Tuberculosis : recast from lectures delivered at Rush medical college, in affiliation with the University of Chicago

Preface

The substance of the lectures on Medical Tuberculosis delivered by the author in Rush Medical College during the past three years is embodied in this book. The form of the work has been somewhat changed ; some more detail has been introduced, in statistical matter and otherwise, and some few things uttered in the necessity of lecture-room discussion have been omitted.

The treatment of the subject is not, and with the size of the volume could not be, exhaustive ; but a correct statement of the science of the disease has been attempted, and at the same time the practical side of the care and management of those sick with its different non-surgical forms, and for the protection of the community from the spread of the disease, has been emphasized.

This latter phase of the subject has heretofore been neglected by many of the profession, to the calamity of both the sick and the well. The old and inadequate way of regarding consumptives and dealing with their diseases was due partly to habit and partly to the gloom with which such invalidism was surrounded. But in this day of better hope for the victims of this amazing disease, and better knowledge of how to prevent it, a new science and a new

4 Preface

gospel need to be taught, to the end that both the profession and the public may be aroused to their duty and opportunities.

This book is submitted in the hope that it may help, if only in a small way, toward this consummation.

The author has great pleasure in expressing his indebtedness to Dr. Henry B. Stehman and Dr. Stanley P. Black for generous and critical assistance in the preparation of the volume.

Los Angeles, California,

Chapter I

Tuberculosis is the most frequent and destructive disease of man. It attacks many organs and appears in many forms, — forms that have been regarded as distinct diseases and known by a variety of names ; and it destroys probably at least oneninth of all the white races. It is now known to be due to the growth in the tissues of the tubercle bacillus, discovered by Koch in 1882, and no tuberculous lesion exists without the presence of this organism or of the direct influence of its growth and development.

The bacillus tuberculosis is only one of many microbes, pathogenic and non-pathogenic, invading the human body. Most of the micro-organisms are received into the body by inspired air and by food and drink, and the number acquired is enormous. In different atmospheres the number of organisms inhaled by an adult person varies from probably half a dozen to several hundred every

IO minute of life. Tubercle bacilli are acquired sometimes through direct contact with abrasions of the skin, wounds and orificial mucous membranes, as well as through the respiratory and digestive organs. Koch's bacillus is a colorless, aerobic, rod-like organism, often slightly curved, probably non-motile

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Fig i. — Bacillus tuberculosis in sputum, stained with carbol-fuchsin and aqueous methylene-blue. X 1000 -

and unflagellate, of variable length to the limit of 3.5 or 4 mikrons, or three-quarters of the diameter of an average red blood-corpuscle, and about one-tenth as broad (Fig. 1). It differs in form and size somewhat, and may be branched or nodulated, all depending on the circumstances under which it has grown and possibly on the bodies through which its generations have passed. The branched or nodulated forms are rarely found save as the result of experimental growth. When stained red, it looks, under the microscope, not unlike a minute cutting of attenuated red hair. Some believe that the different sizes and shapes of the bacilli differ in their infecting powers to the system ; the shorter and thicker specimens, which take the stain best, being the product of the severer cases. 1 If this is true, it would argue that these forms are fewer generations removed from their origin in bovine bacilli.

The bacillus is peculiar in containing various oily substances, thought by some to reside in a (rather supposititious) firm surrounding wall, and giving different appearances when treated by various substances, especially alcohol and ether. Cold alcohol extracts 8 per cent, of the total weight of the bacilli, and becomes very red by the change of a form of chromogen in the presence of alcohol and oxygen. From 8 to 20 per cent, or more by weight is extracted by a mixture of alcohol and ether, depending somewhat on the age of the culture. Ruppel has separated from tubercle bacilli a new ptomain which he has named tuberkulosamine. He

J Dr. Henry Sewall. The Medical News, March 16, 1901.

believes it to exist in the organisms in combination with nucleinic acid.

The tubercle bacillus stains with difficulty, requiring the aid of a mordant like carbolic acid, anilin, or an alkali, but when once stained, it retains its color more tenaciously than most other organisms, and more than the tissues of the body, when treated by decolorizing agents. This power undoubtedly resides in the fatty matters of the bacillus.

