the downfall of Constantinople and the Eastern Empire in 1453. It was the plague which in 1348 overthrew Siena from her proud position as one of the first of the Italian cities and the rival of Florence, and broke the city forever, leaving it as a phantom of its former glory and prosperity. The work on the great cathedral which had progressed for ten years was suspended, and when it was resumed it was upon a scale adjusted to the diminished wealth of the city, and the plan restricted to the present dimensions. As a little relief to the darkness the same plague saw the birth of the novel in the tales of Boccaccio, which were related to a delighted audience of the women who had fled from the plague in Florence to a rural retreat.

The knowledge which has come from the study of infectious disease has served also to broaden our conception of disease and has created preventive medicine; it has linked more closely to medicine such sciences as zooelogy and botany; it has given birth to the sciences of bacteriology and protozooelogy and in a way has brought all sciences more closely together. Above all it has made medicine scientific, and never has knowledge obtained been more quickening and stimulating to its pursuit.

Although the dimensions of this book forbid much reference to the historical development of a subject, some mention must still be made of the development of knowledge of the infectious diseases. It was early recognized that there were diseases which differed in character from those generally prevalent; large numbers of people were affected in the same way; the disease beginning with a few cases gradually increased in intensity until an acme was reached which prevailed for a time and the disease gradually disappeared. Such diseases were attributed to changes in the air, to the influence of planets or to the action of offended gods. The priests and charlatans who sought to excuse their inability to treat epidemics successfully were quick to affirm supernatural causes. Hippocrates (400 B.C.), with whom medicine may be said to begin, thought such diseases, even then called epidemics, were caused by the air; he says, "When many individuals are attacked by a disease at the same time, the cause must be sought in some agent which is common to all, something which everyone uses, and that is the air which must contain at this time something injurious." Aristotle recognized that disease was often conveyed by contact, and Varro (116-27 B.C.) advanced the idea that disease might be caused by minute organisms. He says, "Certain minute organisms develop which the eye cannot see, and which being disseminated in the air enter into the body by means of the mouth and nostrils and give rise to serious ailments." In spite of this hypothesis, which has proved to be correct, the belief became general that epidemics were due to putrefaction of the air brought about by decaying animal bodies, (this explaining the frequent association of epidemics and wars,) by emanations from swamps, by periods of unusual heat, etc.

With the continued study of epidemics the importance of contagion was recognized; it was found that epidemics differed in character and in the modes of extension. Some seemed to extend by contact with the sick, and in others this seemed to play no part; it was further found impossible in many cases to show evidence of air contamination, and contamination of the air by putrefactive material did not always produce disease. Most important was the recognition that single cases of diseases which often occurred in epidemic form might be present and no further extension follow; this led to the assumption in epidemics of the existence of some condition in addition to the cause, and which made the cause operative. In this way arose the theory of the epidemic constitution, a supposed peculiar condition of the body due to changes in the character of the air, or to the climate, or to changes in the interior of the earth as shown by earthquakes, or to the movements of planets; in consequence of this peculiar constitution there was a greater susceptibility to disease, but the direct cause might arise in the interior of the body or enter the body from without. The character of the disease which appeared in epidemic form, the "Genius epidemicus," was determined not by differences in the intrinsic cause, but by the type of constitution which prevailed at that time. The first epidemic of cholera which visited Europe in 1830-37 was for the most part referred to the existence of a peculiar epidemic constitution for which various causes were assigned. It was only when the second epidemic of this disease appeared in 1840 that the existence of some special virus or poison which entered the body was assumed.

Meanwhile, by the study of the material of disease knowledge was being slowly acquired which had much bearing on the causes. The first observations which tended to show that the causes were living were made by a learned Jesuit, Athanasius, in 1659. He found in milk, cheese, vinegar, decayed vegetables, and in the blood and secretions of cases of plague bodies, which he described as tiny worms and which he thought were due to putrefaction. He studied these objects with the simple lenses in use at that time, and there is little doubt that he did see certain of the larger organisms which are present in vinegar, cheese and decaying vegetables, and it is not impossible that he may have seen the animal and vegetable cells.

The first description of bacteria with illustrations showing their forms was given by Loewenhoeck, a linen dealer in Amsterdam in 1675. The fineness of the linen being determined by the number of threads in a given area, it is necessary to examine it with a magnifying lens, and he succeeded in perfecting a simple lens with which objects smaller than had been seen up to that time became visible. It must be added that he was probably endowed with very unusual acuteness of vision. He found in a drop of water, in the fluid in the intestines of frogs and birds, and in his evacuations, objects of great minuteness which differed from each other in form and size and in the peculiar motion which some of them possessed. In the year 1683 he presented to the Royal Society of London a paper describing a certain minute organism which he found in the tartar of his teeth. After these observations of Loewenhoeck became known to the world they quickly found application in disease, although the author had expressed himself very cautiously in this regard. The strongest exponent of the view of a living contagion was Plenciz, 1762, a physician of Vienna, basing his belief not only on the demonstration of minute organisms by Loewenhoeck which he was able to verify, but on certain shrewdly conceived theoretical considerations. He was the first to recognize the specificity of the epidemic diseases, and argued from this that each disease must have a specific cause. "Just as a certain plant comes from the seed of the same plant and not from any plant at will, so each contagious disease must be propagated from a similar disease and cannot be the result of any other disease." Further he says, "It is necessary to assume that during the prevalence of an epidemic the contagious material undergoes an enormous increase, and this is compatible only with the assumption that it is a living substance." But as is so often the case, speculation ran far ahead of the observations on which it is based. There was a long gap between the observations of Loewenhoeck and the theories of Plenciz, justified as these have been by present knowledge. In the spirit of speculation which was dominant in Europe and particularly in Germany in the latter half of the eighteenth and the first half of the nineteenth centuries, hypotheses did not stimulate research, but led to further speculations. As late as 1820 Ozanam expressed himself as follows: "Many authors have written concerning the animal nature of the contagion of disease; many have assumed it to be developed from animal substance, and that it is itself animal and possesses the property of life. I shall not waste time in refuting these absurd hypotheses." The theory of a living contagion was too simple, and not sufficiently related to the problems of the universe to serve the medical philosophers.

