number of active tubercle bacilli; and pigs fed upon this
milk develop a typical tuberculosis, commencing in the glands
of the throat, which can be traced from point to point, with the
utmost precision. It must be assumed that what takes place
in the pig may also take place in the human subject; and a
sufficient number of cases are now on record to show that the
swallowing of tuberculous material is a cause of tuberculosis,
especially amongst children and adolescents. Inhaled tubercle
bacilli from the recently-dried sputum of phthisical patients, like
milk derived from tuberculous udders, may set up tuberculosis
of the lungs or of the alimentary tract, especially when the epithelial
layer is unhealthy or imperfect. The two main causes of
the prevalence of tuberculosis in the human subject are: (1)
tubercle bacilli may become so modified that they can flourish
saprophytically; as yet it has not been possible to trace the
exact conditions under which they live, but we are gradually
coming to recognize that, although when they come from the
body they are almost obligate parasites, they may gradually
acquire saprophytic characters. (2) Many of the domestic
animals are readily infected with tuberculosis, and in turn may
become additional centres from which infection may radiate.
Koch’s tuberculin has been of inestimable value in the early diagnosis of tuberculosis, especially in animals.
Tuberculin, from which the tuberculin test derives its name, consists of the products of the tubercle bacillus when grown for a month or six weeks in peptone meat-broth to which a small proportion, say 5 or 6%, of glycerin has been added. The tubercle bacilli are then killed at boiling-temperature, and are partially removed by sedimentation, and completely by filtration through a Berkfeld or Pasteur-Chamberland filter. If a large dose of this filtered fluid be injected under the skin of a healthy man or brute, it is possible to produce some local swelling and to induce a rise of temperature; but in a similar patient suffering from tuberculosis a very much smaller dose (one which does not affect the healthy individual in the slightest degree) is sufficient to bring about the characteristic swelling and rise of temperature. To obtain trustworthy results the dosage must always be carefully attended to. The reaction is only obtained under certain well-defined conditions. Driven animals seldom, if ever, react properly. Cattle to be tested should be allowed to remain at rest for some time; they should be well fed, and be carefully protected from cold or draughts. After an injection of tuberculin into the subcutaneous tissues (usually in front of the shoulder or on the chest-wall) they should be kept under the same conditions and should be watched very carefully; the temperature should be taken at the sixth hour, and every three hours afterwards up to the twenty-first or even twenty-fourth hour. If during this time the temperature rises to 104° F., there can be little doubt that the animal is tuberculous; but if it remains under 103°, the animal must be considered free from disease: if the temperature remains between these points the case is a doubtful one, and, according to Sir John M'Fadyean, should be retested at the end of a month. It is interesting to note that the test is not trustworthy in the case of animals in which tuberculosis is far advanced, especially when the temperature is already high—103° F. In such cases, however, it is an easy matter to diagnose the disease by the ordinary clinical methods. At first objections were raised to this test on two grounds: (1) that mistakes in diagnosis are sometimes made; (2) that tuberculin may affect the milk of healthy animals into which it is injected. As the methods of using the tuberculin have been perfected, and as the conditions under which the reaction is obtained have become better known, mistakes have rapidly become fewer; whilst it has been amply proved that tuberculin has not the slightest deteriorating effect on the quality of the milk.
