Stephen Paget

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."

Again, a man might receive a lacerated wound under conditions especially favourable to infection: he might tear his hand in a stable where horses had died of tetanus, or he might cut his finger while he was working at the disease in a pathological laboratory, or he might receive a poisoned arrow-wound out in Africa. In any such emergency, he could safeguard his life with a protective dose of antitoxin.

It remains to be added, that the modern study of tetanus has brought into more general use the old rule that the wounded tissues in a severe case of tetanus should be at once excised. Before Nicolaier's work, while the theory still survived that the disease was due to ascending inflammation of a nerve, this rule was neither enforced nor explained.

The results published during the last few years (Medical Annual, 1905-1906) seem to show that the antitoxin has neither gained nor lost ground as a remedy. It is, of course, used in conjunction with all other remedies. Perhaps, in a few years more, something better will be discovered. And that discovery, when it comes, will be, as it were, Nicolaier's gift. The whole study of the disease goes back straight to the rabbits inoculated in 1880-1884: neither is it possible that the disease should be further studied, without the help of bacteriology.

VI
RABIES

Pasteur's study of rabies began in 1880; and the date of the first case treated—Joseph Meister, a shepherd-boy of Alsace—is July 1885. The first part of the work was spent in a prolonged search for the specific microbe of rabies. It was not found: its existence is a matter of inference, but not of observation.[24] In his earlier inoculations, Pasteur made use of the saliva of rabid animals; and M. VallÉry-Radot tells the story, how Pasteur took him on one of his expeditions:—

"The rabid beast was in this case a huge bull-dog, foaming at the mouth and howling in his cage. All attempts to induce the animal to bite, and so infect one of the rabbits, failed. 'But we must,' said Pasteur, 'inoculate the rabbits with the saliva.' Accordingly a noose was made and thrown, the dog secured and dragged to the edge of the cage, and his jaws tied together. Choking with rage, the eyes bloodshot, and the body convulsed by a violent spasm, the animal was stretched on a table, and kept motionless, while Pasteur, leaning over his foaming head, sucked up into a narrow glass tube some drops of the saliva."

But these inoculations of saliva sometimes failed to produce the disease; and, when they succeeded, the incubation-period was wholly uncertain: it might be some months before the disease appeared. Thus Pasteur was led to use, instead of the saliva, an emulsion of the brain or spinal cord; because, as Dr. DubouÉ had suggested, the central nervous system is the chief seat, the locus electionis, of the virus of rabies. But these inoculations also were not always successful, nor did they give a definite incubation-period.

Therefore he followed with rabies the method that he had followed with anthrax. As he had cultivated the virus of anthrax, by putting it where its development could be watched and controlled, so he must put the virus of rabies in the place of its choice. It has a selective action on the cells of the central nervous system, a sort of affinity with them; they are, as it were, the natural home of rabies, the proper nutrient medium for the virus: therefore the virus must be inoculated not under the skin, but under the skull.

These sub-dural inoculations were the turning-point of Pasteur's discovery. The first inoculation was made by M. Roux:—

"Next day, when I informed Pasteur that the intracranial inoculation offered no difficulty, he was moved with pity for the dog. 'Poor beast, his brain is doubtless injured: he must be paralysed.' Without reply I went down to the basement to fetch it, and let it come into the laboratory. Pasteur did not like dogs, but when he saw this one, full of life, inquisitively rummaging about in all directions, he exhibited the greatest delight, and lavished most charming words upon it."

Henceforth all uncertainty was at an end, and the way was clear ahead: Pasteur had now to deal with a virus that had a definite period of incubation, and a suitable medium for development. The central nervous system was to the virus of rabies what the test-tube was to the virus of fowl-cholera or anthrax. As he had controlled these diseases, had turned them this way and that, attenuated and intensified them, so he could control rabies. By transmitting it through a series of rabbits, by sub-dural inoculation of each rabbit with a minute quantity of nerve-tissue from the rabbit that had died before it, he was able to intensify the virus, to shorten its period of incubation, to fix it at six days. Thus he obtained a virus of exact strength, a definite standard of virulence, virus fixe: the next rabbit inoculated would have the disease in six days, neither more nor less.

As he was able to intensify the virus by transmission, so he was able to attenuate it by gradual drying of the tissues that contained it. The spinal cord, taken from a rabbit that has died of rabies, slowly loses virulence by simple drying. A cord dried for four days is less virulent than one that has been dried for three, and more virulent than one dried for five. A cord dried for a fortnight has lost all virulence: even a large dose of it will not produce the disease. By this method of drying, Pasteur was enabled to obtain the virus in all degrees of activity: he could always keep going one or more series of cords, of known and exactly graduated strengths, according to the length of time they had been dried—ranging from absolute non-virulence through every shade of virulence.

And, as with fowl-cholera and anthrax, so with rabies; a virus which has been attenuated till it has been rendered innocuous, can yet confer immunity against its more virulent forms: just as vaccination can protect against smallpox. A man, bitten by a rabid animal, has at least some weeks of respite before the disease can break out; and, during that time of respite, he can be immunised against the disease, while it is still dormant: he begins with a dose of virus attenuated past all power of doing harm, and advances day by day to more active doses, guarded each day by the dose of the day before, till he has manufactured within himself enough antitoxin to make him proof against any outbreak of the disease.

The cords used for treatment are removed from the bodies of the rabbits, by an aseptic method, and are cut into lengths and hung in glass jars, with some chloride of calcium in them, for drying. The jars are dated, and then kept in glass cases in a dark room at a constant temperature. To make sure that the cords are aseptic, a small portion of each cord is sown on nutrient jelly in a test-tube, and watched, to see that no bacteria occur in the tube. For each injection, a certain small quantity of cord is rubbed-up in sterilised fluid; and these subcutaneous injections give no pain or malaise worth considering.

Of course, the treatment is adjusted to the gravity of the case. A bite through naked skin is more grave than a bite through clothing; and bites on the head or face, and wolf-bites, are worst of all. The number and character of the scars are also taken into account. An excellent description of the treatment, by a patient, was published in the Birmingham Medical Review of January 1898. It gives the following tables of treatment:—

1. Ordinary Treatment.

2. Cases of Moderate Gravity.

Same treatment, up to 13th day.

3. Grave Cases.

Same treatment, up to 10th day.

4. Very Grave Cases.

Same treatment as 3, and in addition.

Furious criticism, unbelief, and flagrant misstatement of facts began at once, and lasted more than two years. Of Pasteur's opponents, the chief was M. Peter, who besought the AcadÉmie des Sciences, about once a week, that they should close Pasteur's laboratory, because he was not preventing hydrophobia but producing it. The value of M. Peter's judgment may be estimated by what he had said, a few years earlier, about bacteriology in general—"I do not much believe in that invasion of parasites which threatens us like an eleventh plague of Egypt. After so many laborious researches, nothing will be changed in medicine, there will only be a few more microbes. M. Pasteur's excuse is that he is a chemist, who has tried, out of a wish to be useful, to reform medicine, to which he is a complete stranger."

But it does not matter what was said twenty years ago. In England, the Report of the 1886 Committee, and the Mansion House meeting in July 1889, mark the decline and fall of all intelligent opposition to the work. Among so many thousand cases, during so many years, it would be a miracle indeed if not a single case had failed or gone amiss; but we are concerned here with the thousands. Take, to begin with, four reports from Athens, Palermo, Rio, and Paris. It is to be noted that the patients, alike at Paris and at other Institutes, are divided into three classes:—

It is to be noted also, as a fact proved beyond doubt, that the full benefit of the treatment is not obtained at once; the highest degree of immunity is reached about a fortnight after the discontinuance of the treatment. Those few cases, therefore, where hydrophobia has occurred, not only in spite of treatment, but within a fortnight of the last day of treatment, are counted as cases where the treatment came too late.