Knowledge of the minute organisms was slowly accumulating. The first questions to be determined were as to their nature and origin. How were they produced? Did they come from bodies of the same sort according to the general laws governing the production of living things, or did they arise spontaneously? a question which could not be solved by speculation but by experiment. The first experiments, by Needham, 1745, pointed to the spontaneous origin of the organisms. He enclosed various substances in carefully sealed watch crystals from which the air was excluded, and found that animalculi appeared in the substance, and argued from this that they developed spontaneously. In 1769, Spallanzani, a skilled experimental physiologist, in a brilliant series of experiments showed the imperfect character of Needham's work and the fallacy of his conclusions. Spallanzani placed fluids, which easily became putrid, in glass tubes, which he then hermetically sealed and boiled. He found that the fluid remained clear and unchanged; if, however, he broke the sealed point of such a tube and allowed the air to enter, putrefaction, or in some cases fermentation, of the contents took place. He concluded that boiling the substances destroyed the living germs which they contained, the sealed tubes prevented the air from entering, and when putrefaction or fermentation of the contents took place the organisms to which this was due, being contained in the air, entered from without. Objection was made to the conclusions of Spallanzani that heating the air in the closed tubes so changed its character as to prevent development of organisms in the contents. This objection was finally set aside by Pasteur, who showed that it was not necessary to seal the end of the tube before boiling, but it could be closed by a plug of cotton wool, which mechanically removed the organisms from the air which entered the tube, or if the tube were bent in the shape of a U and the end left open, organisms from the air could not pass into the tube against gravity when air movement within the tube was prevented by bending. The possibility of spontaneous generation cannot be denied, but that it takes place is against all human experience.

It was not possible to attain any considerable knowledge of the bacteria discovered by Loewenhoeck until more perfect instruments for studying them were devised. Lenses for studying objects were used in remote antiquity, but the compound microscope in which the image made by the lens is further magnified was not discovered until 1605, and when first made was so imperfect that the best simple lenses gave clearer definition. With the betterment of the microscope, increasing the magnifying power and the sharpness of the image of the object seen, it became possible to classify the minute organisms according to size and form and to study the separate species. The microscope has now reached such a degree of perfection that objects smaller than one one hundred thousandth of an inch in diameter can be clearly seen and photographed.

Great impetus was given to the biological investigation of disease by the discoveries which led to the formulation of the cell theory in 1840 and the brilliant work of Pasteur on fermentation,[1] but it was not until 1878 that it was definitely proved that a disease of cattle called anthrax was due to a species of bacteria. What should be regarded as such proof had been formulated by Henle in 1840. To prove that a certain sort of organism when found associated with a disease is the cause of the disease, three things are necessary:

1. The organism must always be found in the diseased animal and associated with the changes produced by the disease.

2. The organism so found must be grown outside of the body in what is termed pure cultures, that is, not associated with any other organisms, and for so long a time with constant transfers or new seedings that there can be no admixture of other products of the disease in the material in which it is grown.

3. The disease must be produced by inoculating a susceptible animal with a small portion of such a culture, and the organism shown in relation to the lesions so produced.

It is worth while to devote some attention to the disease anthrax. This occupies a unique position, in that it was the first of the infectious diseases to be scientifically investigated. In this investigation one fact after another was discovered and confirmed; some of these facts seemed to give clearer conceptions of the disease, others served to make it more obscure; new questions arose with each extension of knowledge; in the course of the work new methods of investigation were discovered; the sides of the arch were slowly and painfully erected by the work of many men, and finally one man placed the keystone and anthrax was for a long time the best known of diseases. Men whose reputation is now worldwide first became known by their work in this disease. It was a favorable disease for investigation, being a disease primarily of cattle, but occasionally appearing in man, and the susceptibility of laboratory animals made possible experimental study.

Anthrax is a disease of domestic cattle affecting particularly bovine cattle, horses and sheep, swine more rarely. The disease exists in practically all countries and has caused great economic losses. There are no characteristic symptoms of the disease; the affected cattle have high fever, refuse to eat, their pulse and respiration are rapid, they become progressively weaker, unable to walk and finally fall. The disease lasts a variable time; in the most acute cases animals may die in less than twenty-four hours, or the disease may last ten or fourteen days; recovery from the disease is rare and treatment has no effect. It does not appear in the form of epidemics, but single cases appear frequently or rarely, and there is seemingly no extension from case to case, animals in adjoining stalls to the sick are not more prone to infection than others of the herd. On examination after death the blood is dark and fluid, the spleen is greatly enlarged (one of the names of the disease "splenic fever" indicates the relation to the spleen) and there is often bloody fluid in the tissues.

Where the disease is prevalent there are numbers of human cases. Only those become infected who come into close relations with cattle, the infection most commonly taking place from small wounds or scratches made in skinning dead cattle or in handling hides. The wool of sheep who die of the disease finds its way into commerce, and those employed in handling the wool have a form of anthrax known as wool-sorters' disease in which lesions are found in the lungs, the organisms being mingled with the wool dust and inspired. In Boston occasional cases of anthrax appear in teamsters who are employed in handling and carrying hides. The disease in man is not so fatal as in cattle, for it remains local for a time at the site of infection, and this local disease can be successfully treated.