Tuberculin and similar substances are sometimes used as specific reagents in the diagnosis of tuberculosis in the human subject. When small quantities of old tuberculin are injected subcutaneously into a tuberculous patient in whom, however, no tubercle bacilli may be demonstrable, the temperature begins to rise in six or eight hours and continues to rise for twelve hours or, in rare cases, for an even longer period, a rise of a single degree being considered sufficient to indicate the presence of the disease. Along with this there is usually some swelling and tenderness, with perhaps redness at the seat of injection, whilst there is also some evidence of a vascular congestion in the neighbourhood of any tuberculous lesion. A second method of applying tuberculin as a diagnostic reagent is that of Pirquet, who, after diluting old tuberculin with two parts of normal saline solution and one part of 5% carbolic glycerin, places a drop of the mixture on the skin and scrapes away the epidermis in lines with “a small dental burr.” The skin is similarly treated with normal saline some 2 or 3 in. away from that at which the tuberculin is used. In the tuberculin area a little papule develops; this may become a vesicle, surrounded by slight redness and swelling (in the “saline” area nothing of the kind appears). The swelling begins about six hours after the scarification is made and continues to increase for 24 hours. Reactions, however, are obtained by this test in patients who are not suffering from any active tubercular lesion, whilst on the other hand in certain cases it fails to indicate the presence of tubercle when it is undoubtedly there. Calmette’s or Wolff-Eisner’s ophthalmic reaction test, a third method of using tuberculin, consists in dropping a weak solution of tuberculin into the conjunctival sac of one eye; this is followed by a mild attack of conjunctivitis or inflammation of the eye in the tuberculous patient, whilst in the normal patient no such inflammation should appear. Although this test appears to be of considerable value, it fails to give any information in cases of advanced tuberculosis, of general miliary tuberculosis and of tuberculous meningitis. It certainly possesses one great advantage over the others—it does not give any reaction in the presence of dormant tubercle in persons clinically sound and healthy. The inflammation of the eye may, however, be so acute, especially where strong solutions of tuberculin are used, that considerable damage may be done, more especially should there be any dormant disease of the eye. It must be remembered that in all these tests the exhibition of tuberculin increases for a time the sensitiveness of the patient each time it is administered. It sets up a negative phase, as already described, and renders the patient more susceptible to the action of a fresh dose. It is evident, therefore, that the careful worker wishing to obtain minimal effects will give small doses and gradually repeat these as he may find necessary.
In 1890 Koch, whose brilliant researches on tuberculosis had opened up a new field of investigation and had inspired new hope in the breasts of patients and physicians alike, followed up his method of diagnosis with a method of vaccination with the products of the tubercle bacillus separated from glycerinated broth culture after the vitality of the bacilli had been destroyed. As is frequently the case with new remedies, this was used so indiscriminately that it soon fell into disrepute. The results in certain cases, however, were so successful that careful investigations into the character and action of tuberculin and into the conditions under which it may be used with advantage were undertaken. Tuberculins composed of the triturated bodies of tubercle bacilli, of the external secretions of these bacilli, and of their various constituents in different combinations, were experimented with, but at the present time Koch’s two tuberculins—especially his new tuberculin—hold the field. The “old tuberculin” consists of the glycerin broth culture of the tubercle bacilli mentioned above. The new tuberculin consists of the centrifugalized deposit from a saline solution of the extract of the triturated dead tubercle bacilli; this is stored in small tubes, each containing two milligrammes of solid substance. This is diluted with distilled water containing 20% of glycerin, great care being taken to maintain the sterility of the solution. The dose is usually from 12000 to 11000 of a milligramme for an adult, increasing to 1600; according to Sir A. Wright it should not go beyond this.
Perhaps no one has done more to rehabilitate the tuberculin treatment than Sir Almroth Wright, who after a long series of experiments devised what he called the tuberculo-opsonic index, about which a few words may be of interest. It is well-known that certain cells in the human blood have the power of taking bacteria into their substance and there digesting them. This, the so-called “phagocytic power” of Metchnikoff, was found to vary somewhat under different conditions, and Wright set himself to determine, if possible, what were the factors that modified this variability. He found that the white blood corpuscles, the polymorphonuclear cells, whether from healthy or tuberculous patients, always showed practically the same phagocytic activity when mixed with a fine emulsion of tubercle bacilli and the serum from a healthy patient. If, however, corpuscles from the same individuals, whether healthy or tuberculous, were allowed to act upon the bacilli in the presence of serum drawn from a tuberculous patient, one of three things might happen: (1) the bacilli might be taken up in smaller numbers than in the above series of experiments; (2) they might be taken up in larger numbers; or (3) they might be taken up in what might be called normal numbers. In (1) and (2) Wright holds there is evidence of a tuberculous condition, in (3) of course the evidence is negative. He found, however, that when a dose of tuberculin was injected into a tuberculous patient there was a distinct fall in the number of tubercle bacilli taken up by the leucocytes treated with the serum of the patient. This condition Wright speaks of as the “negative phase.” Increased phagocytic activity of the cells is associated with what is spoken of as the positive phase. The theory is that the blood serum has the power of preparing bacteria to be eaten by the phagocytes in the same sense that boiling, say, prepares food for ready digestion by the human subject, and Wright applied the term opsonin to the unknown constituent or complex of constituents of the serum that