Finally, what was the risk from the bite of a rabid animal, in the days before 1885? It is a matter of guess-work. One writer, and one only, guessed it at 5 per cent.; another guessed it at 55, and a third came to the safe conclusion that it was "somewhere between these limits." Leblanc, who is probably the best guide, put it at 16; and Pasteur himself put it between 15 and 20. But suppose it were only 10; that, before Pasteur, out of every 100 men bitten by rabid animals, 90 would escape and only 10 would die of hydrophobia; then take this fact, that in one year, at one Institute alone, there were 142 patients in class A, bitten by animals that were proved, by the unanswerable test of inoculation, to have been rabid; and 1 death. And every year the same thing; and in all the twelve years together, 2872 such cases (A) and 20 deaths—a mortality not of 10 per cent., but of less than 1 per cent.

1. Athens

The Annales de l'Institut Pasteur, June 1898, contain Dr. Pampoukis' report of three years' work at the Hellenic Institute, from August 1894 to December 1897. During this period 797 cases were treated—590 male and 207 female. The animals that bit them were—dogs, 732; cats, 34; wolf, 1; other animals, 13; and the 17 other patients had been exposed to infection from the saliva of hydrophobic patients. Of the 797 cases, 245 were of class A, 112 B, and 440 C.

"Among the 797 persons treated, there are 2 deaths, one in class B and the other in class C. Thus the mortality has been 0.25 per cent. Besides these 2 who died of rabies there are 5 more, in whom the first signs of rabies showed themselves in less than fifteen days after the last inoculation.

"Finally, beside these 797 cases, there is 1 other case, bitten by a wolf, in which the treatment failed. If we reckon this last case in the statistics of mortality, we have 3 deaths in 798 cases = 0.37 per cent.

"Beside these 798 cases treated at the Institute, there have been others that have not undergone the antirabic treatment, having trusted the assurances of those who are called in Greece empirics. Among these non-treated cases there are 40 who have died of rabies."

2. Palermo

The Annales for April 1896 give the report by Dr. de Blasi and Dr. Russo-Travali of the work of the Municipal Institute at Palermo during 8-1/2 years, from March 1887 to December 1895. The number of cases was 2221; in 1240 (class A), the animals were proved to have been rabid by the result of inoculations; in 981, there was reason to suspect rabies.

"Setting aside 5 patients who died during the course of the treatment, and 5 others who died less than fifteen days after the end of the treatment, we have had to deplore only 9 failures = 0.4 per cent. Even if we count against ourselves the 10 other cases, the mortality is still only 0.85."

3. Rio de Janeiro

The Annales for August 1898 give Dr. Ferreira's report of ten years' work (February 1888 to April 1898) at the Pasteur Institute at Rio. The number of cases treated was 2647, of whom 1987 were male and 660 female. Beside these 2647 there were 1234 who were not treated, because it was ascertained that they were in no danger of rabies; 3 who were brought to the Institute, already suffering from the disease; and 59 who refused treatment.

Of the 2647 persons treated, 10 had pricked their hands at work in the laboratory, 3 had exposed chance scratches on their hands to the saliva of rabid animals, and 1 had been bitten by a rabid patient. Of the rest, 1886 had been bitten on the bare skin, and 747 through clothing.

In 236 cases the rabies of the animal had been proved by inoculation. In 1173 it had been recognised by the signs of the disease. In 1238 there was good reason to suspect that the animal had been rabid.

Of the 2647 patients, in 30 cases the treatment was stopped, because the animals were at last traced, after treatment was begun, and were found not to be rabid. In 65 cases the patients, after treatment was begun, refused to go on with it, and 3 of them died of rabies. In 6 cases rabies developed during treatment; 5 of them had been very badly bitten about the head, and 1 did not come for treatment till the twenty-first day after the bite, and was attacked by rabies two days later. And 5 cases died of other maladies that had nothing to do with rabies. Setting aside these 106 cases, there remain 2541 cases, with 20 deaths = 0.78 per cent. But, of these 20 deaths, 9 occurred within fifteen days of the end of treatment, before protection was fully established. If these 9 deaths be excluded, the figures stand at 2532 cases, with 11 deaths = 0.43 per cent.

4. Paris

Dr. Pottevin's report on the work of the Pasteur Institute (Paris) during 1897 (Annales, April 1898) must be given word for word, without abbreviation.

I

During 1897, 1521 patients received the anti-treatment at the Pasteur Institute: 8 died of rabies. The notes of their cases will be found at the end of this paper.

If we exclude 2 of these 8 cases—the cases of Heniquet and Morin, where death occurred before it was possible for the vaccinations to produce their effect—the results of the vaccinations in 1897 are

In the following table these figures are compared with those of preceding years:—

II

Patients treated at the Pasteur Institute are divided into three classes, as follows:—

A. The rabies of the animal was proved by experiment, by the development of rabies in animals inoculated with its bulb (the upper end of the spinal cord).[25]

B. The rabies of the animal was proved by veterinary examination (dissection of its body).

C. The animal was suspected of rabies.

We give here the patients treated in 1897, under these three classes:—

The following tables, giving the results obtained since the vaccinations were first used, show that the gravity of the bites varies with their position on the body, and that the mortality is always below 1 per cent. among patients bitten by dogs undoubtedly rabid:—

III

In regard to their nationality, the 1521 patients treated at the Pasteur Institute in 1897 were as follows:—

That is, 175 foreigners and 1346 French.

IV

Notes of the eight cases where the treatment failed:—

1. Camille Bourg, 26. Bitten 11th April; treated at the Pasteur Institute, 13th to 30th April; died of rabies at the LariboisiÈre Hospital, 26th May. Six penetrating bites on the ball of the left thumb. The dog was examined by M. Grenot, a veterinary surgeon at Paris, and the dissection gave evidence of rabies. Another person bitten and treated at the same time as Bourg is now in good health.

2. Louis Fiquet, 23. Bitten 22nd April; treated at the Pasteur Institute, 23rd April to 10th May; died of rabies at the Necker Hospital, 4th June. Five bites, two of them deep, round the right thumb. They had been cauterised five hours after infliction. The dog was examined by M. CaussÉ, a veterinary surgeon at Boulogne, and the dissection gave evidence of rabies. Another person bitten at the same time as Fiquet is now in good health.

3. Annette Beaufort, 19. Licked on the hands, which were chapped, on 15th April. The dog was killed next day, examined, and declared to have been rabid by M. Lachmann, a veterinary surgeon at Saint-Étienne. Treated at the Pasteur Institute, 20th April to 7th May. Died of rabies 14th October. Two other persons bitten by the same dog and treated at the Pasteur Institute are now in good health.

4. Julien Heniquet, 53. Bitten 11th March, by a dog that M. Jenvresse, veterinary surgeon at Beaumont-sur-Oise, declared after dissection to have been rabid. One bite had torn the lower lip, the wound had been sutured; three other wounds on the nose. The wounds had not been cauterised. Treated at the Pasteur Institute, 18th May to 5th June. First symptoms of rabies showed themselves 4th June, before the treatment was finished; died 7th June. As the disease had its onset during the course of the inoculations, this case should be excluded from the number of those who died of rabies after treatment.

5. Germain Segond, 7. Penetrating bite on the bare right fore-arm, 23rd May. Cauterised an hour later with a red-hot iron. Treated 26th May to 9th June; died of rabies 22nd July. The dog's bulb had been sent to the Pasteur Institute. A guinea-pig inoculated in the eye 26th May was seized with rabies 10th September.

6. Suzanne Richard, 8. Bitten 12th June on the left leg by a dog, found on dissection to have been rabid by M. Touret, veterinary surgeon at Sannois. The bite, penetrating 3 cm. long, had been sutured; it had been made through a cotton stocking, and had been cauterised in half-an-hour. Treated 13th to 30th June; died of rabies 2nd August. (Notes from M. le Dr. Margny, at Sannois.)

