PART II EXPERIMENTS IN PATHOLOGY, MATERIA MEDICA, AND THERAPEUTICS
Reading edition
I INFLAMMATION, SUPPURATION, AND BLOOD-POISONING
Pathology, the study of the causes and products of diseases, is a younger science than physiology: the use of the microscope was the beginning of pathology; and the microscope, even so late as sixty years ago, was very different to the microscope now. The great pathologists of that time had not the lenses, microtomes, and reagents that are now in daily employment; they knew nothing of the present methods of section-cutting and differential staining. But the publication in 1839 of Schwann's cell-theory marks the rise of modern pathology. In 1843, Darwin wrote his first draft of the doctrine of the origin of species; and Pasteur, that year, was in for his examination at the École Normale. The work of Schwann, Virchow, and Pasteur had such profound influences on science that the span of sixty years seems to cover the modern development of pathology: and this span of years is marked, half-way, by the rise of bacteriology. In 1875, when the Royal Commission on Experiments on Animals was held in London, the evidence was concerned practically with physiology alone: very little was said about pathology, and of bacteriology hardly a word. The witnesses say that they "believe they are beginning to get an idea" of the true nature of tubercle: and the evidence as to the nature of anthrax, given by Sir John Simon, reads now like a very old prophecy:—
"We are going through a progressive work that has many stages, and are now getting more precise knowledge of the contagium. By these experiments on sheep it has been made quite clear that the contagium of sheep-pox is something of which the habits can be studied: as the habits of a fern or a moss can be studied: and we look forward to opportunities of thus studying the contagium outside the body which it infects. This is not a thing to be done in a day, or perhaps in ten years, but must extend over a long period of time. Dr. Klein's present paper represents one very important stage of a vast special study. He gives the identification of the contagium as something which he has studied to the end in the infected body, and which can now in a future stage be studied outside the body."
Thirty years ago, there was no bacteriology, in the present sense of the word: and now the "habits" of these "contagia" have been studied, outside and inside the body, with amazing accuracy. It has been proved, past all possibility of doubt, that the pathogenic bacteria are the cause of infective diseases; they have fulfilled Koch's postulates—that they should be found in the diseased tissues, be cultivated outside the body, reproduce the same disease in animals, and be found again in the tissues of those animals. By an immeasurable amount of hard work crowded into a few years, this New World of bacteriology has been subdued. The Royal Commissioners of 1875, speaking of physiological experiments only, said, "It would require a voluminous treatise to exhibit in a consecutive statement the benefits that medicine and surgery have derived from these discoveries." If physiology in 1875 required a treatise, bacteriology in 1906 requires a library: and it is impossible here to give more than the faintest outline of some of the work that has been done.
But all pathology is not bacteriology; and it would take a treatise of prodigious length to set forth the work of modern pathology in the years before anything was known of bacteria. The microscopic structure of tumours and of all forms of malignant disease, the nature of amyloid, fatty, and other degenerative changes, and the chief facts of general pathology—hypertrophy and atrophy, necrosis, gangrene, embolism, and many more—all these subjects were studied to good purpose, before bacteriology. Above all, men were occupied in the study of inflammation under the microscope. It was this use of the microscope that revolutionised pathology; especially, it made visible the whole process of inflammation, the most minute changes in the affected tissues, the slowing and arrest of the blood in the capillaries, the choking-up of the stream, and the escape of blood-cells out of the capillaries into the tissues. Everything had been made ready for the fuller interpretation that was coming from bacteriology: the old naked-eye descriptions of inflammation were left behind; men set aside the definition of Celsus, that it was rubor et tumor cum colore et dolore—words that sound like Molière's jest about the vis dormitiva of opium—they watched inflammation under the microscope, in such transparent structures as the frog's web and mesentery, the bat's wing, and the tadpole's tail. It was thus that Wharton Jones discovered the rhythmical contraction of the veins in the bat's wing. The discovery of the escape of the white blood-cells, diapedesis, through the walls of the capillaries, was made by Waller and Cohnheim. To those who are opposed to all experiments on animals, it may seem a very small thing that a blood-cell should be on one side or the other of a microscopic film in a tadpole's tail; but this diapedesis, the first move of the blood in its fight against disease, is now seen, in the light of Metschnikoff's work, as a fact of very great importance.
The history of this transitional period, from the study of inflammation in transparent living tissues to the use, in surgery, of the facts of bacteriology, is told in Lord Lister's Huxley Lecture, October 1900. He describes how the foundations were laid in surgical pathology, by microscopical and experimental work on inflammation, coagulation, suppuration, and pyæmia, for bacteriology to build on: how his own share of the work began when he was house-surgeon to Sir John Erichsen at University College Hospital, and afterward to Mr. Syme in Edinburgh, and how it was continued through all his Edinburgh and Glasgow life:—
"After being appointed to the Chair of Surgery in the University of Glasgow, I became one of the surgeons to the Royal Infirmary of that city. Here I had, too, ample opportunities for studying hospital diseases, of which the most fearful was pyæmia. About this time I saw the opinion expressed by a high authority in pathology that the pus in a pyæmic vein was probably a collection of leucocytes. Facts such as those which I mentioned as having aroused my interest in my student days in a case of pyæmia, made such a view to me incredible; and I determined to ascertain, if possible, the real state of things by experiment....
"While these investigations into the nature of pyæmia were proceeding, I was doing my utmost against that deadly scourge. Professor Polli, of Milan, having recommended the internal administration of sulphite of potash on account of its antiputrescent properties, I gave that drug a very full trial as a prophylactic.... At the same time, I did my best, by local measures, to diminish the risk of communicating contagion from one wound to another. I freely employed antiseptic washes, and I had on the tables of my wards piles of clean towels to be used for drying my hands and those of my assistants after washing them, as I insisted should invariably be done in passing from one dressing to another. But all my efforts proved abortive; as I could hardly wonder when I believed, with chemists generally, that putrefaction was caused by the oxygen of the air.
"It will thus be seen that I was prepared to welcome Pasteur's demonstration that putrefaction, like other true fermentations, is caused by microbes growing in the putrescible substance. Thus was presented a new problem: not to exclude oxygen from the wounds, which was impossible, but to protect them from the living causes of decomposition by means which should act with as little disturbance of the tissues as is consistent with the attainment of the essential object.... To apply that principle, so as to ensure the greatest safety with the least attendant disadvantage, has been my chief life-work."[12]
And, of course, the application of that principle is not limited to the performance of the major operations of surgery. It is in daily use in every hospital, and in every practice all the world over, for the safe and quick healing of whole legions of injuries, "casualties," and minor operations.
But what of Semmelweis, and his study of puerperal fever? Did he not, before Lord Lister, and without the help of experiments on animals, discover antiseptic surgery? His claim is urged by those who are opposed to all such experiments. And the answer is, that his work was lost just for want of experiments on animals. If he could have demonstrated, as Pasteur did, the living organism, the thing itself, there in the tissues of an infected rabbit, and in a test-tube, and under a microscope, he might have stopped the mouths of his adversaries. He could not. He could only demonstrate to them the fact that their patients died, and his patients lived: and that some sort of direct infection was the cause of the deaths. The tragedy of his life cannot be told too often, and may be told again here.[13] For want of the final proof that bacteriology, and the inoculation of animals, alone could give, he was unable to hold out against his enemies till Pasteur could rescue him.
In 1846, when he was twenty-three years old, Ignaz Semmelweis was appointed assistant-professor in the maternity department of the huge general hospital of Vienna. For many years, the mortality in the lying-in wards had been about 1.25 per cent., and no more. Then, under a new professor, it had risen; and, for some years before Semmelweis came on the scene, it had been 5 per cent., or even 7 per cent. In October 1841, there had been an epidemic that had lasted till May 1843. In these twenty months, out of 5139 women delivered, 829 had died; that is to say, 16 per cent.
There were two sets of wards in the maternity department. The one set may be called Clinique A, and the other Clinique B. For many years, the mortality had been the same in each. In 1841 a change was made: Clinique A was assigned to the teaching of students, and Clinique B to the teaching of midwives: and, so soon as this change had been made, the mortality in Clinique B became less, but the mortality in Clinique A did not. Commissions of inquiry were held, and in vain. It was suggested that the foreign students were somehow to blame, nobody knew why; and many of them were sent away. Still the deaths went on. Women admitted to Clinique A would go down on their knees and pray to be allowed to go home; almost every day the bell was heard ringing in the wards, for the administration of the Sacrament to a dying woman. People talked about atmospheric influences, and overcrowding, and the tainted air of old wards, and the power of the mind over the body: and Semmelweis set to work.
He observed that cases of protracted labour in Clinique A died, almost all of them; but not in Clinique B. He observed also that cases of premature labour, nearly all of them, did well, whichever Clinique they were in; so did those women who were delivered before they came to the hospital, and were admitted after delivery. He observed also that a row of patients, lying side by side, would all be attacked at once in Clinique A; which never happened in Clinique B. He tried everything: he altered the details of treatment; he used various subterfuges to prevent one of the professors from examining serious cases; he enforced this or that rule in Clinique A, because it was the custom in Clinique B; he slaved away at the notes of the cases—and at last the truth came to him, by the death of one of his friends from a dissection-wound. He says, "My friend's fatal symptoms unveiled to my mind an identity with those which I had so often noticed at the deathbeds of puerperal cases." He saw now that the students, coming straight from the dissecting-rooms, had infected the patients during examination.
In May 1847 he gave orders that every student, before examining, should thoroughly disinfect his hands. But, though he had reckoned with dissecting-room poisons, he had forgotten to reckon with other sources of infection. In October of that year, a woman was admitted who had malignant disease; of twelve women examined after her, eleven got puerperal fever, and died. In November, a woman was admitted who had a suppurating knee-joint, with sinuses; and eight women were infected from her, and died. Therefore Semmelweis said, "Not only can the particles from dead bodies generate puerperal fever, but any decomposed material from the living body can also generate it, and so can air contaminated by such materials." Henceforth he isolated all infected cases, he enforced the strict use of disinfectants: and the mortality in Clinique A, which in May 1847 had stood at 12.24 per cent., fell in December to 3.04, and in 1848 was 1.27.