The beginning of our knowledge of the cause dates from 1851, when small rod-shaped bodies (Fig. 17) were found in the blood of the affected cattle, and by the work of a number of observers it was established that these bodies were constantly present. Nothing was known of their nature; some held that they were living organisms, others that they were formed in the body as a result of the disease. Next the causal relation of these bodies with the disease was shown and in several ways. The disease could be caused in other cattle by injecting blood containing the rods beneath the skin, certainly no proof, for the blood might have contained in addition to the rods something which was the real cause of the disease. Next it was shown that the blood of the unborn calf of a cow who died of the disease did not contain the rods, and the disease could not be produced by inoculating with the calf's blood although the blood of the mother was infectious. This was a very strong indication that the rods were the cause; the maternal and foetal blood are separated by a membrane through which fluids and substances in solution pass; but insoluble substances, even when very minutely subdivided, do not pass the membrane. If the cause were a poison in solution, the foetal blood would have been as toxic as the maternal. The blood of infected cattle was filtered through filters made of unbaked porcelain and having very fine pores which allowed only the blood fluid to pass, holding back both the blood corpuscles and the rods, and such filtered blood was found to be innocuous. It was further shown that the rods increased enormously in number in the infected animal, for the blood contained them in great numbers when but a fraction of a drop was used for inoculation. Attempts were also made with a greater or less degree of success to grow the rod shaped organisms or bacilli in various fluids, and the characteristic disease was produced by inoculating animals with these cultures; but it remained for Koch, 1878, who was at that time an obscure young country physician, to show the life history of the organism and to clear up the obscurity of the disease. Up to that time, although it had been shown that the rods or bacilli contained in the blood were living organisms and the cause of the disease, this did not explain the mode of infection; how the organisms contained in the blood passed to another animal, why the disease occurred on certain farms and the adjoining farms, particularly if they lay higher, were free. Koch showed that in the cultures the organisms grew out into long interlacing threads, and that in these threads spores which were very difficult to destroy developed at intervals; that the organisms grew easily in bouillon, in milk, in blood, and even in an infusion of hay made by soaking this in water. This explained, what had been an enigma before, how the fields became sources of infection. The infection did not spread from animal to animal by contact, but infection took place from eating grass or hay which contained either the bacilli or their spores. When a dead animal was skinned on the field, the bacilli contained in the blood escaped and became mingled with the various fluids which flowed from the body and in which they grew and developed spores. It was shown by Pasteur that even when a carcass was buried the earthworms brought spores developed in the body to the surface and deposited them in their casts, and in this way also the fields became infected. From such a spot of infected earth the spores could be washed by the rains over greater areas and would find opportunity to develop further and form new spores in puddles of water left on the fields, which became a culture medium by the soaking of the dead grass. The contamination of the fields was also brought about by spreading over them the accumulations of stable manure which contained the discharges of the sick cattle. The tendency of the disease to extend to lower-lying adjacent fields was due to the spores being washed from the upper fields to the lower by the spring freshets. Meanwhile Pasteur had discovered that by growing the organisms at higher temperatures than the animal body, it was possible to attenuate the virulence of the bacilli so that inoculations with these produced a mild form of the disease which rendered the inoculated animals immune to the fatal disease. The description of Pasteur's work on the disease as given in the account of his life by his son-in-law is fascinating.

Hides and wool taken from dead animals invariably contained the spores which could pass unharmed through some of the curing processes, and were responsible for some of the cases in man. Owing to the introduction of regulations which were based on the knowledge of the cause of the disease and the life history of the organism, together with the prophylactic inoculation devised by Pasteur, the incidence of the disease has been very greatly lessened. Looking at the matter from the lowest point of view, the money which has been saved by the control of the disease, as shown in its decline, has been many times the cost of all the work of the investigations which made the control possible. It is a greater satisfaction to know that many human lives have been saved, and that small farmers and shepherds have been the chief sharers in the economic benefits. The indirect benefits, however, which have resulted from the application of the knowledge of this disease, and the methods of investigation developed here, to the study of the infections more peculiar to man, are very much greater.

FOOTNOTE: [1] The interesting analogy between fermentation and infectious disease did not escape attention. A clear fluid containing in solution sugar and other constituents necessary for the life of the yeast cells will remain clear provided all living things within it have been destroyed and those in the air prevented from entering. If it be inoculated with a minute fragment of yeast culture containing a few yeast cells, for a time no change takes place; but gradually the fluid becomes cloudy, bubbles of gas appear in it and its taste changes. Finally it again becomes clear, a sediment forms at the bottom, and on re-inoculating it with yeast culture no fermentation takes place. The analogy is obvious, the fluid in the first instance corresponds with an individual susceptible to the disease, the inoculated yeast to the contagion from a case of transmissible disease, the fermentation to the illness with fever, etc., which constitutes the disease, the returning clearness of the fluid to the recovery, and like the fermenting fluid the individual is not susceptible to a new attack of the disease. It will be observed that during the process both the yeast and the material which produced the disease have enormously increased. Fermentation of immense quantities of fluid could be produced by the sediment of yeast cells at the bottom of the vessel and a single case of smallpox would be capable of infecting multitudes.