7. Joseph Vaudale, 33. Bitten on the left hand, 8th August. Six penetrating bites on the back of the hand; had not been cauterised. The dog was declared rabid by M. Verraert, veterinary surgeon at Ostend. Treated at the Pasteur Institute, 11th to 28th August; died of rabies 27th September.

8. Paul Morin, 38. Bitten 24th August on the left cheek, a single bite, 2 cm. long; no cauterisation. The dog was sent to the Alfort School, 25th August, and found to be rabid. Treated at the Pasteur Institute, 26th August to 15th September. Died of rabies some days after the end of treatment (three weeks after the bite, says a note sent to us). The interval between the end of the treatment and the onset of the disease being less than fourteen days, Morin must not be counted in the number of patients inoculated under conditions which permit successful inoculation.

We hardly need follow the work of the remaining years. The figures are as follows:—

The falling off in the number of patients at the Paris Institute is related to the establishment of similar Institutes at Lyon, Marseilles, Bordeaux, Lille, and Montpellier. But is it not possible that a patient, after treatment at the Paris Institute, should die at home of rabies, and his death not be notified to the Institute? The answer is, that the Institute is very careful, so far as possible, to keep in touch with its old patients. For instance, in 1903, it recorded the case of a carpenter in a Welsh village, who had died of rabies nearly two years after treatment. And, of course, an Institute patient, wherever he was, would be of interest to his neighbours: and a death from rabies would excite attention, and would hardly fail to be reported.

It is not impossible that some sort of intensive modification of Pasteur's treatment may be found, not for the prevention, but for the cure of hydrophobia; and two successful cases of this kind have been reported in the Annales of the Paris Institute. Apart from this faint hope, the cure of hydrophobia is where it was in the days of the "Tonquin medicine" and the "Tanjore pills."

VII
CHOLERA

The study of cholera was the hardest of all the hard labours of bacteriology; it took years of work in all parts of the world, and the difficulty and disappointments over it are past all telling. Koch's discovery of the comma-bacillus (1883) raised a thousand questions that were solved only by infinite patience, international unity for science, and incessant research; and the Hamburg epidemic (1892) marks the time when the comma-bacillus was at last recognised as the cause of cholera. A mere list of the men who did the work would fill page after page; it was bacteriology in excelsis, often dangerous,[26] and always laborious.

There is the same heroic note in the story of the preventive treatment of cholera by Haffkine's method; one of the men in whom Pasteur seems to live again. He began in 1889, under Pasteur's guidance, to study the immunisation of animals against the cholera-bacillus. Other men, of course, were working on the same lines—Pfeiffer, Brieger, Metchnikoff, Fischer, GamaleÏa, Klein, Wassermann, and many more—and by 1892 the immunisation of animals was proved up to the hilt. Then came the advance from animals to men, from laboratories to Indian cities, villages, and cantonments; and here the honour is Haffkine's, and his alone. Ferran's inoculations (Spain, 1885) had failed. Haffkine, having tested his method on himself and his friends, went to India, with a commendatory letter from the British Government:—

He reached Calcutta in March 1893, and at the request of Mr. Hankin[27] was invited to Agra; here, in April, he vaccinated over 900 persons, including many English officers. From Agra to Aligarh; and from Aligarh he was asked to more places than he could visit. In 1895 his health failed, and no wonder; and he came back to Europe for a short time:—

"My actual work in India lasted twenty-nine months, between the beginning of April 1893 and the end of July 1895. During this period the anti-cholera vaccination has been applied to 294 British officers, 3206 British soldiers, 6629 native soldiers, 869 civil Europeans, 125 Eurasians, and 31,056 natives of India. The inoculated people belonged to 98 localities in the North-West Provinces and Oudh, in the Punjab, in Lower Bengal and Behar, in the Brahmaputra Valley, and in Lower Assam. No official pressure has been brought on the population, and only those have been vaccinated who could be induced to do so by free persuasion. In every locality, efforts were made to apply the operation on parts of large bodies of people living together under identical conditions, in order to compare their resistance in outbreaks of cholera with that of non-inoculated people belonging to the same unit of population. This object has been obtained in 64 British and native regiments, in 9 gaols, in 45 tea-estates, in the fixed agricultural population of the villages parallel to HardwÂr pilgrim road, in the bustees of Calcutta, in a certain number of boarding-schools, where the parents agreed to the inoculation of their children, in orphanages, etc. The vast majority of inoculated people lived thus under direct observation of the sanitary and medical authorities of India." (Haffkine, Lecture in London. British Medical Journal, 21st Dec. 1895.)

Altogether, upwards of 70,000 injections on 42,179 people—without having to record a single instance of mishap or accident of any description produced by our vaccines. Consider the colossal difficulties of this new treatment: the frequent running short of the vaccine, preventing a second injection; the absolute necessity, at first, of using very small doses of a weak vaccine, lest one disaster should occur; the impossibility of avoiding, now and again, some loss of strength in the vaccine; the impossibility of knowing how long the protection would last. Surely in all science there is nothing to beat this first voyage of adventure single-handed to fight the cholera in India.

Later than Haffkine's 1895 report, we have Dr. Simpson's 1896 report: "Two Years of Anti-choleraic Inoculations in Calcutta. W. J. Simpson, M.D., M.R.C.P., D.P.H., Health Officer, Calcutta." The date of this report is 8th July 1896; and it gives not only the Calcutta results, but all that are of any use for exact judgment:[28] —

"The results of Calcutta are fully confirmed by those obtained in other parts of India, wherever it was possible to make all the necessary observations with precision, and wherever the cases were sufficiently numerous to show the effect of the inoculation.

"Outside Calcutta, since the commencement of the inoculations in India in April 1893, opportunities for an exact comparison of the respective powers of resistance against cholera of inoculated and non-inoculated persons presented themselves; (1) in Lucknow, in the East Lancashire Regiment; (2) in Gaya, in the jail; (3) in Cachar, among the tea-garden coolies; (4) in Margherita, among coolies of the Assam-Burmah Railway Survey; (5) in Durbhanga, in the jail; (6) in the coolie camp at Bilaspur; (7) in Serampur, among the general population."

Here, then, in this 1896 report, are all the results that give an answer to the question, What will happen when cholera breaks out among a number of people living under the same conditions, of whom some have received preventive treatment, and the rest have been left to Nature?

I. Calcutta (1894-1896)

Nature gave a demonstration in 77 houses. In one house, and one only, all the household had been inoculated; in 76, inoculated and non-inoculated were living together; but of these 76 houses, 6 are excluded from the table of results, because the inoculated in them were so few—less than one-tenth of the household—that their escape from cholera might be called chance. The cholera came, and left behind it this fact:—

If we add the 6 houses which Dr. Simpson excludes, we find that in 77 houses there were 89 deaths from cholera, 77 being among the uninoculated and 12 among the inoculated.

Moreover, of these 12 deaths, 5 occurred during the first five days after inoculation—that is to say, during the period in which the protective influence of the vaccine was still incomplete. Then came a period of more than a year, during which the uninoculated had 42 deaths, and the inoculated had one death. The remaining 6 of the 12 deaths occurred more than a year after inoculation, and 5 of these 6 had received only one inoculation of the weak vaccine that was used early in 1894.

Take a good instance that came at the very beginning of the work:—

"A local epidemic took place around two tanks in Kattal Began bustee, ward 19, occupied by about 200 people. In this bustee, about the end of March, 2 fatal cases of cholera and 2 cases of choleraic diarrhoea occurred. The outbreak led to the inoculation of 116 persons in the bustee out of the 200. Since then, 9 cases of cholera, of which 7 were fatal, and 1 case of choleraic diarrhoea have appeared in the bustee, and it is a very extraordinary fact that all these 10 cases of cholera have occurred exclusively among the uninoculated portion of the inhabitants, which, as stated, forms the minority in the bustee; while none of the inoculated have been affected." (Cholera in Calcutta in 1894. W. J. Simpson.)