His work was taken up with enthusiasm by Hebra, Skoda, and Haller; the news of it was sent to every capital in Europe. In February 1849 Haller read a paper on it before the Medical Society of Vienna, and said, "The importance of these observations is above all calculation, both for the maternity department and for the hospitals in general, but particularly for the surgical wards." A committee was nominated to report on the whole matter; but it was opposed by the professor in charge of Clinique A, and nothing came of it. In May 1850, Semmelweis opened a great debate on puerperal fever, which occupied three sittings of the Vienna Medical Society. His opponents were there in full force, all the Scribes and Pharisees of the profession. They brought about a vague distrust of his figures and his facts; they got people to believe that there must be "something else" in puerperal fever, as well as the local infection. Semmelweis began to be discouraged. The University authorities made a dead set against him—they refused to renew his appointment, they got him out of the hospital, and out of Vienna. He went to Pesth, and was Professor of Midwifery there; but the same opposition and hostility were at Pesth as at Vienna. Slowly he began to lose his hold over himself, went down hill, became excitable and odd. The end came in July 1865. At a meeting of University professors, he suddenly took a paper from his pocket and read aloud to them a solemn oath, to be enforced on every midwife and every doctor. His mind had given way: he was moved to an asylum at Vienna, and died there a few weeks later. He was only forty-two when he died—What a wounded name, Things standing thus unknown, shall live behind me.
The contrast between the work of Semmelweis and the work of Pasteur cuts like a knife here. The failure of Semmelweis' teaching may be estimated by the fact that it had all to be done over again. The year of his success at Vienna was 1848. Eight years later, in the Paris Maternity Hospital, between 1st April and 10th May 1856, came such an outbreak of puerperal fever that out of 347 patients 64 died. In 1864, out of 1350 cases, 310 deaths. In Jan.-Feb. 1866, out of 103 cases, 28 deaths: "Women of the lower classes looked upon the Maternité as the vestibule of death." In 1877-78, came the use of carbolic acid and perchloride of mercury at the hospital, thirty years after Semmelweis' work: and, about the same time, Pasteur's discovery of the streptococcus in puerperal fever.[14] Pasteur could demonstrate to his opponents the visible cause of the infection, the thing itself. Roux tells the story:—
"Dans le pus des abcès chauds et dans celui des furoncles on constate un petit organisme arrondi, disposé en amas, qu'on cultive facilement dans le bouillon. On le retrouve dans l'ostéomyélite infectieuse des enfants. Pasteur affirme que l'ostéomyélite et le furoncle sont deux formes d'une même maladie, et que l'ostéomyélite est le furoncle de l'os. En 1878, cette assertion a fait rire bien les chirurgiens.
"Dans les infections puerpérales, les caillots renferment un microbe à grains arrondis se disposant en files. Cet aspect en chapelet est surtout manifesté dans les cultures. Pasteur n'hésite pas à déclarer que cet organisme microscopique est la cause la plus fréquente des infections chez les femmes accouchées. Un jour, dans une discussion sur la fièvre puerpérale à l'Académie de Médicine, un de ses collégues le plus écoutés dissertait éloquemment sur les causes des épidémies dans les maternités. Pasteur l'interrompt de sa place: Ce qui cause l'épidémie, ce n'est rien de tout cela: c'est le médecin et son personnel qui transportent le microbe d'une femme malade à une femme saine. Et comme l'orateur répondit qu'il craignait fort qu'on ne trouve jamais ce microbe, Pasteur s'élance vers le tableau noir, dessine l'organisme en chapelet de grains, en disant, Tenez, voici sa figure." (Roux, L'Œuvre Médicale de Pasteur. Agenda du Chimiste, 1896, p. 528.)
All suppuration, and all forms of "blood-poisoning"—abscesses, boils, carbuncles, erysipelas, puerperal fever, septicæmia, pyæmia—are due to minute organisms, various kinds of micrococcus. It has indeed been shown that suppuration may, in exceptional conditions, occur without micro-organisms: but practically every case of suppuration is a case of infection either from without or from within the body. There is no room here for any account of the work spent on these micrococci: on their identification, isolation, culture, and inoculation. It is the same with all the pathogenic bacteria—each kind has its own habits, phases and idiosyncrasies, antagonisms and preferences: nothing is left unstudied—the influences of air, light, heat, and chemistry; all the facts of their growth, division, range of variation, grades of virulence, vitality, and products; the entire life and death of each species, and everything that it is, and does, and can be made to do. The difficulties of bacteriology are written across every page of the text-books: above all, the difficulties of attenuating or intensifying the virulence of bacteria, and of immunising animals, and of procuring from them an immunising serum of exact and constant strength. Every antitoxin is the outcome of an immeasurable expenditure of hard international work, unsurpassed in all science for the fineness of its methods and the closeness of its arguments.
The older theories of disease had attributed infection to the intemperature of the weather, the powers of the air, or the work of the devil; later, men recognised that there must be a materies morbi, something particulate, transmissible, and perhaps alive, but it was still a "nameless something." Therefore, they over-estimated the constitutional, personal aspect of a case of infective disease, against the plain evidence of case-to-case infection or inoculation: they studied with infinite care and minuteness the weather, the environment, the family history, the previous illnesses of the patient—everything, except the immediate cause of the trouble. But modern pathology, like Pasteur, says, Tenez, voici sa figure.
The antiseptic method was based on bacteriology, resting as it did on the proof afforded by Pasteur that putrefaction was caused by bacteria, and not by the oxygen of the air, as had been previously believed. If any man would measure one very small part of the lives that are saved by this method, let him contrast the treatment of empyema fifty years ago with its treatment now. If he would measure the saving, not of lives but of limbs, let him take the treatment of compound fractures. If he would measure the saving of patients from pain, fever, and long confinement to bed, let him take the ordinary run of surgical cases, not only the major operations but all abscesses, lacerated wounds, foul sores, and so forth.
A serum has also been used of late years for the treatment of micrococcus-infection, and has given good results in many cases. It has been used, also, to avert the risk of such infection in certain operations where the antiseptic method cannot be strictly carried out. For the use of a "polyvalent" serum, reference may be made to the recent paper by Dr. W. S. Fenwick and Dr. Parkinson. (Trans. Roy. Med. Chir. Soc., 1906.)
II ANTHRAX
In animals, anthrax is also called charbon, splenic fever, or splenic apoplexy: in man, the name of malignant pustule is given to the sore at the point of accidental inoculation, and the name of woolsorter's disease is given to those cases of anthrax where the lungs are infected by inhalation of the spores of the bacillus anthracis. The disease occurs among hide-dressers, woolsorters, brushmakers, and rag-pickers: among animals, it occurs in sheep, cattle, horses, and swine:—
"Many of the outbreaks of anthrax in England have been in the neighbourhood of Bradford, and have been traced to the use of infected wool-refuse as manure. A map published by the Board of Agriculture shows that the outbreaks of anthrax are most frequent in those counties of Great Britain where dry foreign wools, hairs, hides, and skins are manufactured into goods. In 1892, there were forty-two outbreaks of anthrax in the West Riding of Yorkshire, as against two in the North Riding, and one in the East Riding. An undoubted fact in connection with anthrax is its tendency to recur on certain farms. During 1895, the disease reappeared on twenty-three farms or other premises in England, and six in Scotland, where it had been reported in the previous year." (Dr. Poore's Milroy Lectures, On the Earth in relation to Contagia, 1899.)
An admirable account of the disease, as it occurs in man, is given by Dr. Hamer and Dr. Bell, in the valuable series of monographs edited by Dr. Oliver of Newcastle, under the title Dangerous Trades (London, John Murray, 1902). Happily, the disease is very rare among men, even among those most exposed to it. For its treatment in man, an antitoxin has been used with some success: but the cases are too few to be of much importance.[15]
The bacillus anthracis was first seen more than fifty years ago: "Anthrax has the distinction of being the first infectious disease the bacterial nature of which was definitely proven."[16] Pollender in 1844, Roger and Davaine in 1850, noted the petits bâtonnets in the blood of sheep dead of the disease, and thought they were some sort of microscopic blood-crystals: it was not till 1863, after Pasteur's study of lactic-acid fermentation, that Davaine realised they were living organisms. Afterward, Koch succeeded in making cultures of them, and reproduced the disease by inoculating animals with these cultures; yet it was said, so late as 1876, that the bacillus anthracis was not the cause of anthrax, but only the sign of it: "Along with the bacilli, there are blood-cells and blood-plasma, and these contain the true amorphous virus of anthrax." Then came Pasteur's work, and reached its end in the experiments at Chartres, and the famous test-inoculations (1881) at Pouilly-le-Fort.
In the Agenda du Chimiste (1896) M. Roux gives the following account of this work, which he watched from first to last:—
"Vaccination against charbon has now been put to the test of practice for fourteen years. Wherever it is adopted, there the losses from charbon have become insignificant. It was followed by vaccination against swine-measles, rouget des porcs, the special study of our poor friend Thuillier. But the immediate result of Pasteur's vaccinations is their least merit: they have given men absolute faith in a science that could show such good works, they have started a movement that is irresistible; above all, they have set going the whole study of immunity, which is bringing us at last to a right way of treating infective diseases.
"Virulence is a quality that microbes can lose, or can acquire. Suppose we came across the anthrax-bacillus so far attenuated, in the way of Nature, that it had lost all power to kill—of course we should fail to recognise it; we should take it for an ordinary bacillus of putrefaction: you must watch it through each phase of its attenuation, to know that the harmless organism is the descendant of the fatal virus. But you can give back to it the virulence that it has lost, if you put it, to begin with, under the skin of a very delicate subject, a mouse only one day old. With the blood of this mouse inoculate another, a little older, and it will die. Passing by this method from younger to older mice, we come to kill adult mice, guinea-pigs, then rabbits, then sheep, etc. Thus, by transmission, the virus gains strength as it goes. Doubtless this increase of virulence, that we bring about by experiment, occurs also in Nature; and it is easy to see how a microbe, usually harmless to this or that species of animals, might become deadly to it. Is not this the way that infective diseases have appeared on the earth from age to age?