Koch has found that the fatty substances which the bacilli contain include two unsaturated fatty acids, one of which is soluble in dilute alcohol, while the other is proof against everything but boiling alcohol and ether. Therefore it must be that the former is removed by the staining fluid which contains alcohol, and that the latter remains after the destaining, and therefore is probably the substance that fixes the stain. It is this staining property that led to the discovery of the bacillus. It was at first supposed that no other bacillus which more or less resembles it had this peculiarity, but several possess it in varying degrees, especially the lepra and smegma bacilli ; while those of butter, hay, and grass have similar tinctorial qualities. The smegma bacilli, unlike tubercle bacilli, are decolorized by thorough treatment with absolute alcohol. 1 Several different organisms are more acid- 'Dr. George Blumer, Bender Laboratory, Albany, N. Y, proof than the Koch bacillus. The peculiar staining property of these bacilli is due to the fat they contain or which surrounds them, acquired probably from the substances in which they grow. Remove the fat by alkalis and this property is gone.

The bacillus grows in various artificial media, but, as compared with many other organisms, it is difficult to propagate. The temperature that most favors its growth is about 37.5° C. (99.5 F.), but it does grow at a temperature as low as 6o° F. under some circumstances; its development is retarded by any considerable variation from this point. It grows fairly well in blood-serum, acidulated agar agar with glycerin, bouillon with glycerin, and even on cooked potato. It has been grown on filter-paper and on common wall-paper, when moistened by human breath or by aqueous vapor emanating from damp soil.

The bacillus multiplies by division, — whether by manifold division into spores remains to be shown, and is unlikely. Many individual bacilli, presumably the older ones, are seen under the microscope to have the appearance of a string of beads, as though just undergoing division into spores; but it is alleged that the spaces between the red dots are vacuoles, or points in the walls or substance of the bacillus that either have not taken the stain or have relinquished it more quickly to the destaining fluid, and that the appearance is no proof of spores.

This bacillus is found in the bodies of various lower animals, where it produces many of the phenomena seen in the human subject. Monkeys, cattle, sheep, goats, swine, horses, chickens, cats, dogs, rats, rabbits, and guinea pigs (even fish fed on tuberculous sputa), and doubtless many other animals, are thus afflicted with, tuberculosis, although it rarely occurs spontaneously in domestic animals except cattle. The proportion of slaughtered cattle found to be tuberculous at inspected abattoirs ranges from 4 to 25 per cent. The butter and milk of the market sometimes contain bacilli. The bovine bacillus tuberculosis is shorter than the human and more virulent to other animals. Rabbits inoculated with it die of the disease in from seventeen to twenty-one days, but where human sputum is used they live from six to twelve weeks, and may for a time thrive and get fat, and even bear young. The same effect is found when cattle are inoculated, but it is substantially impossible to produce tuberculosis in cattle by human bacilli.

That the bacillus develops spontaneously outside of the animal body remains to be proved, but the evidence in favor of that possibility is increasing. It was the claim of Koch that it is a pure parasite originating in the animal body, and never spontaneously a saprophyte existing outside of it. The recurrence of tuberculosis in certain districts and houses, and the encouragement of the growth of the bacillus by organic vapors, lead to the suspicion that it can and does sometimes grow spontaneously outside the animal body.

No degree of cold yet produced (that of liquid air, more than 300 ,J below Fahrenheit zero) is capable of destroying this bacillus; after exposure for hours to such a temperature it will grow in artificial media. Heat of 82. 2 C. (180 F.) promptly kills it, while an exposure of 15 or 20 minutes to a temperature of 6o° C. (140 F.) destroys it in milk. 1 Its vitality is reduced or destroyed by prolonged daylight and fresh air acting from five to seven days, while in confined air it retains its virulence for a long time. Sunshine kills it after a period varying from one to twenty-four hours, depending on the intensity of the rays and the directness of their effect upon it ; and the intensity depends on the clearness of the atmosphere and its freedom from moisture, either visible or invisible. A virulent sputum exposed to twelve and one-half hours of sunshine daily for four days has failed after forty-three days to induce tuberculosis by inoculation in guinea-pigs. The bacillus is destroyed by strong acids, and even by the degree of acidity

'Theobald Smith.

often found in the stomach during digestion, by strong alkalis, and by germicides in general.