2. Lucknow (1893)

The story of the outbreak of cholera in the East Lancashire Regiment must be read carefully:—

"Rumour magnified the events connected with this outbreak, and distorted the facts connected with the inoculations; and as a result, the current of public opinion, which had previously been in favour of inoculation, set in strongly in the opposite direction. The advocates of anti-choleraic inoculations were abused in no particularly measured terms, and the inoculations were held up to be the source of every possible evil and danger ... of the most loathsome diseases, and of every ill which man is heir to. The distrust engendered by these misrepresentations and fulminations was, however, only of a temporary nature; and when the exact circumstances came to be known and understood, the confidence created by the Calcutta experience began to be considerably restored. Inoculations were performed in May 1893, in the East Lancashire, Royal Irish, 16th Lancers, 7th Bengal Infantry, 7th Bengal Cavalry, and general populations in the Civil Lines. In 1894, cholera appeared among the native population of Lucknow, in the form of an epidemic distinguished by its extreme virulence, patients succumbing in the course of a few hours. It is stated that the epidemic was of a most malignant type. In the latter part of July it entered the cantonments, and attacked the East Lancashire, almost exclusively confining its ravages to that regiment."

In the East Lancashire, 185 men were inoculated in May 1893. From the statistical returns obtained from the military authorities at Lucknow, it appears that at the time of the outbreak, in July 1894, the strength of the men, including those in hospital, was 773; and of these, 133 had been inoculated, as recorded in the inoculation register, and 640 had not been inoculated.

The following table shows the total number of attacks and deaths in not inoculated and inoculated:—

The men were moved into camp; but this movement seemed only to make things worse: "the epidemic in the camp appears to have been twice as severe as in the cantonment."[29]

Lucknow came so early in the work of inoculation, that weak vaccines were used in small doses. The cholera, when it broke out, was "of a most malignant type, senior medical officers of long experience in the country stating that such a virulent cholera had not been seen by them for very many years past." More than a year had elapsed between the inoculations and the outbreak of the cholera. It is no wonder that the regiment was not well protected:—

"The small amount of protection which the inoculations afforded in this case may have depended on the mild effects which the injections produced on the men at the time of the operation in 1893, in comparison with the severity of the epidemic which attacked the regiment. It is recorded in the Lucknow Inoculation Registers that only in two men, out of the 185 inoculated in 1893, a marked febrile reaction was obtained; in 77 individuals the vaccinal fever was only slight, while in 66 there was no reaction: an effect which was due to the weakness of the vaccines procurable at that period of work, and to the small doses used. The influence of the vaccines was possibly further reduced, at the time of the epidemic, by a lapse of fourteen to fifteen months." (Haffkine, 1895 Report.)

3. Gaya Jail

On 9th July 1894, an outbreak of cholera occurred in the Gaya jail, and by 18th June there had been 6 cases and 5 deaths. On that day and the next day, 215 prisoners were inoculated. The average number of the prisoners during the outbreak was 207 inoculated, and 202 not inoculated. Surgeon-Major Macrae, superintendent of the jail, reports:—

"The inoculations being purely voluntary, no selection of prisoners was possible, but all classes of the jail were represented—male and female, old and young, habituals and less frequent offenders, strong and weakly, convalescent and even hospital patients sent their representatives; no difference of any kind was made between inoculated and non-inoculated; they were under absolutely identical conditions as regards food, water, accommodation, etc., in fact in every possible respect."

Of course, the best results could hardly be obtained, because the cholera was already at work: it took about ten days for the 1894 vaccine to produce its full effect; and two inoculations were generally made, one five days after the other. This gradual action of the vaccine is well shown in Dr. Simpson's table:—

Haffkine's comment on these figures must be noted here:—

"In the Gaya jail, the inoculations were for the first time applied in a prevalent epidemic, and very weak doses of a relatively weak vaccine were used.... Far higher results have been obtained by an application of stronger doses. In the bustees situated round the tanks in Calcutta, where cholera exists in a permanent state, the disease occurred in 36 houses with inoculated people. In each of these houses there was one part of the family inoculated and another not. The observations were continued for 459 days, with the following results:—

During the first period of 5 days, subsequent to the inoculation with first vaccine, cholera occurred in 8 houses.

75 non-inoculated had 5 cases, with 3 deaths. 52 inoculated had 3 cases, with 3 deaths.

During the second period of 5 days, subsequent to the second inoculation, cholera occurred in 2 houses.

8 non-inoculated had 2 cases, with 2 deaths. 17 inoculated had no cases.

After the 10 days necessary for the preventive treatment had expired, and up to the 459th day, the disease visited 26 houses.

4. Assam-Burmah Railway

For a good instance of lives saved even during an outbreak, take the Assam-Burmah Railway coolies:—

"Three hundred and fifty [30] Khassia Hill coolies had been collected for the survey party of the Assam-Burmah Railway, and put under the escort of a detachment of Goorkhas, when cholera broke out amongst them. The largest part of the coolies immediately submitted to the preventive inoculation, the rest remained uninoculated. The result was that among the not-inoculated minority there were 34 cases, with 30 deaths; whereas the inoculated had 4 fatal cases." (Haffkine, 1895, Lecture in London.)

5. Durbhanga Jail (1896)

The figures in this instance are small: but Surgeon-Captain E. Harold Brown's report is very pleasant reading. Cholera broke out in the jail on 31st March 1896, and by 9th April there had been 8 cases. Next day, 172 prisoners were moved into camp 12 miles away; and 53 were left behind, the sick in the jail hospital, the patients in the cholera huts, with their attendants, the old and infirm, and a few cooks and sweepers. That day, 3 cases occurred in the camp, and 1 in the jail; and on the 11th, at 2 and 4 a.m., 2 more cases were reported in camp. At 7.30 a.m., Haffkine and Dr. Green came to the camp:—

"The prisoners were spoken to on the subject, and seemed to be pleased with the idea, the word tika (inoculation), which was familiar to them from its association with smallpox, appearing to appeal to them. They were accordingly arranged in four rows facing the tent, in front of which Dr. Haffkine was about to commence operations. I was the first subject to be inoculated; and after me the jailor, assistant jailor, hospital assistant, and three warders. The first prisoner in the front rank was next brought up and submitted cheerfully; after which, every alternate man was taken, so that no selection of cases was made, until one-half of the total number were inoculated. Those who had not been inoculated were far from pleased at having been passed over; and, to our surprise, they rose almost to a man, and begged to be inoculated; nor were they satisfied when told that the medicine was exhausted."

The dose administered on this occasion (11th April 1896) was stronger than the Gaya jail dose (18th July 1894): it acted in a few hours, and the reaction was well marked.

"There were fresh cases of cholera that day at 12 (noon), 6, 7, and 7.30 p.m., and at midnight, all in those who had not been inoculated, and all terminating fatally, despite the greatest care and the most prompt and assiduous treatment. On the 12th two further cases occurred, both among the uninoculated, and both died; there being thus eight cases in succession, all from the men who were not inoculated, and all proving fatal."

The inoculations were made at 7.30 A.M. Surgeon-Captain Brown had pain within half-an-hour, and fever in three hours, with temperature 104°, but this was probably due to the fact that I was not able to rest. The prisoners, of course, went to bed: they all reacted before 4 P.M., but did not have so much trouble over it. The last case was on the 15th. The outbreak was a bad type of cholera; out of 30 cases 24 died, some of them in 1-1/2 to 4 hours. "To summarise the combined results of the camp and the jail, we find that of a daily average of 99 non-inoculated there were 11 cases, all fatal = 11.11 per cent.; of 110 inoculated there were 5 cases, with 3 deaths = 2.73 per cent."

6. Bilaspur and Serampur

Here again the figures are small, but worth noting. In a coolie camp at Bilaspur (Central Provinces) 100 non-inoculated had 5 deaths, and 150 inoculated had 1 death. In Serampur, among the general population, 51 non-inoculated had 5 cases and 3 deaths, and 42 inoculated had 2 cases and 1 death.