"See how far we have come, from the old metaphysical ideas about virulence, to these microbes that we can turn this way or that way—stuff so plastic that a man can work on it, and fashion it as he likes."
Pasteur's note on the attenuation of anthrax was presented to the Académie des Sciences on 28th February 1881; and the test-inoculations at Pouilly-le-Fort were made in May of that year. It was hardly to be expected that every country, in every year, should obtain such results as France now takes as a matter of course; and at one time, about twenty-one years ago, there was in Hungary a "conscientious objection" to the inoculation of herds against the disease. But in Italy, from 1st May 1897 to 30th April 1898, the issue of anti-charbon vaccine from one institute alone, the Sero-Therapeutic Institute at Milan, was 165,000 tubes, enough to inoculate 33,734 cattle and 98,792 sheep. And in France, between 1882 and 1893, more than three million sheep, and nearly half a million cattle, were inoculated.
The work done in France was published by M. Chamberland, in the Annales de L'Institut Pasteur, March 1894. The following translation of his memoir—Résultats pratiques des Vaccinations contre le Charbon et le Rouget en France—shows something of the national influence of the Pasteur Institute:—
1. Charbon
"After the famous experiments at Pouilly-le-Fort, MM. Pasteur and Roux entrusted to me the whole method and practice of the vaccinations against charbon. Twelve years have passed, and it is now time to put together the results, and to make a final estimate of the value of these preventive inoculations.
"Every year we ask the veterinary surgeons to report—
1. The number of animals they have vaccinated.
2. The number that have died after the first vaccination.
3. The number that have died after the second vaccination, within the twelve days following it.
4. The number that have died during the rest of the year.
5. The average annual mortality before the practice of vaccination.
"The sum total of all the reports is given in the following tables:—
Vaccination against Charbon (France). Sheep.
Years. Total Number of Animals Vaccinated. Number of Reports. Animals Vaccinated according to Reports received. Mortality. Total. Total loss per 100. Average loss before Vacci- nation.
After First Vacci- nation. After Second Vacci- nation. During the rest of the Year.
1882 270,040 112 243,199 756 847 1,037 2,640 1.08 10%
1883 268,505 103 193,119 436 272 784 1,492 0.77 "
1884 316,553 109 231,693 770 444 1,033 2,247 0.97 "
1885 342,040 144 280,107 884 735 990 2,609 0.93 "
1886 313,288 88 202,064 652 303 514 1,469 0.72 "
1887 293,572 107 187,811 718 737 968 2,423 1.29 "
1888 269,574 50 101,834 149 181 300 630 0.62 "
1889 239,974 43 88,483 238 285 501 1,024 1.16 "
1890 223,611 69 69,865 331 261 244 836 1.20 "
1891 218,629 65 53,640 181 102 77 360 0.67 "
1892 259,696 70 63,125 319 183 126 628 0.99 "
1893 281,333 30 73,939 234 56 224 514 0.69 "
Total 3,296,815 990 1,788,879 5,668 4,406 6,798 16,872 0.94 10%
Vaccination against Charbon (France). Cattle.
Years. Total Number of Animals Vaccinated. Number of Reports. Animals Vaccinated according to Reports received. Mortality. Total. Total loss per 100. Average loss before Vacci- nation.
After First Vacci- nation. After Second Vacci- nation. During the rest of the Year.
1882 35,564 127 22,916 22 12 48 82 0.35 5%
1883 26,453 130 20,501 17 1 46 64 0.31 "
1884 33,900 139 22,616 20 13 52 85 0.37 "
1885 34,000 192 21,073 32 8 67 107 0.50 "
1886 39,154 135 22,113 18 7 39 64 0.29 "
1887 48,484 148 28,083 23 18 68 109 0.39 "
1888 34,464 61 10,920 8 4 35 47 0.43 "
1889 32,251 68 11,610 14 7 31 52 0.45 "
1890 33,965 71 11,057 5 4 14 23 0.21 "
1891 40,736 68 10,476 6 4 4 14 0.13 "
1892 41,609 71 9,757 8 3 15 26 0.26 "
1893 38,154 45 9,840 4 1 13 18 0.18 "
Total 438,824 1,255 200,962 177 82 432 691 0.34 5%
"Comparing the figures in the fourth column with those in the second, we see that a certain number of veterinary surgeons neglect to send their reports at the end of the year. The number of reports that come to us even tends to get less each year. The fact is, that many veterinary surgeons who do vaccinations every year content themselves with writing, 'The results are always very good; it is useless to send you reports that are always the same.'
"We have every reason to believe, as a matter of fact, that those who send no reports are satisfied; for if anything goes wrong with the herds, they do not fail to let us know it at once by special letters.
"Anyhow, thanks chiefly to new veterinary surgeons who do send reports, we see that in the twelve years, up to 1st January of this year, we have had exact returns as to 1,788,879 sheep and 200,962 cattle—about half of all those that were vaccinated.
"The mortality among sheep and cattle is slightly higher after the first vaccination than after the second. This fact seems to us easy to explain. The animals reported dead include both those that died as the result of the vaccinations, and those that, being already infected at the time, died of the actual disease. But, at the time of second vaccination, the animals are already more or less protected: hence a lower mortality from the actual disease, and a lower sum total.
"The whole loss of sheep is about 1 per cent.: the average for the twelve years is 0.94. So we may say that the whole average loss of vaccinated sheep, whether from vaccination or from the disease itself is about 1 per cent. The loss of vaccinated cattle is still less: for the period of twelve years, it is 0.34, or about 1/3 per cent.
"These results are extremely satisfactory. It is to be noted especially that the average annual death-rate from charbon, before vaccination—the average given in these reports—is estimated at 10 per cent. among sheep, and 5 per cent. among cattle. But even if we put it at 6 per cent. for sheep, and 3-1/3 per cent. for cattle, and say that the worth of a sheep is 30 francs, and of an ox or a cow 150 francs—which is well below their real value—even then it is obvious that the advantage of these vaccinations to French agriculture is about five million francs in sheep, and two million in cattle. And these figures are rather too low than too high.
2. Rouget
"Some years after the discovery of vaccination against charbon, M. Pasteur discovered the vaccine for a disease of swine known under the name of rouget. From 1886, these vaccines were prepared and sent out under the same conditions as the vaccines against charbon. The following table gives the reports that have come to us of this disease:[17] —
Vaccination against Rouget (France).
Years. Total Number of Animals Vaccinated. Number of Reports. Animals Vaccinated according to Reports received. Mortality. Total. Total loss per 100. Average loss before Vacci- nation.
After First Vacci- nation. After Second Vacci- nation. During the rest of the Year.
{
For these two years
1886 France 49 7,087 91 24 56 171 2.41 20%
and other countries
1887 are put 49 7,467 57 10 23 90 1.21 "
together.
1888 15,958 31 6,968 31 25 38 94 1.35 "
1889 19,338 41 11,257 92 12 40 144 1.28 "
1890 17,658 41 14,992 118 64 73 254 1.70 "
1891 20,583 47 17,556 102 34 70 206 1.17 "
1892 37,900 38 10,128 43 19 46 108 1.07 "
Total 111,437 296 75,455 534 188 345 1,067 1.45 20%
"The total average of losses during the past seven years is 1.45 per cent., or about 1-1/2 per cent.
"This average is appreciably higher than the average for charbon. But it must be noted that the mortality from rouget among swine, before vaccination, was much higher than that from charbon among sheep. It was about 20 per cent.; a certain number of reports speak of losses of 60 and even 80 per cent.: so that almost all the veterinary surgeons are loud in their praises of the new vaccination."
The rest of M. Chamberland's paper is concerned with the defects, such as they are, of the vaccinations, and the need of absolute cleanliness in the making of them: which is somewhat difficult for this vast number of vaccinations of animals all over France, and in other parts of the world. The whole story of the discovery is told in M. Valléry-Radot's Life of Pasteur: and the whole story of rouget, in the same most fascinating book, vol. ii., p. 180.
III TUBERCLE
Before Laennec, tubercle had been taken for a degenerative change of the tissues, much like other forms of degeneration. It was Laennec who brought men to see that it is a disease of itself, different from anything else; and this great discovery of the specific nature of tubercle, and his invention of the stethoscope, place him almost level with Harvey. He founded the facts of tubercle, and on that foundation Villemin built. In 1865, Villemin communicated to the Académie des Sciences his discovery that tubercle is an infective disease; that he had produced it in rabbits, by inoculating them with tuberculous matter. En voici les preuves, he said. He appealed to these inoculations to prove his teaching:—
La tuberculose est une affection spécifique. Sa cause réside dans un agent inoculable. L'inoculation se fait très-bien de l'homme au lapin. La tuberculose appartient donc à la classe des maladies virulentes.
It was no new thing to say, or to guess, that phthisis was or might be infective. So far back as 1500, Frascatorius had said that phthisis came "by the gliding of the corrupt and noisome humours of the patient into the lungs of a healthy man." Surely, if clinical experience could suffice, men would have made something out of this wisdom of Frascatorius. They made nothing of it; they waited three hundred years for Villemin to inoculate the rabbits, and then the thing was done—En voici les preuves. Three years later, Chauveau produced the disease in animals, not by inoculation, but by the admixture of tuberculous matter with their food. Then, as the work grew, there came a short period of uncertainty: different species of animals are so widely different in their susceptibility to the disease that the results of further inoculations seemed to go against Villemin; and it was not till 1880 that Cohnheim finally established Villemin's teaching, and even went beyond it, making inoculation the very proof of tubercle:—
"Everything is tuberculous, that can produce tuberculous disease by inoculation in animals that are susceptible to that disease: and nothing is tuberculous, that cannot do this."