The bacillus has a tryptic faculty by which it is capable of transforming various albuminoid substances into peptones and tryptophan. Its life power and its virulence differ according to the animal body in which it is developed. Under certain conditions it has great tenacity of life; it is even capable of being cultivated after it has been for many months incarcerated in scars in the animal body, yet at times it is killed in lung-tissues or old cavities, the expectorated bacilli, if present, being incapable of artificial cultivation.

Certain animals seem to be perfectly immune to this organism. Many are relatively immune — that is, under ordinary conditions of health they do not acquire the disease when inoculated, but do acquire it if greatly reduced in vitality. This is an experience that is nearly identical with that of the human body, which, when in every part perfectly well and vigorous, rarely, if ever, takes the disease. The blood-serum is germicidal to a certain degree, as the leukocytes are, to this organism. Repeated propagation of the bacilli in laboratory media lessens their virulence to animals.

Several staining fluids have been used with success for tubercle bacilli, but the most practical is the carbol-fuchsin stain, composed of i part fuchsin, 5 parts carbolic acid, 10 parts absolute alcohol, and 85 parts water. (The same purpose substantially is accomplished by the following formula : Saturated alcoholic solution of fuchsin, 1 part ; five per cent, watery solution of carbolic acid, 9 parts.) This solution may be kept for a number of weeks, but should be renewed the moment it shows any precipitate or fails to stain perfectly.

For decolorizing, a watery solution of nitric or sulphuric acid, 10 to 20 per cent, may be used. Or 3 per cent, hydrochloric acid in a 70 per cent, solution of alcohol. The specimen is immersed in one of these solutions till all red color disappears and till washing with water will not restore it to any considerable degree. Then it should be washed free of acid and mounted, when the bacilli alone will be colored red. A better solution is one that contains a contrast stain, whereby with one process the red color may be removed from all parts of a specimen except the bacilli, and all the other portions stained blue. One such solution is composed of 2 parts or less of methylene-blue (not methyl-blue) to 100 parts of a 25 per cent, watery solution of sulphuric acid. Another solution of perhaps equal value is composed of nitric acid 2 parts, alcohol 3 parts, and water 5 parts, with the addition of methylene-blue to saturation. The use of these solutions leaves the bacilli stained red in i8 Tuberculosis

a blue field, which facilitates the search for them under the microscope. When colorless acid solutions are used, a most excellent counter-stain is a I per cent, watery solution of malachite-green, which produces instantaneously a beautiful green field, but leaves the bacilli with their red stain undiminished.

The demonstration of tubercle bacilli is not dimcult, and any student with an ordinary microscope outfit, including a 1-12 immersion objective and a light-condenser below the stage, can easily become an expert. A few tools and solutions are necessary, and when one begins right and acquires the best methods, he can mount a specimen for the microscope in from five to ten minutes. The things needed are : a spirit-lamp, two needles fixed in handles (the base of a common large sewingneedle forced into the end of a soft piece of wood will do), a Stewart cover-glass forceps, an ordinary dissecting forceps, thin cover-glasses, slides, a solution for staining and another for decolorizing (or a contrast stain), and a bottle of glycerin or Canada balsam.

The sputum is best secured, after rinsing the mouth thoroughly, by having the patient expectorate into a clean dish or a bottle with a wide mouth. Then the sputum should be spread out upon glass over a black surface, and one of the small pearly lumps or flecks of purulent matter that usually abound in the expectoration should be picked out with the needles for the examination. The bacilli are usually found in these little particles, but they are found nearly as constantly in the larger masses of pure pus. The portion selected should with needles be spread on a cover-glass, or spread out by rubbing it between two of them, which are then pulled apart. It is best not to have the film too thin or too uniform in thickness; if some particles are too thick to be well stained and studied with the microscope, there will be enough other surface for study, and the thicker and darker spots will aid in focusing the microscope. It is, of course, best to examine sputum soon after it is expectorated ; otherwise more or less decomposition and granular degeneration will be found in it; but this will not prevent the discovery of the bacilli, which persist in spite of the degeneration.