7. The Cachar Tea-Gardens (1895)

This series of inoculations was begun in February 1895, for the protection of the coolies on various tea-estates. The results are excellent, and deal with large numbers.[31] The latest report from Dr. Arthur Powell, the Medical Officer, is quoted in Dr. Simpson's 1896 report:—

To the preceding instances, which are rather old now, must be added the following more recent report, from the Indian Medical Gazette, September 1901:—

"We are glad to see, from a paragraph in the Report of the Sanitary Commissioner for Bengal (Major H. J. Dyson, I.M.S., F.R.C.S.), that an increased number of anti-cholera inoculations were performed during the year 1900. Assistant-Surgeon G. C. Mukerjee, who was in charge of this work, reports that in the Puralia Coolie Depot no less than 13,291 persons were inoculated against cholera, including over 1000 children. All these cases of inoculation were among labour emigrants proceeding to the tea-gardens of Assam and Cachar. The employers of labour are beginning to realise the value of cholera inoculation. It is unfortunately not always easy, or even possible, to follow up the after-history of persons inoculated; but Major Dyson has quoted a table, received from the Superintendent of Emigration, which shows the number of cases among the inoculated and the non-inoculated at Goalundo. From this table, it is seen that out of 1527 non-inoculated coolies, who passed through Goalundo, 33, or 2.09 per cent., got cholera; whereas of 873 inoculated coolies, only 2, or 0.2 per cent., were attacked by the disease; that is, the unprotected suffered about ten times as much as the inoculated. Assistant-Surgeon Mukerjee also reports that during his cold-weather tour he passed through some villages in the Manbhum district, in which he had practised inoculation the previous year: and, though there had been epidemics of cholera in them, the inoculated persons escaped. They came to him in numbers, stating that they owed their safety to the inoculation."

Of course, the preventive treatment touches points only here and there on the map of India, with its 300,000,000 people. Probably it will never become so general in India as vaccination. Cholera in India recalls what Ambroise ParÉ, more than 400 years ago, wrote of the plague, "Here in Paris it is always with us." But, wherever preventive inoculation has been done, there it has done good.

The Medical Annual for 1905 contains an account of some preventive inoculations recently made during an epidemic in Japan. Among the inoculated, the attack-rate was much lower than among the uninoculated; and the mortality was 45.5 per cent., as against 75 per cent.

Another most important result of the discovery of the cholera bacillus is its use in diagnosis. For example, if a case of suspected cholera is landed at a British port, the sanitary authority at once takes steps to ascertain whether the specific microbe is present; and, according to the answer given by bacteriology, either allows the patient to proceed on his journey, or adopts measures of isolation to prevent the spread of the disease to others. Thus, thanks to the insular position of Great Britain, this dreadful disease has for many years been prevented from invading her population.

VIII
PLAGUE

The bacillus pestis was discovered by Kitasato and Yersin, working independently, in 1894. Yersin's discovery was made at Hong Kong, whither the French Government had sent him to study plague: an excellent account of his work is given in the Annales de l'Institut Pasteur, September 1894. The first experiments in preventive inoculation, in animals, were made by Yersin, Calmette, and Borrel, working conjointly, in 1895. They found that it was possible to confer on animals a certain degree of immunity, by the hypodermic injection of dead cultures of the bacillus. These experiments were made on rabbits and guinea-pigs.

Haffkine's fluid was first used on man in January 1897. It is a bouillon containing no living bacilli, and nothing offensive to the religious beliefs of India.[33] He proved its efficacy on rabbits; and then, on 10th January 1897, inoculated himself with a large dose, four times as strong as the subsequent standard dose. A few days later, Lieut.-Col. Hatch, Principal of the Grant Medical College, Bombay, and other members of the College Staff, were inoculated. These first inoculations were described by Haffkine in a lecture (1901) at Poona:—

"In a short time, a number of the most authoritative physicians in Bombay, European and native, official medical officers and private practitioners, submitted themselves for inoculation. It is a matter of gratification to me to be able to quote, among these authorities, the Head of the Medical Service of the Presidency, Surgeon-General Bainbridge, who not only got himself inoculated, but inoculated also the members of his family. Previous to that, Surgeon-General Harvey, the able Director-General of the Indian Medical Service, submitted himself to inoculation in 1893 against cholera; and, in 1898, against plague. It was the example of these gentlemen, whose competence in the matter of health could not be disputed, that encouraged thousands of people, rich and poor, in Bombay and elsewhere, to come forward for inoculation. Thus his Excellency the Viceroy thought it right to tell you here, in Poona, that previous to his starting for the plague-stricken districts he and his staff had also undergone the prophylactic inoculation. In due course, mothers brought their children to be protected by the new 'vaccination.'"

Within a few months, 8142 persons in or near Bombay were inoculated. It was not possible, in Bombay, during the rush of plague-work, to follow up every one of these 8142 persons. But there is reason to believe, making some allowance for oversights, that only 18 = 0.2 per cent. of them, were attacked during the epidemic; that, of these 18, only 2 died: and that these 2 died within twenty-four hours of inoculation, i.e., had the plague in them already at the time of inoculation.

And, with regard to a small group of the inoculated, there are the following more definite facts. This group lived outside Bombay, across the harbour, in a village called Mora. The population of Mora, at the time of the epidemic, was estimated at less than 1000. Out of this number 429 were inoculated; which, if the population be reckoned at 1000 exactly, left 571 uninoculated. Among the 429 inoculated, there were 7 cases of plague, with no deaths: among the uninoculated there were 26 cases, with 24 deaths.

Just a week after Haffkine had informed the Indian Government that he had tested his fluid on himself, plague broke out in the Byculla House of Correction, Bombay, on 23rd January 1897. Between the 23rd and the afternoon of the 30th, there were 14 cases, with 7 deaths. On the afternoon of the 30th, 152 prisoners were inoculated, and 172 were left uninoculated. The outbreak ceased on 7th February. The figures, as corrected by the Plague Commission, are, among the inoculated, 1 case, which recovered; among the uninoculated, 7 cases, with 2 deaths.

For a full and severe examination of the reports, statistics, and other evidence concerning this and other outbreaks in which preventive inoculations were made, the Report (1901) of the Indian Plague Commission must be studied. The Commissioners, Professor T. R. Fraser, Mr. J. P. Hewett, Professor (now Sir) A. E. Wright, Mr. A. Cumine, Dr. Ruffer, and Mr. C. J. Hallifax, Secretary, travelled and took evidence in India from November 1898 to March 1899: during which time they held 70 sittings and examined 260 witnesses, some at great length. The evidence and the report are published in five large volumes. The report, 540 pages in all, deals exhaustively with the whole subject. It represents the very least—what might almost be called the very worst—that can be said of Haffkine's fluid: and, of course, it reads rather differently from the reports of the men who, with their lives in their hands, and worked almost past endurance, fought plague themselves. The following paragraphs give, so far as possible, the bare facts of various outbreaks of the disease in 1897-99, in which Haffkine's fluid was used.

1. Daman

Plague broke out in Daman, a town in Portuguese territory, north of Bombay, and in constant communication with Bombay by sea, in March 1897. By the end of the month, when a Government cordon was placed round the town, about 2000 out of 10,900 had fled. The outbreak reached its height in mid-April, and was practically over by the end of May. Inoculations were begun on 26th March. The total population on that day (2000 having gone out, and 670 having died of plague) is estimated at 8230. Of these, 2197 were inoculated, and 6033 were left uninoculated. Among the inoculated there were 36 deaths = 1.6 per cent.; among the uninoculated 1482 deaths = 24.6 per cent.