Then, in 1881, came the welcome news that Koch had discovered the bacillus of tubercle. In his first published account of it (24th March 1882) he says:—
"Henceforth, in our warfare against this fearful scourge of our race, we have to reckon not with a nameless something, but with a definite parasite, whose conditions of life are for the most part already known, and can be further studied.... Before all things, we must shut off the sources of the infection, so far as it is in the power of man to do this."[18]
In November 1890 he announced, in the Deutsche Medizinische Wochenschrift, the discovery of tuberculin. Its failure was one of the world's tragedies. The defeat may not be final, and we may live to see phthisis fought and beaten with its own weapons: but, for the present, it is more to the purpose to consider what other benefits have been gained, from the discovery of the tubercle-bacillus in 1881, in every civilised country in the world.
1. It has given to everybody a more reasonable and hopeful view of phthisis and the diseases allied to it. The older doctrine of heredity, that the child inherits the disease itself, has given way to the doctrine that the inheritance, in the vast majority of cases, is not that of the disease itself, but that of a tendency or increased susceptibility to the disease.
2. It has brought about an immense improvement in the early and accurate diagnosis of all cases. The bacillus found in the sputa, or in the discharges, or in a particle of tissue, is evidence that the case is tuberculous.
3. It has given evidence, which till 1901 was hardly called in question,[19] that tabes mesenterica, a tuberculous disease which kills thousands of children every year, is due in many cases to infection from the milk of tuberculous cows. In England alone, in 1895, the number of children who died of this disease was 7389, of whom 3855 were under one year old.
4. It has proved, and has taught everybody to see the proof, that the sputa of phthisical patients are the chief cause of the dissemination of the disease. By insisting on this fact, it has profoundly influenced the nursing and the home-care of phthisical patients; and it has begun to influence public opinion in favour of some sort of notification of the disease, and in favour of enforcing a law against spitting in public places and conveyances. In some of the principal cities of the United States, laws on this subject have already been enacted.
5. It has greatly helped to bring about the present rigorous control of the meat and milk trades. The following paragraph, taken almost at random, will suffice here:—
"Bacteriological examinations during the past year have shown that more milks are tuberculosis-infected than is generally supposed, and the importance of carefully supervising milk supplies is becoming more and more acknowledged. Veterinary surgeons are practically agreed that tuberculin is a reliable and safe test for diagnosing the presence of tuberculosis in animals, but affords no index of the extent or degree of the disease. The test, however, will not produce tuberculosis in healthy animals, and has no deleterious effect upon the general health of the animals. The London County Council have decided that all cows in London cowsheds shall be inspected by a veterinary surgeon regularly once in every three months, and that a systematic bacteriological examination shall be conducted of milks collected from purveyors." (Medical Annual, 1901.)
6. Tuberculin has come into general use for the detection of tuberculosis in cattle, to "shut off the sources of the infection." A full account of this method in different countries was given by Professor Bang, of Copenhagen, at the Fourth Congress on Tuberculosis, Paris, 1898. The injection of tuberculin is followed in eight to twelve hours by a well-marked rise of temperature, if the animal be tuberculous. Of this test, Professor McFadyean, Principal of the Royal Veterinary College, London, says:—
"I have no hesitation in saying that, taking full account of its imperfection, tuberculin is the most valuable means of diagnosis in tuberculosis that we possess.... I have most implicit faith in it, when it is used on animals standing in their own premises and undisturbed. It is not reliable when used on animals in a market or slaughter-house. A considerable number of errors at first were found when I examined animals in slaughter-houses after they had been conveyed there by rail, etc. Since that, using it on animals in their own premises, I have found that it is practically infallible. I have notes of one particular case, where twenty-five animals in one dairy were tested, and afterwards all were killed. There was only one animal which did not react, and it was the only animal not found to be tuberculous when killed."
Two instances of the validity of this test will suffice. In 1899, it was applied to 270 cows on some farms in Lancashire. Of these cows, 180 reacted to the test, 85 did not react, and 5 were doubtful. Tuberculous disease was actually found, when they were killed, in 175 out of the 180 = 97.2 per cent. (Lancet, 5th August 1899.) In 1901, Arloing and Courmont published a critical account of the whole subject, and gave the following facts. In 80 calves, which on examination after death were found not tuberculous, the test was negative: in 70 older cattle, which were tuberculous, the test was positive in every case but one, though the dilution of the serum was 1 in 10.[20] It would be easy to add instances of the value of this test, for it is practised far and wide over the world.
7. More recently, the discovery of the "opsonic index," and its use by Sir Almroth Wright and others, has given a great advance to the observation and treatment of cases of tuberculosis. The administration of the "new tuberculin" is now timed and measured with an accuracy which was absolutely impossible a few years ago.
It is a far cry, from the present method of counting how many tubercle-bacilli are taken up by a single blood-cell, back to Villemin's rabbits. Every inch of the way, from 1881 onward, the pathological study of every form of tuberculosis, medical or surgical, human or bovine, has been dependent on bacteriology; that is to say, on experiments on animals.
IV DIPHTHERIA
The bacillus of diphtheria, the Klebs-Loeffler bacillus, was first described by Klebs in 1875, and was first obtained in pure culture by Loeffler in 1884. Its isolation was a matter of great difficulty, and the work of many years, because of its association in the mouth with other species of bacteria. The following table, from Hewlett's Manual of Bacteriology, is a good instance of one of many practical difficulties. Out of 353 cases of diphtheria, bacteriological examination found the diphtheria-bacillus alone in 216 cases. In the remaining 137 it was associated with the following organisms:—
Streptococci 6
Staphylococci 55
Bacilli 19
Torulæ 9
Sarcinæ 6
Streptococci and micrococci 2
Micrococci and bacilli 9
Streptococci and bacilli 1
Torulæ and bacilli 1
Micrococci and sarcinæ 6
Micrococci and torulæ 4
Many forms present together 19
—
137
—
In December 1890 came the news that Behring and Kitasato had at last cleared the way for the use of an antitoxin:—
"Our researches on diphtheria and on tetanus have led us to the question of immunity and cure of these two diseases; and we succeeded in curing infected animals, and in immunising healthy animals, so that they have become incapable of contracting diphtheria or tetanus."
Aronsen, Sidney Martin, Escherich, Klemensiewicz, and many more, were working on the same lines; and in 1893, Behring and Kossel and Heubner published the first cases treated with antitoxin. Then, in 1894, came the Congress of Hygiene and Demography at Budapest, and Roux's triumphant account of the good results already obtained. Thus the treatment is not many years old; but, if the whole world could tabulate its results, the total number of lives saved would already be somewhere above a quarter of a million. Men found it hard at first to believe the full wonder of the discovery: the medical journals of 1895 and 1896 still contain the fossils of criticism—all the may be and must be of the earlier debates on the new treatment. The finest of all these fossils is embedded in the Saturday Review of 2nd Feb. 1895—It is a pity that the English Press should continue to be made the cat's-paw of a gang of foreign medical adventurers. To get at the truth, we must reckon in thousands: take, out of a whole mass of evidence, all just alike, the reports from London, Berlin, Munich, Vienna, Strasbourg, Cairo, Boston, and New York; these to begin with. Or the following facts, cut almost at random out of the medical journals:—
"The medical report of the French army states that since the introduction of the serum-treatment of diphtheria, the mortality among cases of that disease had fallen from 11 per cent. to 6 per cent." (Brit. Med. Journ., 3rd September 1898.)
"Professor Krönlein (Zürich) exhibited statistical tables, showing that the prevalence of diphtheria in the canton of Zürich had been nearly uniform during the past fifteen years; and that the mortality rapidly decreased as soon as antitoxic serum was used on a somewhat larger scale. In his clinic, all the patients were examined bacteriologically, and serum was administered in every case of diphtheria without exception. Of 1336 cases treated before the serum-period, 554 = 39.4 per cent. died; whilst during the serum-period there were 55 deaths among 437 cases = 12 per cent. In cases of tracheotomy, the death-rates before and during the serum-period were 66 and 38.8 per cent. respectively." (Lancet, 7th May 1898, Report of German Surgical Congress at Berlin.)
"Dr. Kármán was entrusted by the Hungarian Government with the task of instituting measures for preventing the spread of diphtheria in a village and its neighbourhood. As general hygienic regulations accomplished nothing, he tried preventive inoculation.... Among 114 children thus treated, there was during the next two months no case of diphtheria, although the disease was prevalent in the village up to the date at which inoculation commenced, and continued to rage in the surrounding villages afterwards. During those two months, only one case of diphtheria appeared in the village, and that was in an uninoculated child; while, in the previous five months, 18.3 per cent. of the village children had been attacked, of whom eight died, six not having been treated with serum. Considering the wretched hygienic condition of the village, the harmlessness of preventive inoculations, and the continuance of the disease in the neighbouring villages, where diphtheria-vaccination was not carried out, the extraordinary value of the inoculations, in the prophylaxis of diphtheria, can hardly be denied." (Brit. Med. Journ., 16th January 1897.)
"The most striking confirmation of the value of antitoxin has been afforded where the supply ran short during an epidemic. In Baginsky's clinic, the interruption of the serum-treatment promptly raised the mortality from 15.6 to 48.4 per cent." (Brit. Med. Journ., 20th October 1895.)
"In an analysis of the ratio of mortality in 266 German cities of about 15,000 inhabitants, it was found that the ratio of mortality per 100,000 of the living, before antitoxin was used, varied from 130 to 84 from 1886 to 1893, while the ratio from 1894 to 1897 varied from 101 to 35. It is a significant fact that during 1894, when, although antitoxin was used to a certain extent, it was not in general use, the ratio was 101; that when antitoxin was used more extensively, in 1895, the ratio was 53; that in 1896 it was 43; that in 1897, when antitoxin was very generally used, the rate fell to 35." (Trans. Massachusetts Med. Soc., 1898.)
"Dr. Gabritchefski points out that in recent years the number of persons (in Russia) attacked by the disease has increased, the figures for the whole of Russia rising from about 100,000 or 120,000, ten years ago, to considerably over 200,000 in 1897. The introduction of the serum treatment has, however, had a marked effect on the mortality of the disease; and the actual number of deaths from diphtheria has either not increased at all, or has slightly diminished." (Lancet, 5th Aug. 1899.)