The film on the cover-glass is to be dried carefully in the heat at a point a few inches above the flame of a spirit-lamp, when it may be passed through the flame rather quickly two or three times, to fix it to the glass. It is then ready for staining, and is to receive from a pipette, while being held level by the cover-glass forceps (which need not let go its bite till all the staining process is done), enough of the carbol-fuchsin solution to cover the slip as deeply as possible and not have it flow off. This must now be heated slowly to nearly or quite the boiling point.

As soon as this is accomplished the staining is sufficient, and the solution may be washed off with cold water, and the decolorizing solution with the methylene-blue applied immediately and in the same manner. In one minute this solution may be washed off, best by holding the cover-glass edgewise or nearly so in a stream of water ; then the specimen is dried by pressure between folds of soft cloth or bibulous tissue-paper or by warmth over the flame, and mounted in water or glycerin for immediate inspection, or in Canada balsam if it is to be preserved. If the specimen is to be kept for any length of time, the balsam must of course be used ; and if the acid has been completely washed out, the specimen will keep indefinitely without deterioration ; but if any acid remains, it will sooner or later destroy all the color in the bacilli. The red stain should never be allowed to dry on the cover-glass.

If a very careful search is to be made in suspected sputum containing few if any bacilli, the specimen may be centrifugated for five minutes (or sedimented by standing in a test-tube for a day) after its tenacity has been destroyed by caustic soda, and the sediment stained and examined in the usual way. To liquefy the sputum, water is added in amount depending on the tenacity of the sputum, and then from i to 5 per cent, of a saturated aqueous solution of soda, and the mixture boiled until perfect fluidity is produced, but no longer. The sediment secured by the centrifuge will contain elastic fibers from the walls of the air-vesicles if dissolution of lung-tissue is going on, but these will not interfere with the demonstration of bacilli.

In searching for bacilli in urine the centrifuge is used with a fresh specimen, or the urine, antisepticized with 2 to 5 drops to the ounce of carbolic acid, may be sedimented for twenty-four hours in a deep conical glass and the sediment examined in the usual way, except that a thicker layer of sediment may be spread upon the cover-glass than of the sputum. The best way of all is to centrifugate the lowest dram of the sedimented specimen.

To search for bacilli in milk the same method may be used, only the fat in the sediment is a hindrance, and may be removed by immersing the dried cover-glass preparation in chloroform for five minutes before staining. Suspected butter may be manipulated thoroughly with a little water, the water being then centrifugated. Any bacilli present may be discovered in the sediment. The presence of salt in the mixture does not interfere with the process.

It is difficult to find bacilli in the fluid of pleural effusion and in pus from cold abscesses, even when tuberculosis is present; but such fluids injected into the peritoneal cavity of guinea-pigs usually produce tuberculosis.

The discovery of bacilli in animal tissues requires a much more elaborate process. The tissue is first hardened, preferably in absolute alcohol; it is then imbedded in celloidin and cut into sections; the sections are immersed in oil of cloves or in equal parts of alcohol and ether to remove the celloidin, and are then put in alcohol, and finally into water. They are next stained in carbol-fuchsin solution, being allowed to remain in the mixture, kept at room-temperature, for twenty-four hours, although perfect staining will take place in two hours at a temperature of 6o' J C. (140 F.). They are then decolorized in weak hydrochloric acid ( 1 or 2 per cent.) in 70 per cent, alcohol, but this process is not carried to the point of complete decolorization. Contrast-staining is done with a 2 per cent, watery solution of methylene-blue. Finally the sections are dehydrated in alcohol, cleared by oil of cloves or xylol, and mounted in balsam.

A large amount of experimental work has been done with tubercle bacilli, in cultures under varying conditions, through artificial tuberculosis in animals, and in efforts to develop in the blood of animals a substance capable of destroying or repressing the bacilli in the human body.