CHAPTER VI

CLASSIFICATION OF THE ORGANISMS WHICH CAUSE DISEASE.—BACTERIA: SIZE, SHAPE, STRUCTURE, CAPACITY FOR GROWTH, MULTIPLICATION AND SPORE FORMATION.—THE ARTIFICIAL CULTIVATION OF BACTERIA.—THE IMPORTANCE OF BACTERIA IN NATURE.—VARIATIONS IN BACTERIA.—SAPROPHYTIC AND PARASITIC FORMS.—PROTOZOA.—STRUCTURE MORE COMPLICATED THAN THAT OF BACTERIA.—DISTRIBUTION IN NATURE.—GROWTH AND MULTIPLICATION.— CONJUGATION AND SEXUAL REPRODUCTION.—SPORE FORMATION.—THE NECESSITY FOR A FLUID ENVIRONMENT.—THE FOOD OF PROTOZOA.—PARASITISM.—THE ULTRA-MICROSCOPIC OR FILTERABLE—ORGANISMS.—THE LIMITATION OF THE MICROSCOPE.—PORCELAIN FILTERS TO SEPARATE ORGANISMS FROM A FLUID.— FOOT AND MOUTH DISEASE PRODUCED BY AN ULTRA-MICROSCOPIC ORGANISM.— OTHER DISEASES SO PRODUCED.—DO NEW DISEASES APPEAR?

The living organisms which cause the infectious diseases are classified under bacteria, protozoa, yeasts, moulds, and ultra-microscopic organisms. It is necessary to place in a separate class the organisms whose existence is known, but which are not visible under the highest powers of the microscope, and have not been classified. The yeasts and moulds play a minor part in the production of disease and cannot be considered in the necessary limitation of space.

[Illustration: FIG. 17.—VARIOUS FORMS OF BACTERIA, a, b, c, d, Round bacteria or cocci: (a) Staphylococci, organisms which occur in groups and a common cause of boils; (b) streptococci, organisms which occur in chains and produce erysipelas and more severe forms of inflammation; (c) diplococci, or paired organisms with a capsule, which cause acute pneumonia; (d) gonococci, with the opposed surfaces flattened, which cause gonorrhoea. e, f, g, h, Rod-shaped bacteria or bacilli: (e) diphtheria bacilli; (f) tubercle bacilli; (g) anthrax bacilli; (h) the same bacilli in cultures and producing spores; a small group of spores is shown. (i) Cholera spirillae. (j) Typhoid bacilli. (k) Tetanus bacillus; i, j, k are actively motile, motion being effected by the small attached threads. (l) The screw-shaped spirochite which is the cause of syphilis.]

The bacteria (Fig. 17) are unicellular organisms and vary greatly in size, shape and capacity of growth. The smallest of the pathogenic or disease-producing bacteria is the influenza bacillus, 1/51000 of an inch in length and 1/102000 of an inch in thickness; and among the largest is a bacillus causing an animal disease which is 1/2000 of an inch in length and 1/25000 of an inch in diameter. Among the free-living non-pathogenic forms much larger examples are found. In shape bacteria are round, or rod-shaped, or spiral; the round forms are called micrococci, the rod-shaped bacilli and the spiral forms are called spirilli. A clearer idea of the size is possibly given by the calculation that a drop of water would contain one billion micrococci of the usual size. Their structure in a general way conforms with that of other cells. On the outside is a cell membrane which encloses cytoplasm and nucleus; the latter, however, is not in a single mass, but the nuclear material is distributed through the cell. Many of the bacteria have the power of motion, this being effected by small hair-like appendages or flagellae which may be numerous, projecting from all parts of the organisms or from one or both ends, the movement being produced by rapid lashing of these hairs. A bacterium grows until it attains the size of the species, when it divides by simple cleavage at right angles to the long axis forming two individuals. In some of the spherical forms division takes place alternately in two planes, and not infrequently the single individuals adhere, forming figures of long threads or chains or double forms. The rate of growth varies with the species and with the environment, and under the best conditions may be very rapid. A generation, that is, the interval between divisions, has been seen to take place in twenty minutes. At this rate of growth from a single cholera bacillus sixteen quadrillion might arise in a single day. Such a rate of growth is extremely improbable under either natural or artificial conditions, both from lack of food and from the accumulation in the fluid of waste products which check growth. Many species of bacteria in addition to this simple mode of multiplication form spores which are in a way analogous to the seeds of higher plants and are much more resistant than the simple or vegetative forms; they endure boiling water and even higher degrees of dry heat for a considerable time before they are destroyed. When these spores are placed in conditions favorable for bacterial life, the bacterial cells grow out from them and the usual mode of multiplication continues. This capacity for spore formation is of great importance, and until it was discovered by Cohn in 1876, many of the conditions of disease and putrefaction could not be explained. Spores, as the seeds of plants, often seem to be produced when the conditions are unfavorable; the bacterium then changes into this form, which under natural conditions is almost indestructible and awaits better days.

The bacteria are divided into species, the classification being based on their forms, on the mode of growth, the various substances which they produce and their capacity for producing disease. The differentiation of species in bacteria is based chiefly upon their properties, there being too little difference in form and size to distinguish species. The introduction of methods of culture was followed by an immediate advance of our knowledge concerning them. This method consists in the use of fluid and solid substances which contain the necessary salts and other ingredients for their food, and in or on which they are planted. The use of a solid or gelatinous medium for growth has greatly facilitated the separation of single species from a mixture of bacteria; a culture fluid containing sufficient gelatine to render it solid when cooled is sown with the bacteria to be tested by placing in it while warm and fluid, a small portion of material containing the bacteria, and after being thoroughly mixed the fluid is poured on a glass plate and allowed to cool. The bacteria are in this way separated, and each by its growth forms a single colony which can be further tested. It is self-evident that all culture material must be sterilized by heat before using, and in the manipulations care must be exercised to avoid contamination from the air. The refraction index of the bacterial cell is so slight that the microscopic study is facilitated or made possible by staining them with various aniline dyes. Owing to differences in the cell material the different species of bacteria show differences in the facility with which they take the color and the tenacity with which they retain it, and this also forms a means of species differentiation. The interrelation of science is well shown in this, for it was the discovery of the aniline dyes in the latter half of the nineteenth century which made the fruitful study of bacteria possible.