Of course there will still be bad diphtheria years and good diphtheria years: for example, the death-rate of the population of England, from diphtheria, was higher during the years 1893-1899 than during the years 1889-1892. Antitoxin can no more prevent a bad diphtheria year than an umbrella can prevent a wet day. But in limited outbreaks of diphtheria, such as occur in a village, an asylum, a school, or a large family of young children, it can be used, and is used, as a prophylactic, and with admirable results. The example of Dr. Kármán, just quoted, is one of the earliest instances of this preventive use of antitoxin: other instances, of equal importance, are given in the Boston Medical and Surgical Journal, December 1897 and March 1898; and in the Lancet, 2nd April 1898, and 28th January 1899. A summary of later experiences of this preventive use of antitoxin in different countries is given by Dr. Wilcox of New York, and Dr. Stevens of Philadelphia, in Gould's Year-Book for 1902:—
"At a meeting of the Société de Pédiatrie (Paris), held June 1901, a resolution was adopted affirming that preventive inoculations present no serious dangers, and confer immunity in the great majority of cases for some weeks, and recommending their employment in children's institutions and in families in which scientific surveillance cannot be exercised. Netter stated that he had collected 32,484 observations (cases) of prophylactic injections, and after eliminating cases in which the disease developed in less than twenty-four hours after injection, or more than thirty days after, there were 6 per cent. of failures. On the other hand, the author stated that he had recently made ninety preventive injections with but 2.17 per cent. of failures. Potter reports a series of twenty-four families in which preventive injections were used. Only one case of diphtheria occurred. In another series of cases, in which no prophylactic injections were given, the disease occurred secondarily in one-third of the houses, and one-sixth of the inmates contracted the disease, in spite of the fact that a large number of the primary cases were removed to the hospital. Blake reports a series of thirty-five prophylactic injections. The treatment was instituted after three cases of diphtheria had developed in a children's home. No secondary cases developed. Voisin and Guinon describe an epidemic of diphtheria in the Salpetrière Hospital among idiots and epileptics. Prophylactic injections were given to all those exposed to the contagion. After that, but four cases appeared, all mild in character. One severe case developed, however, two weeks later, ending fatally in twenty-four hours, showing that the prophylactic action of the antitoxin, while efficacious, is not of very long duration."
It would be easy to prolong ad infinitum the proofs of the curative and preventive efficacy of the antitoxin: it would be impossible to find any evidence to be weighed for one moment against these proofs. There are three early records that ought to be quoted more fully: the 1894 report from the Hospital for Sick Children, Paris; the 1896 report of the American Pædiatric Society; and the 1898 report of the Clinical Society of London.
I
The report from the Hospital for Sick Children, Paris, is contained in a memoir, Sérum-Thérapie de la Diphtérie, the joint work of MM. Roux, Martin, and Chaillon (Annales de l'Institut Pasteur, September 1894). It gives the results of the serum-treatment during February to July 1894. The cases were not selected: the antitoxin was given in every case that was proved, by bacteriological examination, to be diphtheria—with the exception of 20 cases where the children were just dying when they were brought to the hospital. No change was made either in the general treatment or in the local applications to the throat; these were the same that had been used in former years: le sérum est le seul élément nouveau introduit.
In 1890-1893, before the serum-treatment, 3971 children were admitted to the diphtheria wards, and 2029 of them died. The percentage of these deaths was—
In 1890 55.88 " 1891 52.45 " 1892 47.64 " 1893 48.47 } Average = 51.71.
The serum was used from 1st February to 24th July 1894. During this period 448 children were admitted, of whom 109 died = 24.5.
During the same period (February to June) the Trousseau Hospital, where the serum was not used, had 520 cases, with 316 deaths = 60.0.
The cases at the Hospital for Sick Children must be divided into those that required tracheotomy and those that did not require it:—
Mortality among Cases not requiring Tracheotomy.
In 1890 47.30 " 1891 46.64 " 1892 38.8 " 1893 32.02 } Average = 33.94.
During the serum-period, the mortality of these cases was 12.0. At the Trousseau Hospital, without the serum, the mortality of these cases during the same period was 32.0.
Mortality among Cases requiring Tracheotomy.
In 1890 76.35 " 1891 68.36 " 1892 74.6 " 1893 73.45 } Average = 73.49.
During the serum-period, the mortality of these cases was 49.0. At the Trousseau Hospital, without the serum, the mortality of these cases during the same period was 86.0.
Setting aside, out of the 448 children, those cases of "membranous sore throat" or "pseudo-diphtheria," in which the Klebs-Loeffler bacillus was not found, there remain 320 cases where it was found. Of these 320 children, 20 were just dying on admission, and did not receive the serum. Of the 300 who received it, 78 died = 26.0. Before the serum-period, the mortality of these cases at the same hospital was about 50.0. The complications of diphtheria, such as paralysis, were much less frequent during the serum-period than they had been before it.
II
Report of the American Pædiatric Society's Collective Investigation into the use of Antitoxin in the treatment of diphtheria in private practice. (Eighth Annual Meeting, Montreal, May 1896.) From the New York Medical Record, 4th July 1896.
This vast collection of cases is of special interest, because they occurred in private practice. In most of them the nature of the disease was proved by bacteriological examination; in the rest, the clinical evidence was decisive: "It is possible that among the latter we have admitted some streptococcus cases, but the number of such is certainly very small." All other doubtful cases, 244 in number, were excluded.
Three thousand three hundred and eighty-four cases were reported by 613 physicians from 114 cities and towns, in 15 different States, the District of Columbia, and the Dominion of Canada. To these 3384 cases were added 942 cases from tenement-houses in New York, and 1468 cases from tenement-houses in Chicago. The New York and Chicago cases were, most of them, treated by a corps of inspectors of the Health Board of the city; and the municipal surveillance was very strict at Chicago:—
"There are very few hospitals in America that receive diphtheria patients.... It was the custom in Chicago to send an inspector to every tenement-house case reported, and to administer the serum unless it was refused by the parents. These cases were therefore treated much earlier, and the results were correspondingly better than were obtained in New York, although the serum used was the same in both cities, viz., that of the New York Health Board."
The sum total of results was 5794 cases, with 713 deaths = 12.3 per cent., including every case returned; but 218 were moribund at the time of injection, or died within twenty-four hours of the first injection. "Should these be excluded, there would remain 5576 cases in which the serum may be said to have had a chance, with a mortality of 8.8 per cent.
Of 996 cases injected on the first day of the disease, 49 died = 4.9 %
" 1616 " on the second " 120 " = 7.4 "
" 1508 " on the third " 134 " = 8.8 "
" 758 " on the fourth " 147 " = 20.7 "
" 690 " on or after the fifth " 244 " = 35.3 "
And in 232 cases, where the day of injection was unknown, there were 19 deaths = 8.2 per cent.
"No one feature of the cases of diphtheria treated by antitoxin has excited more surprise among the physicians who have reported them than the prompt arrest, by the timely administration of the serum, of membrane which was rapidly spreading downward below the larynx. Such expressions abound in the reports as 'wonderful,' 'marvellous,' 'in all my experience with diphtheria, have never seen anything like it before,' etc.
"Turning now to the operative cases, we find the same remarkable effects of the antitoxin noticeable. Operations were done in 565 cases, or in 16.7 per cent. of the entire number reported. Intubation was performed 533 times, with 138 deaths, or a mortality of 25.9 per cent. In the above are included 9 cases in which a secondary tracheotomy was done, with 7 deaths. In 32, tracheotomy only was done, with 12 deaths, a mortality of 37.4 per cent. Of the 565 operative cases, 66 were either moribund at the time of operation or died within twenty-four hours after injection. Should these be deducted, there remain 499 cases operated upon, by intubation or tracheotomy, with 84 deaths, a mortality of 16.9 per cent.
"Let us compare the results of intubation, in cases in which the serum was used, with those obtained with this operation before the serum was introduced. Of 5546 intubation cases in the practice of 242 physicians, collected by M'Naughton and Maddren (1892), the mortality was 69.5 per cent. Since that time, statistics have improved materially by the general use (in and about New York, at least) of calomel fumigations. With this addition, the best results published (those of Brown) showed in 279 cases a mortality of 51.6 per cent.
"But even these figures do not adequately express the benefit of antitoxin in laryngeal cases. Witness the fact that over one-half the laryngeal cases did not require operation at all. Formerly, 10 per cent. of recoveries was the record for laryngeal cases not operated upon. Surely, if it does nothing else, the serum saves at least double the number of cases of laryngeal diphtheria that has been saved by any other method of treatment."
III
In 1898, the Clinical Society published the Report of their Special Committee, based on 633 cases (Trans. Clin. Soc., xxxi., 1898, pp. 1-50). The whole report should be read carefully; but there is room here for nothing more than the latter part of it. This is given at length.
A Table showing the General Mortality of cases treated, on the same day of the disease, with and without Antitoxin.
Antitoxin Committee: 633 Cases treated with Antitoxin. Metropolitan Asylums Board 1894: 3042 Cases treated without Antitoxin. Difference of Percentage.
Day of the C D M Day of C D M
Disease on a e o Admission a e o
which s a r to s a r
Treatment e t t Hospital e t t
was begun. s. h i s. h a
s. l s. l
i i
t t
y. y.
% %
1st 20 2 10.0 1st 133 30 22.5 12.5
2nd 92 10 10.8 2nd 539 146 27.0 16.2
3rd 133 20 15.0 3rd 652 192 29.4 14.4
4th 130 26 20.0 4th 566 179 31.6 11.6
5th 258 66 25.5 5th 1,152 355 30.8 5.3
and after.
Totals 633 124 19.5 Totals 3,042 902 29.6 10.1
B Summary and Conclusions of the Committee's Report
"The material for the investigation of the clinical value of the antitoxin serum in the treatment of diphtheria was not obtained from selected, but from consecutive, cases, reported from the general hospitals and the fever hospitals of the Metropolitan Asylums Board; all were made use of which fulfilled the requirements of the Committee.
"The Committee rejected all cases in which satisfactory proof of the existence of true diphtheria was not shown, either by the presence of the Bacillus diphtheriæ upon bacteriological examination, or by the occurrence of paralysis in the course of the illness. All were also rejected in which the amount of antitoxin administered was stated in cubic centimetres and not in normal units, the Committee having no means by which the strength of the antitoxin could in these cases be determined.