The Commissioners criticise these figures severely, and do not accept them as exact. But they admit the evidence as to the results of inoculation among the Parsee community of Daman. Of this community, 306 in number, 277 were inoculated, and only 29 were left uninoculated. Among the inoculated there was 1 death = 0.36 per cent.: among the uninoculated there were 4 deaths = 13.8 per cent.

They admit, also, the house-to-house investigations made by Major Lyons, I.M.S., President of the Bombay Government Plague Committee. At the end of May, he visited 89 houses, in 62 of which both inoculated and uninoculated were living together. He found that out of 382 inoculated, 36 had died = 9.4 per cent.; out of 123 uninoculated, 38 had died = 30.9 per cent.

2. Lanauli

Plague attacked Lanauli, a small hill-station and railway depot, during April to September 1897. The entire population was estimated at about 2000. Inoculations were begun on 24th July in two wards of the town, and a daily house-to-house inspection was instituted. The figures reported, on the basis of the average daily strength of the two groups, are as follows:—

The Commissioners criticise the method on which these figures are based, and do not accept them as accurate. But they agree that inoculation "exerted a distinct preventive effect"; and they admit Major Baker's evidence—"In the place where inoculation had been made use of, the town was thriving and full of people; and the other part of the town was absolutely empty. One side had plague, and the other had none."

3. Kirki

The figures here were obtained under especially favourable circumstances; and the Commissioners have, practically, no fault to find with their accuracy. The following account is by Surgeon-Major Bannerman, Superintendent of the Plague Research Laboratory, Bombay:—

4. Belgaum

In Belgaum, a town of Southern India with a normal population of about 30,700, two outbreaks of plague occurred in quick succession. The first outbreak lasted from November 1897 to May 1898; the second, from July 1898 to January 1899. During the two epidemics, 2466 persons were inoculated. Of these, it was reported that only 61 (or 62) had been attacked, of whom 33 died = 1.34 per cent. But these figures, in the judgment of the Commission, cannot be accepted as even approximately correct. There are, however, two groups of these Belgaum cases, one of which the Commission admits as substantially accurate, and the other as absolutely accurate. These groups are, (1) the Army cases; (2) the cases reported by Major Forman, R.A.M.C., Senior Medical Officer of the Station.

(1) The Army Cases.-These cases occurred in the 26th Madras Infantry, which was living in lines close to the cantonment and the city. The first case of plague in the regiment was on 12th November 1897. Ten days later, the regiment was moved out into camp. Inoculation was begun, by Surgeon-Major Bannerman, on 23rd December, up to which time there had been, among the regiment and its families and followers, 78 cases, with 49 deaths. The following account of the inoculations is given by Surgeon-Major Bannerman:—

"No difficulty was experienced in persuading the men to consent to inoculation, when it was explained to them that they would be free to return to their houses in the lines after being operated on. General Rolland was the first to be operated on, and his example, combined with that of the officer commanding, and their medical officer, who were all operated on in front of the men, sufficed to convince the Sepoys of the harmlessness of the operation: and the only difficulty that then remained was to perform the operation fast enough.... The community was, practically, completely inoculated by the end of the year. The total operated on was 1665, out of a population of 1746 living in the lines at that date. The 81 not operated on were infants, women far advanced in pregnancy, and the sick in hospital chiefly, though one solitary Sepoy has, up to the present time, refused to submit to operation."

From this time onward to the end of the first epidemic, though the disease was at its height in January in the neighbouring city and cantonment, and though the men were allowed to go freely to these places after inoculation, only 2 out of the 1665 were attacked, and both recovered.

When the second epidemic came, in July 1898, the troops, families, and followers, were reinoculated at their own request, 1801 in all. "Practically no one was left in the lines unprotected by inoculation." From this time onward to the end of the second epidemic, though it was much more severe than the first, only 12 cases occurred. In the first epidemic, before inoculation, 78 cases occurred, and 2 after it: in the second, and much more severe, epidemic, though the sanitary measures adopted in both epidemics were similar, only 12 cases occurred. "It would hardly appear to be open to doubt," says the Commission, "that the practical immunity of the regiment, during the second outbreak, was due to inoculation."

(2) Major Forman's evidence before the Commission is very striking, though the figures are small. The following abstract of it is given in the Report of the Commission:—

5. The Umarkhadi Jail, Bombay

Plague broke out in this jail on the last day of 1897, and 3 prisoners died. Next day, 1st January 1898, all the prisoners were paraded, and all were willing to be inoculated. But it was decided to divide them into two equal groups, and inoculate one group. There were 402 altogether: 2, when their turn came, refused to be inoculated: thus 199 were inoculated, and 203 were left uninoculated. No distinction was made between the two groups: "They had the same food and drink, the same hours of work and rest, and the same accommodation." The plague did not come wholly to an end till March. The figures, since the inmates of a jail are a shifting population, are based on the average daily number of each group: this was 147 for the inoculated, and 127 for the uninoculated. The figures are:—

The Commission draw attention to "the important fact that, during the whole period of the outbreak, the number of attacks among the inoculated was only one-third of the number among the uninoculated; and that the disease among the inoculated was remarkably mild, resembling mumps more than plague, though the cases among the uninoculated were of average severity." According to Surgeon-Major Bannerman, the hospital authorities were doubtful whether these three cases among the inoculated were plague at all.

6. Undhera

The figures for Undhera are very valuable: "The conditions," says Surgeon-Major Bannerman, "approached very nearly the strictness of a laboratory experiment." Even the Commissioners are enthusiastic here.

Undhera is an agricultural village, 6 miles from Baroda. Plague broke out in it, in January 1898. A careful census was taken, and showed a population of 1029. By 12th February there had been 76 deaths. On that day the village was visited by Mr. Haffkine, Surgeon-Major Bannerman, and other experts, and 513 persons were inoculated:—By reference to the census papers, the whole of the inhabitants were called out, house by house, and the half of each household inoculated. In this way, an endeavour was made to inoculate half the men, half the women, and half the children in each family, and to arrange that a fairly equal proportion of the sickly-looking should be placed in each division. The plague lasted 42 days after the inoculations, and affected 28 families. On 4th April a house-to-house investigation was made by Mr. Haffkine, Surgeon-General Harvey, Surgeon-Major Bannerman, and Captain Dyson. The figures are as follows:—

Thus, out of 28 families, where the protected and the unprotected lived and ate and slept together, the protected, 71, had 3 deaths; and the unprotected, 64, had 27. The percentage of attacks was four times higher among the unprotected; the percentage of deaths was ten times higher.

7. Khoja Community, Bombay

The head of this community, H.H. Sir Sultan Shah, Aga Khan, K.C.I.E., opened a private station for the inoculation of the community in March 1897, and again in December of that year. He was himself inoculated three times, and many of the community so often as five times. The work of inoculation went on daily, and by 20th April 1898 the number of persons inoculated or reinoculated was 5184. The whole community, according to a careful census taken at the beginning of 1898, numbered 9350; but, since many families had fled to avoid the infection, this number is too low. The Commissioners guess 9770: Haffkine, to the disadvantage of his own statistics, guesses so high as 13,330. The number of the inoculated or reinoculated shifted, of course, as the work went on: their average daily number during the four months of plague, January to April 1898, was 3814.

During these four months, the number of deaths from all causes in the whole community was 184. According to the average mortality of the community in times of no plague, the deaths from all causes during four months would be 102. It may fairly be assumed that the extra deaths, 82, were due to plague: and, indeed, 64 plague-deaths were either acknowledged by the relatives, or certified by the burial-books of the community. Of these 82 deaths, 3 occurred among the inoculated or reinoculated, and 77 among the uninoculated.

The Commissioners find fault with these figures: "Nevertheless, quite apart from the statistics put before us, which we think inaccurate, we do not doubt that inoculations had a good effect, especially as much weight must be allowed to the opinion of a community so intelligent as that of the Khojas."