Certain animals convenient for the laboratory are found very susceptible to tuberculosis, when the bacilli are introduced by means of inoculation of sputum under the skin, by inoculation into the anterior chamber of the eye, or by injection into the peritoneal or pleural cavity or into the blood-vessels. Among these animals the most commonly used are guinea-pigs, rabbits and field mice, named here in the order of their susceptibility. Tuberculosis of the lungs has been produced in laboratory animals by causing them to inhale the dust of dry, powdered sputum; by feeding them on infected sputum they have acquired the disease in the intestinal tract ; and after inoculating a part of the body with bacilli a local development of tuberculosis can be produced in a distant part by lowering its vitality in some way, as through traumatic injury to a joint. Cattle prove refractory to these methods to a surprising degree when human sputum is used.

Where local inoculation is performed, the tuberculous process extends from this point by means of the lymph-channels, and attacks the lymphatic glands first reached, which swell and pass through the several stages of the disease.

In efforts to produce a serum for the cure of tuberculosis, horses and other animals have been subjected to repeated hypodermic injections of pure cultures of the tubercle bacillus, or of the products of artificial bacterial growth, the dosage being so gauged as not to imperil the animal. Gradually a tolerance of the poison is developed; larger and larger doses can be endured without reaction, until finally the animal appears to be immune to the poison. Then the blood-serum (secured by an ordinary phlebotomy) is separated from the other elements of this fluid, is antisepticized for preservation, and is prepared for therapeutic use.

The fluid products of the artificial growth of the tubercle bacillus were first separated from the cultures by the discoverer of the bacillus, and have become known as tuberculin or Koch's lymph. The substance has come into extensive use for diagnostic purposes for cattle, and to some extent for human subjects, and to a moderate degree as a remedy for tuberculosis. It is obtained usually from a glycerin-bouillon culture of the bacillus, which is concentrated to one-tenth volume by rapid evaporation over a water-bath, and then forced through a porcelain filter to separate the dead bodies of the bacilli. The fluid is then preserved by the addition of some antiseptic, as half of one per cent, of carbolic acid, or an equivalent amount of trikresol. In the evaporation it is, of course, the water, not the glycerin, that disappears, and so tuberculin is a rather concentrated solution in glycerin. It is proof against rather high temperatures; boiling temperature it stands well, and even higher heat (248 F.). It is tolerably constant, and retains its power and properties for a long time.

One property of tuberculin, when administered hypodermically in even minute doses, is to produce fever in animals and patients afflicted with any form of active tuberculosis. The fever reaction comes on a few hours after a dose of 1 to 5 milligrams is administered, is attended with all the symptoms which usually accompany fever, and passes off with the usual discomforts a few hours afterward. Ten years ago Koch experimented extensively with tuberculin on different forms of tuberculosis in the hope of curing the disease, but with little or no success except upon lupus.

Tuberculin is used enormously in many countries for the diagnosis of tuberculosis in cattle, and laws exist in most of the states of our own country requiring, under certain regulations, the examination of cattle and the destruction of those found to have the disease.

Probably there are several substances combined in tuberculin — some derived from the bacilli, and some from the culture media — and it has fairly been inferred that but one ingredient of the mixture produces the fever. Repeated efforts have been made to eliminate this ingredient, but with only moderate success. Klebs has, as he believes, precipitated it by chemicals, producing a substance which he has named anti-phthisin; also another, which is this substance plus an extract from the bodies of the bacilli, and which he has named tuberculocidin. These substances produce less fever in tuberculosis than tuberculin does.

Koch has produced two new tuberculin products, which he calls respectively upper tuberculin or T O, and tuberculin residuum or T R. The T O contains the soluble products of the bacilli, and is nearly identical with the original tuberculin ; the T R contains the insoluble parts of the bacilli. In its manufacture the bodies of the dried bacilli are ground into fine powder in a mortar, and centrifugated with water; and the sediment is again dried, ground, and centrifugated, and this process is repeated until the substance of the bacilli is rendered soluble. The fluid of the first centrif ligation is T O ; the final product is T R. The latter substance is suspended in a 20 per cent, solution of glycerin, and when injected hypodermically does not cause abscesses. The T R has been used to a considerable extent as a therapeutic agent.