"Six hundred and thirty-three cases form the basis on which the report is drawn up; 549 were treated with antitoxin obtained from the laboratory of the Royal Colleges of Physicians and Surgeons; the remainder, 84 in number, were injected with antitoxin obtained from other sources. In nine instances, antitoxin from two different sources was injected into the same patient.
"Statistics of the disease before the use of antitoxin are introduced as control series; these were obtained from the fever hospitals of the Metropolitan Asylums Board, and from the general hospitals; and, like the antitoxin series, are compiled from consecutive and not from selected cases.
"The general mortality, under the antitoxin treatment, was 19.5 per cent.; a reduction of 10 on the percentage mortality of the cases treated in the hospitals of the Metropolitan Asylums Board in 1894. If 15 fatal cases, in which death took place within twenty-four hours of the first injection, be deducted, the mortality falls to 15.6 per cent.; which is very little more than half the mortality during 1894 under other forms of treatment.
"The lessened mortality is especially noticeable in the earlier years of life, the percentage mortality of children under five being 26.3, as opposed to 47.4. In the next period of five years, the percentage of mortality is 16.0, as opposed to 26.0; whilst after ten years of age the difference in the mortality is slight.[21]
"Laryngeal diphtheria is admittedly the most dangerous form. The laryngeal cases have a percentage mortality of 23.6 in the antitoxin, as compared with 66.0 in the non-antitoxin series. In the cases in which laryngeal symptoms are so severe as to necessitate tracheotomy, the saving of life by the use of antitoxin is very marked, the mortality being reduced one-half, to 36.0 as opposed to 71.6 per cent.
"The strongest evidence of the value of the antitoxin treatment is that, in addition to reducing the general mortality by one-third, the duration of life in the fatal cases is decidedly prolonged. These two facts taken together conclusively prove the beneficial effects of the antitoxin treatment.
"The incidence of paralysis is greater in the antitoxin than in the control series. This increased number is partly explained by the lessened mortality, and partly by the longer duration of life in the fatal cases affording time for the development of paralytic symptoms. The percentage mortality of those who had some form or other of paralysis is lower in the antitoxin than in the control series; so that, notwithstanding the apparent greater risk of paralysis supervening, the probability of final recovery is greater.
"No definite conclusion can be drawn, for the reasons stated in the body of the report, as to the advantage of administering the whole of the antitoxin within forty-eight hours of the first injection, or continuing it for a longer period; but evidence is afforded of the importance of its administration as early as possible in the course of the disease; the percentage mortality in cases injected on the first and second days of the disease being 10.7, as compared with 25.5 for those first receiving the injection on the fifth or some subsequent day.
"No conclusion can be drawn, from the cases reported on, as to the amount of antitoxin which should be used to produce the best effects; but they show that the administration of very large doses is followed by no pronounced ill effects.
"The injection of antitoxin is responsible for the production of rashes, joint-pains, and possibly for the occurrence of late pyrexia. In 34.7 per cent. the injections were followed by rashes. Some amount of fever accompanied the rash in 60 per cent. In only 9.4 per cent. of those in whom rashes were observed did death ensue.
"Joint-pains were observed in 40, or 6.3 per cent. of the whole number, and all but five of them had a rash as well.
"In 26, or 65 per cent. of the joint-pains, some rise of temperature accompanied the pain. A rise of temperature during convalescence, accompanied by either rash or joint-pain, occurred in 27, or 4.2 per cent. of the whole number.
"No connection could be traced between the amount of antitoxin administered and the occurrence of rashes or late pyrexia, but the pain in and about the joints appears to have a relationship to the amount of antitoxin used.
"The results of the Committee's investigation tend to show that by the use of antitoxin—
1. The general mortality is reduced by one-third.
2. The mortality in tracheotomy falls by one-half.
3. Extension of membrane to the larynx very rarely occurs after the administration of antitoxin.
4. The duration of life in the fatal cases is decidedly prolonged.
5. The number of fatal cases is less when antitoxin is used early in the illness than in those which do not receive it until a later period.
6. The frequency of the occurrence of paralysis is not diminished, but the percentage of recoveries in cases with paralysis is slightly increased.[22]
7. Rashes are produced in about one-third of the cases, and are attributable to the antitoxin.
8. Pain, and occasionally swelling about the joints, are produced in a number of cases.
9. Even when used in large doses, no serious ill effects have followed the injection of antitoxin."
The foregoing reports belong to ancient history. Let us leave them, and study the record of the hospitals of the Metropolitan Asylums Board. They serve a city of 121 square miles, and 4-1/2 millions of inhabitants.
The use of the antitoxin in the hospitals of the Metropolitan Asylums Board began in 1895. It had been used in 1894 on a few cases only, during the latter part of the year, and had been procured with much difficulty from various sources, chiefly from the Institute of Preventive Medicine. On 9th November 1894, the Board applied to the Laboratories' Committee of the Royal Colleges of Physicians and of Surgeons, asking them to undertake the supply. Arrangements were made for this purpose; and the sum of £1000 was given by the Goldsmiths' Company. Dr. Sims Woodhead, then Director of the Laboratories of the Conjoint Colleges, now Professor of Pathology at Cambridge, was put in charge of the bacteriological work and the preparation of the serum, with a host of expert colleagues: the administration of the treatment was the work of the medical officers of the hospitals of the Metropolitan Asylums Board. The experiences of 1895 are given in the following passages from the joint report to the Board from the medical superintendents:—
"The period covered by the report extends from 1st January 1895 to 31st December of the same year. During this time—with the exception of an interval of three months at the Eastern Hospital, when its use was suspended; of three months at the Fountain, and to a considerable extent throughout the year at the South-Eastern Hospital, when all cases were consecutively treated, irrespective of their severity—the serum was administered only to cases which at the time of admission were severe, or which threatened to become so. In a certain number, the patients being moribund at the time of their arrival, and beyond the reach of any treatment, no antitoxin was given. No change has taken place during the year in the local treatment of the cases, nor has there been any new factor in the treatment other than the injection of antitoxin.
"It must be clearly understood that, with the exceptions previously stated, it has been the practice at each of the hospitals to administer serum to those cases only in which the symptoms on admission were sufficiently pronounced to give rise to anxiety, the mild cases not receiving any.
"No less than 46.4 per cent. of the antitoxin cases were under five years of age, against 32.5 per cent. in the non-antitoxin group; and only 16.1 per cent. in the former class were over ten years of age, against 33.8 per cent. in the latter. The high fatality of diphtheria in the earlier years of life is notorious.
"It is obvious, therefore, that to compare the mortality of those treated with antitoxin with that of those which during the same period were not so treated, would be to institute a comparison between the severe cases and those of which a large proportion were mild. This would clearly be misleading.
"The only method by which an accurate estimate can be obtained as to the merits of any particular form of treatment, is by comparing a series of cases in which the remedy has been employed with another series not so treated, but which are similar, so far as can be, in other respects. This, in the present instance, is impossible; but, having regard to the fact that 61.8 of the 1895 cases were treated with serum, an approximately accurate conclusion can be drawn by contrasting all cases of diphtheria completed during 1895, the antitoxin period, with all cases completed during 1894.
"The year 1894 has been selected for the purpose of comparison, not only because it is the year immediately preceding the antitoxin period, but because the average severity of the cases has been, in our opinion, about equal. Moreover, the death-rate in 1894 was slightly lower than it had been in any previous year.
" ... Of 3042 patients of all ages treated during 1894, 902 died—a mortality of 29.6 per cent.; whereas, of 3529 cases treated during 1895, 796 died—a mortality of 22.6 per cent.; the difference in percentage between the two rates being therefore 7.1. This, assuming that the former rate would otherwise have been maintained, represents a saving of 250 lives during the past year.
Influence of Age. Table showing variations in reduction of mortality obtained with Antitoxin at different ages.
Ages. Antitoxin Cases, 1895 All Cases, 1895 All Cases, 1894 Diff. in Mortalities, 1894 and 1895.
Cases. Deaths. Mortality per cent. Cases. Deaths. Mortality per cent. Cases. Deaths. Mortality per cent.
Under 5 1013 379 37.4 1453 497 34.2 1171 556 47.4 13.2
" 10 1829 575 31.4 2720 744 27.3 2246 836 37.2 9.9
" 15 2056 606 29.4 3144 779 24.7 2609 877 33.6 8.9
All ages 2182 615 28.1 3529 796 22.5 3042 902 29.6 7.1
For every age-group, with the single exception of that comprising the years 15 to 20 (the numbers of which are small), the percentage mortality was less in the 1895 than in the 1894 cases. The reduction in mortality was greatest in early life.
Influence of Time of coming under Treatment. Table showing percentage mortality in relation to day of disease on which cases came under treatment.
Day of Disease. 1894. 1895. Difference.
1st 22.5 11.7 10.8
2nd 27.0 12.5 14.5
3rd 29.4 22.0 7.4
4th 31.6 25.1 6.5
5th and over 30.8 27.1 3.7
Total 29.6 22.5 7.1
"It will be seen that the percentage mortality of cases admitted on the same day of disease is less in every instance in the year 1895. The difference is most marked in the case of those patients who were admitted on the first and second day of illness, viz., 10.8 and 14.5 respectively.
"Both in 1894 and 1895, no less than over 37 per cent. of the patients were admitted on, or after, the fifth day of disease. And, moreover, while in 1894 as many as 59.2 per cent. of the fatal cases were not brought under treatment until the fourth day, or later, in 1895, the antitoxin year, the proportion was even higher, viz., 67.7 per cent.
Laryngeal Cases
"The tracheotomy results at each hospital are more favourable in the year 1895 than in 1894, the mortality ranging in the latter year at the different hospitals between 90 per cent. and 59.4 per cent., whereas in 1895 the range was from 56.2 to 40.5.