8. Hubli

This, the greatest and most amazing of all instances of preventive plague-work, was done in a town of 50,000 persons. The following report, by Surgeon-Captain Leumann, was forwarded to the Plague Commissioners by Mr. E. K. Cappel, Collector of DhÁrwÁr, with this comment:—

The Hubli report must be put at full length, for the vivid picture it gives of plague in India, and of the difficulties besetting the magnificent work of the Indian Medical Service. It is a story that Mr. Kipling ought to write. And it is to be noted that Surgeon-Captain Leumann, who saved Hubli, recognised the extreme importance of other methods than inoculation—disinfection, isolation of cases, evacuation of infected districts. He says:—

"While paying the highest tribute to the value of Mr. Haffkine's inoculation method, which I claim, here in Hubli, to have put to perhaps the severest test to which it has yet been subjected, I am of the opinion that individual protection is, on however great a scale conducted, of less importance to that of general protection and hygiene (considering each method separately, that is to say), for it seems to me more radical, if not more rational, to eradicate a disease than to leave it to pursue its course and only protect people against its ravages."

Sanitation, therefore, was Dr. Leumann's faith. Now for his works:—

"I first started inoculation here on 11th May.... When I began my inoculations, I operated first of all on some European or native gentlemen in front of a crowd of poor and low-caste people, whom I had gathered together in the worst-affected area, and they were thus soon induced to ask for inoculation themselves.... They have presented themselves, by the hundred, at all times of the day, before myself and others, for the purpose of being inoculated.[34] ... I have never experienced the slightest difficulty in inoculating Mussulmanis or any other purdÁh women in Hubli.... The very men who, in March last, created a disturbance in Hubli, were not only the first and the most willing to undergo inoculation, but also to bring their wives and families to my hospital, or to invite me to their homes to inoculate them.

"Inoculated persons holding certificates of double inoculation have, at my special wish and order, been left in their homes throughout this epidemic; only their clothes, house, and property being disinfected on the occurrence of a plague case or death in their house. As the vast majority of plague cases have never been notified before death in Hubli (nor, in my experience of nearly two years, elsewhere, if native supervision be largely resorted to), it will readily be understood that the majority of the inoculated have actually been living in the same house, or even room, with a plague case (often of the pneumonic type, whose terrible power of spreading the disease was first shown by Professor Childe, I.M.S., of Bombay) during the whole of the time that case was living, probably attending on the patient, breathing the same stuffy air, and, perhaps, sharing the same blanket; and I attach at the end of this report a long series of cases where such conditions have occurred, the non-inoculated dying of plague, and the inoculated escaping, almost to a man.

"Various critics on my work, not knowing what the actual facts were and are, have at different times asserted that the inoculated inhabitants of Hubli left the town in larger numbers than the non-inoculated. Exactly the reverse was the case. The British officers on plague duty here, and all the Divisional Superintendents, invariably replied (officially and in writing when so required) that the non-inoculated left Hubli in far greater numbers and proportion than the inoculated; and my own observations entirely bear out this statement.

"It has been urged that those who received inoculation were of a class or classes better protected than others against plague by reason of their habits, the food they eat, the houses they live in, etc. In reply, I unhesitatingly state that if there be but one town in India where that line of argument will not hold good, it certainly is Hubli; for not only were the poorer, dirtier, lower-caste people the first to be persuaded to receive inoculation, but I made it my personal and special duty to work amongst them. My first few thousand inoculations were almost entirely amongst the lowest and poorest of the people. The Brahmins are, perhaps, of all castes, supposed to be the most cleanly in their houses, habits, etc., yet the Brahmins of Hubli (who at first, imagining themselves immune, were the foremost and greatest perverters of the truth concerning its efficacy, and the last to apply for the protection inoculation affords), simply inundated the various inoculation centres, as soon as plague began to spread in their midst, clamouring for the very method of which they had only lately tried to prevent others from availing themselves.

"Unfortunately, the average native, educated or not, appears to have the very greatest aversion to notifying any case of sickness—plague or other—and hence, in my opinion, it becomes more necessary than ever to protect the people by inoculation, since they will not help to protect themselves by the foremost and simplest of sanitary and hygienic measures.[35] With so few police (and those none too good) to help one; an inadequate British Staff; with so much reliance placed in Native Superintendents and Supervisors, and a Municipality so bankrupt that it could not apparently afford to buy enough blankets out of its own funds for the patients in the Plague Hospitals—the work of segregation, house-to-house inspection, etc., became, from a medical point of view, absurdly insufficient.

"The total number of inoculations performed in Hubli, both on actual inhabitants and on people from outside (villages) between 11th May and 27th September, amounts to some 78,000 altogether."

I

II

"It appears that if the 47,427 inhabitants had remained, as they did—in their town, without running away by rail or otherwise, or without camping out in a mass—and if no inoculation had been resorted to—they would have lost 24,899 souls, or a little over half of their number. The official records show that this has actually occurred, during the present terrible outbreak, in a number of large villages, of 2000 inhabitants and over, in the Hubli taluka and elsewhere in the DhÁrwÁr District, where no inoculation was done, and no camping-out was possible on account of the wet weather." (Haffkine's commentary on Dr. Leumann's report.)

That is the story of Hubli; and, as it stands, it is almost incredible. The Commissioners, by very strict inquiry, reduced it to credibility without robbing it of glory. The inquiry brought out more instances of the immeasurable difficulty of the work. Natives who wished to avoid inoculation would escape through the back door at the sight of a plague officer: bribery, personation, sale or transfer of certificates of inoculation, concealment of cases and of deaths, were all practised by those who wished not to be inoculated, or to get the privileges of the inoculated without inoculation, or to save their infected houses from being disinfected and unroofed. Again, with the people dying like flies, and many of them bearing no mark of identification, and with the medical officers overworked past human endurance, the wonder is, not that the statistics were faulty, but that there are any statistics at all. Certainly, the Commission is well within the mark in saying, "It is quite clear that a very large number of lives must have been saved in Hubli by inoculations during the whole course of the epidemic there. Moreover, we may note that an arithmetical estimate is not the only criterion by which we can appreciate the value of inoculations. And in Hubli their value is approved by the consensus of opinions of officers who have seen probably far more of this process and its results in practice than any other persons in India, and who, having every facility for forming a sound judgment as to its effect where plague was really virulent, are satisfied as to its great value."

Finally, as at Daman so at Hubli, there are lesser groups of statistics, of that kind which is approved by the consensus of opinions of officers. These are, (1) Lieutenant Keelan's house-to-house investigation; (2) the Southern Mahratta Spinning Mills; (3) the Southern Mahratta Railway employÉs.

1. Lieutenant Keelan made a house-to-house visitation of 200 houses, in each of which there were protected and unprotected persons living together, and in each of which there had been one or more cases of plague. The figures for 69 of these houses are appended to Captain Leumann's report. They are as follows:—

These 69 houses were selected: there was nothing unfair in the method of selection, still, they were "good houses"; they are not, therefore, exact for statistics; but, as the Commissioners say, they are "of interest as quite special examples of successful inoculation."

2. In the Southern Mahratta Spinning and Weaving Company's Mills, a careful record of inoculation was kept and checked by the manager. The number of the workpeople at the time when inoculation was begun, 21st June, was 1173. At the end of the epidemic the figures were:—

Here, again, the figures have not a statistical value: "We are not informed whether the inoculations were performed simultaneously; or at what stage of the outbreak the average strength of the inoculated was reached." All the same, what Major Bannerman says of them is true—The experience in this company's mill at Hubli should be an object lesson to all mill-owners in plague-stricken towns.

3. The figures for the Southern Mahratta Railway are given by Major Bannerman in his "Statistics" (1900): they are not mentioned in the Report of the Plague Commission. They are of great value, because the daily shifting of the numbers was recorded as the work of inoculation went on, and the date of each case of plague was also noted. Major Bannerman gives the following account:—

"The railway employÉs were living in barracks, and in the railway yard, apart from the general population of Hubli town. They were under close daily inspection by English officials, who formed a committee for this purpose, with Dr. Chenai as their medical adviser. The results may therefore be regarded as accurate in a high degree, the numbers dealt with not being excessive, and the supervision strict."