From the simplicity of structure it is not improbable that the bacteria are among the oldest forms of life, and all life has become adapted to their presence. They are of universal distribution; they play such an important part in the inter-relations of living things that it is probable life could not continue without them, at least not in the present way. They form important food for other unicellular organisms which are important links in the chain; they are the agents of decomposition, by which the complex substances of living things are reduced to elementary substances and made available for use; without them plant life would be impossible, for it is by their instrumentality that material in the soil is so changed as to be available as plant food; by their action many of the important foods of man, often those especially delectable, are produced; they are constantly with us on all the surfaces of the body; masses live on the intestinal surfaces and the excrement is largely composed of bacteria. It has been said that life would be impossible without bacteria, for the accumulation of the carcasses of all animals which have died would so encumber the earth as to prevent its use; but the folly of such speculation is shown by the fact that animals would not have been there without bacteria. It has been shown, however, that the presence of bacteria in the intestine of the higher animals is not essential for life. The coldest parts of the ocean are free from those forms which live in the intestines, and fish and birds inhabiting these regions have been found free from bacteria; it has also been found possible to remove small animals from their mother by Caesarian section and to rear them for a few weeks on sterilized food, showing that digestion and nutrition may go on without bacteria.

Certain species of bacteria are aerobic, that is, they need free oxygen for their growth; others are anaerobic and will not grow in the presence of oxygen. Most of the bacteria which produce disease are facultative, that is, they grow either with or without oxygen; but certain of them, as the bacillus of tetanus, are anaerobic. There is, of course, abundance of oxygen in the blood and tissues, but it is so combined as to be unavailable for the bacteria. Bacteria may further be divided into those which are saprophytic or which find favorable conditions for life outside of the body, and the parasitic. Many are exclusively parasitic or saprophytic, and many are facultative, both conditions of living being possible. It has been found possible by varying in many ways the character of the culture medium and temperature to grow under artificial conditions outside of the body most, if not all, of the bacteria which cause disease. Thus, such bacteria as tubercle bacilli and the influenza bacillus can be cultivated, but they certainly would not find natural conditions which would make saprophytic growth possible.

Bacteria may be very sensitive to the presence of certain substances in the fluid in which they are growing. Growth may be inhibited by the smallest trace of some of the metallic salts, as corrosive sublimate, although the bacteria themselves are not destroyed. If small pieces of gold foil be placed on the surface of prepared jelly on which bacteria have been planted, no growth will take place in the vicinity of the gold foil.

Variations can easily be produced in bacteria, but they do not tend to become established. In certain of the bacterial species there are strains which represent slight variations from the type but which are not sufficient to constitute new species. If the environment in which bacteria are living be unusual and to a greater or less degree unfavorable, those individuals in the mass with the least power of adaptibility will perish, those more resistant and with greater adaptability will survive and propagate; and the peculiarity being transmitted a new strain will arise characterized by this adaptability. Bacteria with slight adaptability to the environment of the tissues and fluids of the animal body can, by repeated inoculations, become so adapted to the new environment as to be in a high degree pathogenic. In such a process the organisms with the least power of adaptation are destroyed and new generations are formed from those of greater power of adaptation. When bacteria are caused to grow in a new environment they may acquire new characteristics. The anthrax bacilli find the optimum conditions for growth at the temperature of the animal body, but they will grow at temperatures both above and below this. Pasteur found that by gradually increasing the temperature they could be grown at one hundred and ten degrees. When grown at this temperature they were no longer so virulent and produced in animals a mild non-fatal form of anthrax which protected the animal when inoculated with the virulent strain. The well known variations in the character of disease, shown in differences in severity and ease of transmission, seen in different years and in different epidemics, may be due to many conditions, but probably variation in the infecting organisms is the most important.

The protozoa, like the bacteria, are unicellular organisms and contain a nucleus as do all cells. They vary in size from forms seen with difficulty under the highest power of the microscope to forms readily seen with the unaided eye. Their structure in general is more complex than is the structure of bacteria, and many show extreme differentiation of parts of the single cells, as a firm exterior surface or cuticle, an internal skeleton, organs of locomotion, mouth and digestive organs and organs of excretion. They are more widely distributed than are the bacteria, and found from pole to pole in all oceans and in all fresh water. There are many modes of multiplication, and these are often extremely complicated. The most general mode and one which is common to all is by simple division; a modification of this is by budding in which projections or buds form on the body and after separation become new organisms. In other cases spores form within the cell which become free and develop further into complete organisms. These simple modes of multiplication often alternate in the same organism with sexual differentiation and conjugation. There is never a permanent sexual differentiation, but the sexual forms develop from a simple and non-sexual organism. Usually the sexual forms develop only in a special environment; thus the protozoon which in man is the cause of malaria, multiplies in the human blood by simple division, but in the body of the mosquito multiplication by sexual differentiation takes place. Under no conditions is multiplication so rapid as with the bacteria, and in general the simpler the form of organism the more rapid is the multiplication. It is common to all of the protozoa to develop forms which have great powers of resistance, this being due in some cases to encystment, in which condition a resistant membrane is formed on the outside, in others to the production of spores. A fluid environment is essential to the life of the protozoa, but the resistant forms can endure long periods of dryness or other unfavorable environmental conditions. The universal distribution of the protozoa is due to this; the spores or cysts can be carried long distances by the wind and develop into active forms when they reach an environment which is favorable. Their distribution in water depends upon the amount of organic material this contains. In pure drinking water there may be very few, but in stagnant water they are very numerous, living not on the organic material in solution in this, but on the bacteria which find in such fluid favorable conditions for existence. The food of protozoa consists chiefly of other organisms, particularly bacteria, and they are classed with the animals. The protozoa are the most widely distributed and the most universal of the parasites. The infectious diseases which they produce in man, although among the most serious are less in number than those produced by bacteria. So marked is the tendency to parasitism that they are often parasitic for each other, smaller forms entering into and living upon the larger. Variation does not seem to be so marked in the protozoa as in the bacteria, though this is possibly due to our greater ignorance of them as a class. We are not able, except in rare instances, to grow them in pure culture, and study innumerable generations under changes in the environment, as the bacteria have been studied.