"The combined tracheotomy mortality for all the hospitals, which in 1894 was 70.4 per cent., has fallen to 49.4 per cent. in 1895. This is a lower death-rate than has ever been recorded in any single hospital of the Board for a year's consecutive tracheotomies. In other words, rather more than 50 per cent. of children on whom the operation has been performed have been saved since the employment of antitoxin. In one of the hospitals no less than a fraction under 60 per cent. survived, although the recoveries in that hospital in any previous year did not exceed 25 per cent., and in the preceding year—viz., 1894—were as low as 10 per cent.
"The improved results in the tracheotomy cases of 1895 have also been shared by analogous cases in which the operation was not performed. The percentage mortality of all laryngeal cases has fallen from 62 in 1894 to 42.3 in 1895.
"Moreover, the number of laryngeal cases which required tracheotomy has fallen in 1895 to 45.3 per cent., whereas in 1894 it was 56 per cent.
"The following tables briefly summarise the foregoing results. As no returns for 1894 were furnished by the Fountain Hospital by reason of the smallness of the numbers, the Fountain cases have also been omitted from the 1895 figures, in order that the two series may be rendered strictly comparable:—
1. Comparative Mortality of Laryngeal Cases at all Hospitals, except the Fountain.
Year. Cases. Deaths. Percentage Mortality.
1894 466 289 62.0
1895 468 196 41.8
2. Comparative Results in Tracheotomy Cases at all Hospitals, except the Fountain.
Year. Cases. Deaths. Percentage Mortality.
1894 261 184 70.4
1895 219 108 49.3
3. Comparative Number of Laryngeal Cases which required Tracheotomy at all Hospitals, except the Fountain.
Year. Cases. Tracheotomies. Percentage of Tracheotomies.
1894 466 261 56.0
1895 468 219 46.8
"On these tables further comment seems unnecessary.
Summary
"The improved results in the diphtheria cases treated during the year 1895, which are indicated by the foregoing statistics and clinical observations, are—
1. A great reduction in the mortality of cases brought under treatment on the first and second day of illness.
2. The lowering of the combined general mortality to a point below that of any former year.
3. The still more remarkable reduction in the mortality of the laryngeal cases.
4. The uniform improvement in the results of tracheotomy at each separate hospital.
5. The beneficial effect produced on the clinical course of the disease.
Conclusions
"A consideration of the foregoing statistical tables and clinical observations, covering a period of twelve months, and embracing a large number of cases, in our opinion sufficiently demonstrates the value of antitoxin in the treatment of diphtheria.
"It must be clearly understood, however, that to obtain the largest measure of success with antitoxin it is essential that the patient be brought under its influence at a comparatively early date—if possible, not later than the second day of disease. From this time onwards, the chance of a successful issue will diminish in proportion to the length of time which has elapsed before the treatment is commenced. This, though doubtless true of other methods, is of still greater moment in the case of treatment by antitoxin.
"Certain secondary effects not unfrequently arise as a direct result of the injection of antitoxin in the form in which it has at present to be administered, and even assuming that the incidence of the normal complications of diphtheria is greater than can be accounted for by the increased number of recoveries, we have no hesitation in expressing the opinion that these drawbacks are insignificant when taken in conjunction with the lessened fatality which has been associated with the use of this remedy.
"We are further of the opinion that in antitoxic serum we possess a remedy of distinctly greater value in the treatment of diphtheria than any other with which we are acquainted."
Now let us take the whole record of all the hospitals together. The disease was first admitted in 1888; this year is therefore to be reckoned as incomplete.
Year. Percentage Mortality. Year. Percentage Mortality.
1888 59.35 1897 17.69
1889 40.74 1898 15.37
1890 33.55 1899 13.95
1891 30.63 1900 12.27
1892 29.35 1901 11.15
1893 30.42 1902 11.04
1894 29.29 1903 9.69
1895, first antitoxin year 22.85 1904 10.08
1896 21.20 1905 8.3
These results, of course, are but one instance of what has happened, since 1895, in every country all over the civilised world. Securus judicat orbis terrarum. We have Siegert's tables (1900), based on no less than 40,038 cases admitted in nine years to sixty-nine hospitals in Germany, Austria, Switzerland, and Paris. He divides these nine years into a "pre-serum period," an "introduction year," and a "serum period." In the pre-serum period the general mortality was 41.5, and the mortality of cases requiring operation was 60; in the serum period, the general mortality was 16.5, and the mortality of cases requiring operation was 37.5.
Any bad results that have been recorded from the use of the antitoxin are so rare, in comparison with the hundreds of thousands of injections made, that they do not come to be considered here. And, even though a few have occurred, we may be sure that some of them were due, not to the antitoxin, but to the natural course of the disease.[23] The lesser drawbacks, the occurrence of joint pains and of rashes, are transient and in no way serious.
It has been supposed, and said, that the use of the antitoxin increases the complications of the disease. On this point, the best authority is Professor Woodhead's monumental Report (1901), dealing with the Metropolitan Asylums Board cases for 1895 and 1896. He sums up the matter thus:—
"The free use of antitoxin does not raise the percentage of cases of albuminuria. As regards vomiting, the statistics give little information, as vomiting is usually met with only in the very severe cases. This also holds good of anuria. The number of cases of adenitis appears to be distinctly reduced by the use of antitoxin, as the percentage of cases falls as the injections of antitoxin are pushed. The use of antitoxin has also had a perceptible effect in diminishing the cases of nephritis, and it certainly has not aggravated the kidney complications of diphtheria. There can be no doubt that in cases treated with antitoxin there is a greater percentage of cases in which joint-pains occur than in cases not so treated; these, however, are transitory, and are probably the result of some slight change in the blood set up by the action of the serum itself, and not by the antitoxic substance in the serum. The number of primary abscesses has undoubtedly been reduced by the use of antitoxin. It may also be accepted that antitoxic serum has some effect in temporarily raising the temperature, but only during the periods of joint-pains and serum rashes; all these, however, are of comparatively slight importance as compared with the effect the antitoxin has in diminishing the percentage mortality and alleviating the more severe symptoms.
"It is of importance to observe that amongst the cases of paralysis following diphtheria the death-rate (32 per cent.) was actually higher amongst those not injected with antitoxin than amongst those where antitoxin was used (30.5 per cent.), although the former paralyses must be looked upon as being the result of a comparatively mild attack of the disease. From this it is evident that, when once paralysis supervenes in these cases, it is quite as fatal in its effects as in the cases (usually those of a more severe type) where antitoxin has been given. Antitoxin cannot cure the degeneration of the nerve, but it can neutralise the diphtheria toxin, and so put a stop to the advance of the degenerative changes due to its action. In 1896, when, of course, antitoxin was given much more freely, the percentage of deaths in the non-injected cases where paralysis had come on fell to 18.4.
"Antitoxin rashes occur at a comparatively late stage of the disease. They cannot be looked upon as in any way dangerous, although the secondary rise of temperature, and the irritation of the skin which usually accompany their presence are very undesirable complications, and may retard somewhat the convalescence of nervous and irritable patients.
"Antitoxin appears to diminish the liability of the lungs to inflammatory change in severe attacks of diphtheria."
Now let us take another point of view. If anybody really doubts whether the antitoxin did really save these lives in the hospitals of the Metropolitan Asylums Board, what answer has he got to the following table? It is published in the Board's Report for 1904, and was drawn up by Dr. MacCombie, Medical Superintendent of the Brook Hospital. It shows the supreme importance of giving the antitoxin at the very beginning of the disease. The figures in brackets are the total numbers of the cases in the eight years:—
Percentage Mortality according to Time of coming under Treatment.
Day of Disease. 1897. 1898. 1899. 1900. 1901. 1902. 1903. 1904.
(204) 1st 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
(1278) 2nd 5.4 5.0 3.8 3.6 4.1 4.6 4.2 5.43
(1374) 3rd 11.5 14.3 12.2 6.7 11.9 10.5 17.6 10.63
(1086) 4th 19.0 18.1 20.0 14.9 12.4 19.8 16.7 19.51
(1382) 5th and after 21.0 22.5 20.4 21.2 16.6 19.4 17.3 13.11
Here we see that in 1482 patients, who got the antitoxin within forty-eight hours of the onset of the disease, the mortality was 2-1/4 per cent. In 1278 patients, who did not get the antitoxin till the third day, the mortality was 11-3/4 per cent. That is the result of one day's delay over sending the child into hospital.
Again, it is not only lives that are saved, but suffering that is avoided. Just lately, at a meeting of the Chelsea Clinical Society (May 1906), reference was made to this point by Dr. Foord Caiger, Medical Superintendent of the South-Western Hospital. "The number of tracheotomies is less than half what it used to be;" and again, "Instead of the spectacle of a number of patients in great distress, with swollen necks and stuffed-up noses, fretful and crying, such cases are now quite the exception, and, in the few one does come across, the condition lasts for a comparatively short time." And again, "It was quite unusual (before 1895) for a nurse to care to stay very long in charge of one of the diphtheria wards, because she found the work so depressing. But nowadays the diphtheria wards are perhaps the most popular in the hospital, a fact which is mainly owing to the change in the general aspect of the patients and the greatly reduced mortality." (Clinical Journal, May 23, 1906.)
V TETANUS
Before bacteriology, the cause of tetanus (lock-jaw) was unknown, and men were free to imagine that it was due to inflammation travelling up an injured nerve to the central nervous system. This false and mischievous theory was abolished by the experimental work of Sternberg (1880), Carle and Rattone (1884), and Nicolaier (1884), who proved, once and for all, that the disease is an infection by a specific flagellate organism. Their work was of the utmost difficulty, for many reasons. First, because tetanus, in some tropical countries, is so common that it may fairly be called endemic; and many of these tropical cases, there being no record of any external infection, had been taken as evidence that the disease can occur "of itself." Of this frequency of tetanus in tropical countries, Sir Patrick Manson, in his book on Tropical Diseases (1898), says:—
"Tetanus is an exceedingly common disease in some tropical countries. In Western Africa, for example, a large proportion of wounds, no matter how trifling as wounds they may be, if they are fouled by earth or dirt, result in tetanus. The French in Senegambia have found this to their cost. A gentleman who had travelled much in Congoland told me that certain tribes poison their arrows by simply dipping the tips in a particular kind of mud. A wound from these arrows is nearly sure to cause tetanus. In many countries, so general and so extensive is the distribution of the tetanus-bacillus that trismus neonatorum (tetanus of newly-born infants) is a principal cause of the excessive infant mortality."