Von Ruck has produced a watery extract of tubercle bacilli for a therapeutic agent.

Chapter II

What happens in the human body infected with tuberculosis? While there can be no tuberculosis without bacilli, tubercles are sometimes absent in this disease. Such cases occur where there is an unusual and rapid dissemination of the tubercle bacilli throughout the body, — to such a degree that the patient dies from the overpowering effect of the poisoning before the tubercle nodules can be formed.

The bacilli do not travel by their own activity, so far as we know, although there is some evidence that they have motile power; but as they develop they spread, because in their very multiplication they must extend. A bacillus divides in the center; it grows, and with its growth it pushes or is pushed into a new field. Then the bacilli are sometimes moved by the leukocytes of the blood, as they migrate outward and inward from the vessels and among the tissues ; and, finding their way into the blood-stream, the bacilli are carried far.

What usually happens is the formation of translucent, grayish, spherical nodules 1-25 to 1-8 of an inch in diameter, known as " tubercles," which it is a property of the bacillus to produce, or to provoke the tissues to produce. The nodules accumulate in distinct masses, giving an appearance known as tubercular. We use the term tuberculous as meaning affected with tuberculosis ; the word tubercular as meaning filled with or covered with little granular nodules, whether of tuberculosis or not. Some of the skin diseases are tubercular in their appearance, but are not tuberculous.

The tubercles of this disease develop rapidly and crowd into masses of various shapes and sizes, depending on the tissue and part invaded. This endless development of the tubercles enables them very soon to fill the center of the affected region so that it is one continuous mass, and the tubercular appearance is lost except at the periphery. The tubercles then develop only around the outside, and so the mass spreads. If the disease occurs in the lungs, some of this substance gets into the bronchi. Perhaps the lesion began in the lining of the bronchi, and the material is carried along to fresh regions by the movement of the air in respiration and by gravity, and so spreads, and new foci of the disease begin.

If we cut through a single tubercle and examine its contents, we find it has few morphologic elements, and these substantially constant. Bacilli, of course, are always present; two kinds of cells — the epithelioid (or eudotheliod ) and the lymphoid; and the appearance known as the "giant-cell." In histologic examinations the giant-cell has been usually regarded as diagnostic of tubercle. It is not completely so, since it is sometimes found under other conditions ; but the presence of tubercle bacilli is diagnostic. There are no blood vessels in the tubercle; as the mass develops the vessels become plugged up and disappear. They may endure for some time among the general tuberculous aggregation in tissues that have not yet become completely transformed, but in the center of a mass that is wholly composed of tubercles there are no blood-vessels.

The giant-cell is a globular body, made up of a central mass of granular substance and around its periphery a few nuclei. These nuclei are never in the center. The center is a homogeneous substance, and is probably in the beginning stage of degeneration. The nuclei are the left-over elements of the epithelioid cells, both the cells and the nuclei that occupied the site of the center of the giant-cell having lost their outlines in the degenerative change. As we see the giant-cell under the microscope it is in section or flattened out, and the nuclei appear around its circumference, but in the site of its growth they probably encompass the central granular mass completely.

When a mass of tubercles attains anything like the size of the end of the little finger, it becomes degenerate in the center, and there begins the process we know as caseous degeneration, which is a, peculiar form of necrosis. The tendency of all tuberculous nodules is toward this change in the center, and I believe the inside of a giant-cell illustrates the beginning of the process. The caseous substance has crudely the appearance of soft cheese, hence its name. Poverty of blood in the center of the tuberculous mass and lack of nourishment for the cells contribute to the degeneration.

This is one of the things that the bacilli do — they cause the development of masses of tubercles, and the plugging of the vessels so that the center of the mass loses its nutrition, and thereby becomes degenerate as a necessary consequence. In course of time the caseous matter undergoes a further degeneration and becomes soft and semi-liquid ; it has at first a battery consistency, then a more liquid form; and finally chemical changes in its substance produce certain acids. These last unite with the lime-salts that are dissolved in the blood and are present in this liquid, and produce small stony particles, the calcareous degeneration of the caseous matter. Patients occasionally expectorate these little masses of the size of a small finger-nail or even lareer.