If we regard the living things on earth from the narrow point of view as to whether they are necessary or useless or hostile to man, the protozoa must be regarded as about the least useful members of the biological society. It is very possible that such a conclusion is due to ignorance; so closely are all living things united, so dependent is one form of cell activity upon other forms that it is impossible to foretell the result of the removal of a link. The protozoa do not seem to be as necessary for the life of man as are the bacteria; they produce many of the diseases of man, many of the diseases of animals on which man depends for food; they cause great destruction in plant life, and in the soil they feed upon the useful bacteria. It is well to remember, however, that fifty years ago several of the organs of the body whose activity we now recognize as furnishing substances necessary for life were regarded as useless members and, since they became the seat of tumors, as dangerous members of the body. The only organ which now seems to come into such a class is the vermiform appendix, and its lowly position among organs is due merely to an unhappy accident of development.

The class of organisms known as the filterable viruses or the ultra-microscopic or the invisible organisms have a special interest in many ways. The limitation in the power of the microscope for the study of minute objects is due not to a defect in the instrument but to the length of the wave of light. It is impossible to see clearly under the microscope using white light, objects which are smaller in diameter than the length of the wave which gives a limit of 0.5 mu. or 1/125,000 of an inch. By using waves of shorter length, as the ultra-violet light, objects of 0.1 mu. or 1/250000 of an inch can be seen; but as these methods depend upon photography for the demonstration of the object the study is difficult. The presence of objects still smaller than 0.1 m. can be detected in a fluid by the use of the dark field illumination and the ultra-microscope, the principle of which is the direction of a powerful oblique ray of light into the field of the microscope. The objects are not visible as such, but the dispersion of the light by their presence is seen.

The demonstration that infectious diseases were produced by organisms so small as to be beyond demonstration with the best microscopes was made possible by showing, that some fluid from a diseased animal was infectious; and capable of producing the disease when inoculated into a susceptible animal. The fluid was then filtered through porcelain filters which were known to hold back all objects of the size of the smallest bacteria and the disease produced by inoculating with the clear filtrate. There are a number of such filters of different degrees of porosity manufactured, and they are often used to procure pure water for drinking, for which use they are more or less, generally however, less efficacious. The filter has the form of a hollow cylinder and the liquid to be filtered is forced through it under pressure. For domestic use the filter is attached by its open end to the water tap and the pressure from the mains forces the water through it. In laboratory uses, denser filters of smaller diameters are used, and the filter is surrounded by the fluid to be tested. The open end of the filter passes into a vessel from which the air is exhausted and filtration takes place from without inward. The test of the effectiveness of the filter is made by adding to the filtering fluid some very minute and easily recognizable bacteria and testing the filtrate for their presence. These filters have been studied microscopically by grinding very thin sections and measuring the diameter of the spaces in the material. These are very numerous, and from 1/25000 to 1/1000 of an inch in diameter, spaces which would allow bacteria to pass through, but they are held back by the very fine openings between the spaces and by the tortuosity of the intercommunications. When the coarser of such filters have been long in domestic service in filtering drinking water, bacteria may grow in and through them giving greater bacterial content to the supposed bacteria-free filtrate than in the filtering water.

That an animal disease was due to such a minute and filterable organism was first shown by Loeffler in 1898 for the foot and mouth disease of cattle. This is one of the most infectious and easily communicable diseases. The lesions of the disease take the form of blisters which form on the lips and feet and in the mouths of cattle, and inoculation with minute quantities of the fluid in the blisters produces the disease. Loeffler filtered the fluid through porcelain filters, hoping to obtain a material which inoculated into other cattle would render them immune, and to his surprise found that the typical disease was produced by inoculating with the filtrate. Naturally the first idea was that the disease was caused by some soluble poison and not by a living organism, but this was disproved in a number of ways. The most powerful poison known is obtained from cultures of the tetanus bacillus of which 0.000,000,1 of a gram (one gram is 15.43 grains) kills a mouse, or one gram kills ten million mice. Loeffler found that 1/30 gram of the contents of the vesicles killed a calf of two hundred kilograms weight, and assuming that the essential poison was present in the fluid in one part to five hundred it would be several hundred times more powerful than the tetanus poison. Further, the disease produced by inoculation of the filtrate was itself inoculable and could be transmitted from animal to animal. It was also found that when the virus was filtered several times it ceased to be inoculable, showing that each time the fluid was passed through the filter some of the minute organisms contained in it were held back.

It is not known whether these organisms belong to the bacteria or protozoa, and naturally nothing is known as to their form, size and structure. Up to the present about twenty diseases are known to be due to a filterable virus, and among these are some of the most important for animals and for man. Among the human diseases, yellow fever, poliomyelitis, and dengue are so produced; of the animal diseases in addition to foot and mouth disease, pleuropneumonia, cattle plague, African horse sickness, several diseases of fowls and the mosaic disease of the tobacco plant have all been shown to be due to a filterable virus. Of these organisms the largest is that which produces pleuropneumonia in cattle, and this alone has been cultivated. It gives a slight opacity to the culture fluids, and when magnified two thousand diameters appears as a minute spiral or round or stellate organism having a variety of forms. Its size is such that it passes the coarse, but is held back by the finer, filters and it is possible that this does not belong to the same class with the others.[1] The diseases produced by the filterable viruses taken as a class show much similarity. They run an acute course, are severe, and the immunity produced by the attack endures for a long time.