Next, because the tetanus-bacillus has its natural abode in the superficial layers of the soil: here it is associated with a vast number of other organisms, so that its identification and isolation were a work of immeasurable complexity. What mixed company it keeps, is shown by Houston's estimate of the number of microbes per gramme in twenty-one samples of different soils. This number ranged from 8326 in virgin sand, and 475,282 in virgin peat, to 115,014,492 in the soil from the trench of a sewage-farm. In all rich and well-manured soil the tetanus-bacillus may possibly be present; but it was the work of years to dissociate it from the myriads of organisms outnumbering it.
Next, because it cannot be got to grow in cultures exposed to the air: its proper place is below the surface of the soil, away from the air; it is "strictly anaërobic," and the attempts to cultivate it by ordinary methods failed again and again. It had to be cultivated below the surface of certain nutrient media, or in a special atmosphere of nitrogen or hydrogen.
These and other difficulties for many years delayed the final proof of the true pathology of tetanus. The success of the work was mainly due to Nicolaier. He started from the well-known fact that tetanus mostly comes of wounds or scratches contaminated with particles of earth—such mischances as the grinding of dirt or gravel into the skin, or the tearing of it by a splinter of wood or a rusty nail; as Dr. Poore says, in his Milroy Lectures (1899), "Every child who falls on the ground and gets an abrasion of the skin, all tillers of the soil who get accidental wounds in the course of duty, and every horse which 'breaks its knees' by falling in the London streets, runs potentially a risk of inoculation with tetanus." Nicolaier therefore studied the various microbes of the soil, and made inoculations of garden-mould under the skin of rabbits. He was able, by these inoculations, to produce tetanus in them; and the discharge from the points of inoculation, put under the skin of other rabbits, produced the disease again. He also identified the bacillus, and cultivated it; but in these cultures it was mixed with other organisms, and he failed to isolate it from them. Carle and Rattone, and Rosenbach, were able to produce tetanus in animals by inoculating them with discharge from the wounds of patients attacked by the disease. Finally, Kitasato, in 1889, found a way of obtaining pure cultures of the bacillus. Beginning with impure cultures such as Nicolaier had made, he kept these at a temperature of 36° C. till the bacillus had spored; then, by repeated exposures of the cultures to a temperature of 80° C. for three-quarters of an hour at a time, he killed-off all organisms except the spores of the tetanus-bacillus; then he kept these in an atmosphere of hydrogen, at a temperature of 20° C., and thus got pure cultures.
Brieger, Fränkel, Cohen, Sidney Martin, Kanthack, and others, have studied the chemical products of the disease, have obtained them from cultures and from infected tissues, and have been able with these toxins to produce the disease in animals. As with the other infective diseases, so with tetanus, there have been two main lines of researches; the one, toward a fuller knowledge of the chemical changes in the blood and in the central nervous system; the other, toward a fuller knowledge of the nature and ways of the bacillus, and its method of invasion. Before any study of immunity or immunisation, or of neutralisation of the toxins in man by an antitoxin, came the study of the toxins and of the bacillus. It was proved, by an immense quantity of hard work, that the bacillus does not tend to invade the blood, or to pass beyond the lymphatic glands in the immediate neighbourhood of the site of inoculation; that it stays in and about the wound, and there multiplies, and from this site pours into the blood the chemical products which cause the disease; and that these chemical substances have a selective action on certain nerve-cells in the brain and the spinal cord. This is the bare outline of the facts; and no account can be given here of the intricate problems of bacteriology and animal chemistry that have been answered, or are still waiting an answer. At least, it is evident that the whole pathology of tetanus was found, proved, and interpreted by the help of experiments on animals; and that these alone did away with the old false doctrine that the disease was due to rapid extension of inflammation up a nerve to the brain.
In 1894 came the use of an antitoxin in cases of the disease, and, in 1895, 42 cases were reported, with 27 recoveries. It cannot be said that any one of the diverse preparations of tetanus-antitoxin, up to this present time, has triumphed over the disease. Tetanus is of all diseases the hardest to reckon with: the first sign of it is the last stage of it; there is no warning, nothing, it may be, but a healed scratch, till the central nervous system is affected with sudden and rapidly advancing degeneration of certain cells. These and other difficulties have stood in the way of an antitoxin treatment; and there is no less difficulty in estimating the efficacy of that treatment. The recovery, under antitoxin, of a "chronic" case cannot always or altogether be attributed to the treatment; and in a very acute case, antitoxin, like everything else, has but small chance of success. Various reports on the antitoxin treatment, published during 1897-1899, give the following figures:—
26 cases, with 12 recoveries.
98" 57"
36" 25"
22" 11"
51" 36"
10" 7"
Probably the paper by Dr. Lambert of New York, in the Medical News, July 1900, gives fairly the general opinion of the treatment, so far as the subcutaneous administration of antitoxin is concerned:—
"The following cases of tetanus, treated with antitoxin, comprise published and unpublished cases. We have a total of 279 cases, with a mortality of 44.08 per cent.: but of these we must rule out 17 cases—4 deaths from intercurrent diseases, 8 deaths in cases in which the antitoxin was given but a few hours before death, and 5 recoveries in which antitoxin was not given until after the twelfth day (as they probably would have recovered without it). We have left 262 cases, with 151 recoveries, and 111 deaths, a mortality of 42.36 per cent. Dividing the cases into acute and chronic, we have 124 acute cases, with 35 recoveries and 89 deaths, a mortality of 71.77 per cent., and 138 chronic cases, with 116 recoveries and 22 deaths, a mortality of 15.94 per cent. In interpreting critically these statistics, we see that in acute cases the mortality is but slightly reduced, being but 72 per cent. instead of 88 per cent. But, in the less acute cases, there is a decided improvement, from 40 per cent. to 16 per cent. Taking the statistics as a whole, there is a distinct improvement in the mortality of tetanus since the introduction of antitoxin."
It would be foreign to the present purpose to pursue this matter further: for the other treatments, used by Baccelli and by Krokiewicz, and the sub-dural use of antitoxin, are also founded on experiments on animals; and the same will be true of any better method that shall be developed out of them.
The preventive use of the tetanus-antitoxin, for the immunisation of human beings or of animals, has given excellent results. Horses are very apt to be infected by tetanus; and the antitoxin has been used in veterinary practice, both for prevention and for cure. The curative results are not, at present, very good. But, as regards protection against the disease, there is evidence that horses can be immunised against tetanus by the antitoxin with almost mechanical accuracy. In some parts of the world, the loss of horses by tetanus is so common that their immunity is a very important matter; and that the antitoxin does confer immunity on them is shown by statistics from France and from the United States:—
1. France.—"The results of Nocard's method of preventive inoculations in veterinary practice are most striking. Among 63 veterinarians, there have been inoculated 2737 animals with preventive doses of antitoxin, and not a single case of tetanus developed; while during the same period, in the same neighbourhoods, 259 cases of tetanus developed in non-inoculated animals." (Med. News, 7th July 1900.)
2. United States.—"Joseph MacFarland and E. M. Ranck, in addition to a synopsis of the method of manufacture of tetanus-antitoxin, give some facts of interest and importance in regard to its use for prophylaxis and treatment. The studies were made upon several hundred horses used for the production of various immunised serums in one of the large laboratories of the United States. The horses, because of the constant manipulations, frequently became infected with tetanus, and in 1897 and 1898, when scrupulous cleanliness and disinfection were the only precautions employed to prevent the disease, the death-rate varied from 8 to 10 per cent. During 1899 nearly two hundred horses were subjected to systematic immunisation with tetanus-antitoxin; and, in spite of otherwise similar conditions, the death-rate descended to 1 per cent." (Medical Annual, 1901.)
The preventive use of the antitoxin has, of course, a very limited range outside veterinary surgery. Tetanus, thanks to the use of antiseptic or aseptic methods, not only in hospital surgery but also in amateur and domestic surgery, has become a very rare disease, except in tropical countries. It is no longer a "hospital disease"; and, even in war, it no longer has anything like the frequency that it had, for instance, in the War of the Rebellion. A student may now go all his time at a large hospital without seeing more than a very few cases. But, now and again, attention is called to some wholly unsuspected risk of the disease. For example, certain cases of tetanus occurred in Dundee among workers at the jute-mills there:—
"The last victim was a female worker in the jute-mill, who, six days after a crushed and lacerated wound of the foot, developed tetanus and died within twenty-four hours. Some of the dust, taken from under the machine in which the foot was crushed, was found to contain an unusually large number of tetanus-bacilli. The source of the jute used is India." (Medical News, August 1900.)
Again, at the Gebaer Anstalt at Prague, in 1899, an outbreak of tetanus occurred, with several deaths; but it was stopped when a preventive dose of the antitoxin was given to the new patients on admission.
Again, an amazing number of deaths from tetanus, in the United States, are due to wounds of the hands with toy-pistols. It is said that after the Fourth of July festivities in 1899, no less than 83 cases of tetanus were reported, 26 of them in and around New York. Almost all of them were due to gunshot wounds of the hand with toy-pistols: the unclean wad of the cartridge, made of refuse paper picked up in the streets, penetrates deep into the tissues of the hand, taking the germs of the disease with it, out of the reach of surgical disinfection. These cases of tetanus in the United States from toy-pistol wounds are so frequent, that immunisation has been recommended for them. The Medical News, 1st June 1901, has the following note:—"H. G. Wells states that tetanus is endemic in Chicago, the specific organism being present in the dirt of the streets. Every Fourth of July an epidemic occurs, because these bacilli are carried deeply into wounds before wads from blank cartridges.... The writer thinks that such cases should receive a prophylactic dose, say, 5 c.c. of tetanus-antitoxin, as soon as possible after the wound is first seen. It seems certain that if antitoxin prophylaxis were adopted, there would be no further Fourth of July epidemics, and this end would justify the means."