Considered in its biological relations, infection is the adaptation of an organism to the environment which the body of the host offers. It is rather singular that variations in organisms represented by such adaptation do not more frequently arise, in which case new diseases would frequently occur. It cannot be denied that new diseases appear, but there is no certain evidence that they do, and there is equally no evidence that diseases disappear. From the meagre descriptions of diseases, usually of the epidemic type, which have come down to us from the past, it is difficult to recognize many of the diseases described. The single diseases are recognized by comparing the causes, the lesions and the symptoms with those of other diseases, and new diseases are constantly being separated off from other diseases having more or less common features. Many new diseases have been recognized and named, but it is always more than probable that previously they were confounded with other diseases. Smallpox is such a characteristic disease that one would think it would have been recognized as an entity from the beginning, but although the description of some of the epidemics in remote times conform more or less to the disease as we know it, the first accurate description is in the eighth century by the Arabian physician Rhazes. Cerebro-spinal meningitis was not recognized as a separate disease until 1803, diphtheria not until 1826, and the separation between typhoid and typhus fever was not made before 1840. Nor is it sure that any diseases have disappeared, although there seems to have been a change in the character of many. It is difficult to reconcile leprosy as it appears now with the universal horror felt towards it, due to the persistence of the old traditions. It is possible, however, that the disease has not changed its character, but that such diseases as smallpox, syphilis, and certain forms of tuberculosis were formerly confounded with leprosy, thus giving a false idea of its prevalence.

In certain cases the adaptation of the organism is for a narrow environment; for example, the parasitism may extend to a simple species only, in others the adaptation may extend to a number of genera. In certain cases the adaptation is mutual, extending to both parasite and host and resulting in symbiosis, and this condition may be advantageous for both. Certain of the protozoa harbor within them cells of algae utilizing to their own advantage the green chlorophil of the algae in obtaining energy from sunlight and in turn giving sustenance to the algae. Although the algae are useful guests, when they become too numerous the protozoan devours them. It is evident that symbiosis is the most favorable condition for the existence of the parasite, and an injurious action exerted by the parasite on the host unfavorable. The death of the host is an unfortunate incident from the parasite's point of view in that it is deprived of habitation and food supply, being placed in the same unfortunate situation as may befall a social parasite by the death of his host.

FOOTNOTE: [1] Flexner has recently succeeded in isolating and cultivating the organism of poliomyelitis, but the organism is so small that its classification is not possible.



CHAPTER VII

THE NATURE OF INFECTION.—THE INVASION OF THE BODY FROM ITS SURFACES.—THE PROTECTION OF THESE SURFACES.—CAN BACTERIA PASS THROUGH AN UNINJURED SURFACE.—INFECTION FROM WOUNDS.—THE WOUNDS IN MODERN WARFARE LESS PRONE TO INFECTION.—THE RELATION OF TETANUS TO WOUNDS CAUSED BY THE TOY PISTOL.—THE PRIMARY FOCUS OR ATRIUM OF INFECTION.—THE DISSEMINATION OF BACTERIA IN THE BODY.—THE DIFFERENT DEGREES OF RESISTANCE TO BACTERIA SHOWN BY THE VARIOUS ORGANS.—MODE OF ACTION OF BACTERIA.—TOXIN PRODUCTION.—THE RESISTANCE OF THE BODY TO BACTERIA.—CONFLICT BETWEEN PARASITE AND HOST.—ON BOTH SIDES MEANS OF OFFENSE AND DEFENSE.—PHAGOCYTOSIS.—THE DESTRUCTION OF BACTERIA BY THE BLOOD.—THE TOXIC BACTERIAL DISEASES.—TOXIN AND ANTITOXIN.—IMMUNITY.—THE THEORY OF EHRLICH.

As has been said, infection consists in the injury of the body by living organisms which enter it. The body is in relation to the external world by its surfaces only, and organisms must enter it by some one of these surfaces. It is true that the bacteria in the intestine—either those normally present or unusual varieties—may, under certain circumstances, produce substances which are injurious when absorbed; but this is not infection, and is analogous to any other sort of poisoning. Each surface of the body has its own bacterial flora. Organisms live on the surface either on matter which is secreted by the surface or they use up an inappreciable amount of body material. Many of these bacteria are harmless, some are protective, producing by their growth such changes in the surface fluids that these become hostile to the existence of other and pathogenic forms. The surfaces also frequently harbor pathogenic organisms which await some condition to arise which will permit them to effect entrance into the tissues.

The surfaces of the body protect from invasion to a greater or less degree. The skin protects by the impervious horny layer on the outside, the external cells of which are dead and constantly being thrown off. Bacteria are always found on and in this layer, but the conditions for growth here are not very favorable and the surface is constantly cleansed by desquamation. The new cells to supply the loss are produced in the deepest layer of the epidermis, and the movement of cells and fluids takes place from within outwards. The protection is less perfect about the hairs and the sweat glands. Infection by the route of the sweat glands is, however, uncommon, for the sweat is a fluid unfavorable for bacterial growth and the flow acts mechanically in washing away organisms which may have entered the ducts. Infection by the route of the hair follicles is common. There is no mechanical cleansing as by the sweat, the space around the hair is large and the accumulated secretion of the hair glands and the desquamated cells furnish a material in which bacteria may grow. Growing as a mass in this situation, they may produce sufficient toxic material to destroy adjacent living cells and thus effect entrance. Infection from the eye is not common, the surface, though moist, is smooth; the eyelashes around the margin of the lids give some mechanical protection from the entrance of bacteria contained in dust, and the movements of the lids and the constant and easily accelerated secretion of tears act mechanically in removing foreign substances. It is possible that the mechanical cleansing of the skin by the daily bath may have some action in preventing infection.

The internal surfaces are much more exposed to attack and the protection is not so efficient. The moisture of these surfaces is both a protection and a source of danger. It protects by favoring the lodgment near the orifices of organisms which are in the inspired air, for when bacteria touch a moist surface they cannot be raised from this and carried further by air currents. The moisture is a source of danger in that it favors the growth of bacteria which lodge on the surface. The respiratory surface which is most exposed to infection from the air is further protected by the cilia, which are fine hair-like processes covering the cells of the surface and which by their constant motion sweep out fine particles of all sorts which lodge upon them. The cavity of the mouth harbors large numbers of organisms, many of them pathogenic. It forms a depot from which bacteria may pass to communicating surfaces and infection from these may result. Food particles collect in the mouth and provide culture material, and there are many crypts and irregularities of surface which oppose mechanical cleaning. Infection of the middle ear, the most common cause of deafness, takes place by means of the Eustachian tube which connects the cavity of the ear with the mouth. Organisms from the mouth can extend into the various large salivary glands by means of the ducts and give rise to infections. The tonsils, particularly in children, provide a favorable surface for infection. The mucous surface extends into these forming deep pockets lined with very thin epithelium, and in these debris of all sorts accumulates and provides material favorable for bacterial growth.

The lungs at first sight seem to offer the most favorable surface for infection. The surface, ninety-seven square yards, is enormous; it is moist, the epithelial covering is so thin as to give practically no mechanical protection, large amounts of air constantly pass in and out, and the surface is in contact with this. They are protected from infection in many ways. The tubes or bronchi by which the air passes into and from the lungs are covered with cilia; the surface area of these tubes constantly enlarges as they branch, the sum of the diameters of the small tubes being many times greater than that of the windpipe, and this enlargement by retarding the motion of the air favors the lodgment of particles on the surface whence they are removed by the action of the cilia. The entering air is also brought closely in contact with a moist surface at the narrow opening of the larynx. That bacteria and other foreign substances can enter the lungs in spite of these guards is shown not only by the infections which take place here, but also by the large amount of black carbon deposited in them from the soot contained in the air.

Infection rarely takes place from the surface of the gullet or oesophagus which leads from the mouth to the stomach. This is due to the smoothness of the surface and to the rapidity with which food passes over it. Infection by the stomach also is rare, for this contains a strong acid secretion which destroys many of the bacteria which are taken in with the food. It is found impossible to infect animals with cholera unless the acidity of the stomach contents be neutralized by an alkali. Many organisms, although their growth in the stomach is inhibited, are not destroyed there and pass into the intestines, where the conditions for infection are more favorable. This large and very irregular surface is bathed in fluid which is a good culture medium and but a single layer of cells covers it. The organisms which cause many of the infectious diseases in both man and animals find entrance by means of the alimentary canal, as cholera, dysentery, typhoid fever, chicken cholera, hog cholera.

Infection by the genito-urinary surface is comparatively rare. The surface openings are usually closed, and the discharge of urine has a mechanical cleansing effect. The wide tube of the vagina is further protected by a normal bacterial flora which produces conditions hostile to other and pathogenic bacteria. The most common infections are the sexual diseases, which are due to organisms which find favorable conditions for growth in and on the surface and which are conveyed from a similar surface by sexual contact.

It remains a question whether bacteria can penetrate an intact surface producing no injury at the point of entrance and be carried by the lymph or blood into internal organs where they produce disease. Internal infections are often found with seemingly intact body surfaces, but it is impossible to exclude the presence of minute or microscopic surface injuries by which the organisms may have entered. It is also possible that a slight injury at the point of entrance may heal so completely as to leave no trace.

The chief danger from wounds is that their surfaces may become infected. Death from wounds is due more frequently to infection than to the actual injury represented by the wounds. Much depends upon the character of the wound. Infection of clean wounds which are made by a sharp cutting instrument and from which there is abundant haemorrhage with sealing of the edges of the wound by clotted blood, rarely happens. Typical wounds of this sort are often made in shaving, and infection of such wounds is extraordinarily rare. If, with the wound, pathogenic organisms are placed in the tissue, or foreign substances such as bits of clothing are carried in with a bullet, for example, or if the instrument causing the wound be of such a character as to produce extensive lacerations of tissue, infection is more apt to occur. The less frequency of infection in modern wars is in part due to the simpler character of the wounds and in part to the fact that modern fixed ammunition is practically free from germs. The old spear-head, the arrow, the cross bow bolt, had little regard for the probabilities of infection. Whether infection follows a wound depends both upon the entry of pathogenic organisms and upon these finding in the tissues suitable opportunities for growth. In wounds in which there is much laceration of tissue organisms find the most favorable conditions for development. The very slight wounds produced by the exploded cap in the toy pistol give suitable conditions for the development of the bacillus which produces tetanus or lockjaw. The deaths of children from lockjaw following a Fourth of July celebration have often exceeded the total deaths in a Central American revolution. The tetanus bacillus is a widely distributed organism, whose normal habitat is in the soil and which is usually present on the dirty hands of little boys. The toy-pistol wounds are made by small bits of paper or metal being driven into the skin by the explosion of the cap. The wound is of little moment, the surface becomes closed, and a bit of foreign substance, a few dead cells and the tetanus bacilli from the surface remain enclosed and in a few days the fatal disease develops. Infection of the surfaces of old wounds such as the surface of an ulcer takes place with difficulty. Large numbers of leucocytes which give protection by phagocytosis are constantly passing to the surface, and there is also a constant stream of fluid towards the surface. On such a surface there may be an abundant growth of pathogenic organisms, but no infection results.