The figures, based on the average numbers in each group, are as follows:—

These eight instances must suffice: many must be left out—among them, DhÁrwÁr and Gadag, where Miss Corthorn, M.B., did work as splendid as Leumann's work at Hubli; and Mr. Anderson's work in the Ahmednagar villages; and many more. These plague-reports are to be read, not for their record of heroic zeal and resourcefulness, but only as one more example of many thousand lives saved by a method learned from experiments on animals.

But, of course, there is not, and perhaps there never will be, a national acceptance and adoption of this method through the length and breadth of India. It does not work miracles; it is an uncomfortable process to submit to; privileges must be offered with it, or the native will often prefer to take his chance; the protection is of uncertain duration; all sorts of lies are told about it, partly by anti-vivisectionist writers, partly by native political agitators, partly by the hakims. For instance, at a meeting of hakims at Masti, Lahore, on 11th April 1898, the following resolutions were passed:—

And among statements to be made to the Plague Commissioners was the following, from a native practitioner in Bombay (April 1899):—

All these difficulties were well stated by Surgeon-General Harvey, Director-General of the Indian Medical Service, at the discussion on Haffkine's discourse before the Royal Society, June 1899:—

"The people of England should consider the difficulties attending the work of a bacteriologist in India.... He had no doubt as to the value of the inoculations. At Undhera he carefully examined the results of the experiment, and, as far as he could judge, there was no possibility of error. The results in that experiment were such as to be 90 per cent. in favour of the inoculated against the uninoculated. The natives of India were, however, a strange people, and it was difficult to prophesy how they would act. In Calcutta, the mention of inoculations had driven in hot haste from the city 300,000 people, many of whom afterwards returned and were inoculated; while at Hubli he had seen the inhabitants come in their thousands to be inoculated and pay for the inoculations. The medical officer in charge at Hubli had performed about 80,000 inoculations, and had only observed some 12 abscesses. He thought that 12 abscesses only, in 80,000 inoculations, showed good results. But, after all, what were the numbers of inoculations performed to the 300,000,000 inhabitants of India? He felt that even if every one consented to be inoculated it was impossible to provide the vaccine or the medical officers for such a demand. It was accordingly to sanitary improvements that he looked with the most confidence to protect India against the plague."

Therefore, now and for many years to come, preventive inoculation must fall into line with the other world-wide ways of fighting plague—quarantine, notification, isolation, all sanitary measures, destruction of rats—le rat, le gÉnie de la peste—evacuation of infected towns, disinfection or unroofing of infected houses. Happily, this is just what it does. That admirable paper, the Indian Medical Gazette (September 1901), has put this fact very simply: "No one ever imagined that inoculation was the only means of fighting plague. Its great value consists in its immediate application. To sanitate, ventilate, and practically rebuild a town or village takes time; and in the meantime thousands die." For sudden outbursts of plague—since rats are one chief source of infection, and notification is fundamentally abhorrent to native custom, and evacuation may ruin trade, or spread infection, or be impossible by reason of the rains—since "East is East, and West is West"—it is not always possible to provide, for an Indian village smitten by plague, the excellent arrangements of the Western world. In all such cases, and in all cases of epidemic plague within narrow limits, as in jails, barracks, mills, and the like centres of human life; and in all inner communities, such as the Parsee community at Daman, or the Jewish community at Aden—by every test of this kind, the saving power of preventive inoculation has been proved, again and again, past all doubt. As for those larger death-traps, Hubli, DhÁrwÁr, and the rest of them, here, though the statistics are inexact, we have the word of the men and women themselves who stood between the dead and the living, and the plague was stayed. Such faults as there were, in 1899, in the treatment—the contamination of this or that stock of the fluid, and the inadequate method of standardisation—have been duly noted by the Commission. The rush for the fluid in 1899 may be estimated from the following paragraphs:—

It would take too long for the present purpose to consider what has been done, not only for the prevention of plague, but also for its cure by a serum treatment. The results obtained by this treatment in India have not been very good; but Yersin and others report better results in other countries. Good results are reported from Amoy (1896), Nhatrang (1898), Oporto (1899), and Buenos Ayres (1899-1900). In Glasgow, the prophylactic use of Yersin's serum seems to have done excellent service: the success of its curative use was not very striking. The curative results at Nhatrang (Yersin, Annales de l'Institut Pasteur, March 1899) are notable. Nhatrang is an Annamese fishing-village; and the plague, when it was left to itself, killed every case that it got:—

"La peste s'est montrÉe excessivement meurtriÈre chez les Annamites. Sur 72 cas de peste, 39 personnes chez lesquelles la maladie a ÉvoluÉ normalement, ou qui n'ont ÉtÉ traitÉs que par des mÉdecins indigÈnes, sont mortes sans exception. Les 33 autres cas ont pu Être traitÉs par le sÉrum, quelquefois dans de bonnes conditions, mais le plus souvent quelques heures seulement avant la mort. MalgrÉ cela, nous avons obtenu 19 guÉrisons et 14 dÉcÈs, ce qui fait une mortalitÉ de 42 per cent., chez les traitÉs. Ainsi, d'une part, 100 pour 100 de mortalitÉ chez les non-traitÉs; de l'autre, 42 per cent. chez les malades qui ont reÇu du sÉrum. Ces chiffres confirment les rÉsultats que j'avais obtenu en Chine en 1896."

A long review of this curative treatment, fairly hopeful but nothing more, is given in the Report of the Plague Commission, vol. v., pp. 269-320. The Commissioners are of opinion that it ought not yet to be extended, as a general measure, over all the districts affected with plague; and that there is need of more work in bacteriology before it can be thus extended. "We desire to record our opinion that, though the method of serum-therapy, as applied to plague, has not been crowned with a therapeutic success in any way comparable to that obtained by the application of the serum method to the treatment of diphtheria, none the less the method of serum-therapy is in plague, as in other infectious diseases, the only method which holds forth a prospect of ultimate success."

It is a strange contrast, between this opinion and the statements made by the opponents of all experiments on animals. Some of these statements will be found in Part IV. of this book. Happily for the world, no amount of foul language can hinder the good work; and, when we talk of Empire-building, and of deeds that win the Empire, we must reckon bacteriology among them: as Lord Curzon did, in his speech at Calcutta, March 3, 1899—What is this medical science we bring to you? It is built on the bed-rock of pure irrefutable science; it is a boon which is offered to all, rich and poor, Hindu and Mohammedan, woman and man.

IX
TYPHOID FEVER. MALTA FEVER

Typhoid Fever

The names of Klebs, Eberth, and Koch, are associated with the discovery, in 1880-81, of the bacillus of enteric fever, bacillus typhosus; and it was obtained in pure culture by Gaffky in 1884. It has been studied from every point of view, in man and in animals; in the blood, tissues, and excretions; in earth, air, water, milk, and food; in its distribution, methods of growth, and chemical products. Especially, the study of its chemical products has been directed toward (1) immunisation against the disease, (2) bacteriological diagnosis of the disease at an early stage.

The date of the first protective inoculations against typhoid is July to August 1896: they were made at Netley Hospital, by Professor Wright and Surgeon-Major Semple. The first inoculations in Germany, made by Pfeiffer and Kolle, were published two months later. The story of these famous Netley inoculations is told in the British Medical Journal, 30th January 1897. Eighteen men offered themselves—

"A good deal of fever was developed in all cases, and sleep was a good deal disturbed. These constitutional symptoms had to a great extent passed away by the morning, and laboratory work went on without interruption.... With two exceptions, all these vaccinations were performed upon Medical Officers of the Army or Indian Medical Services, or upon Surgeons on Probation who were preparing to enter those services."

Good luck attend all eighteen of them, and immunity against typhoid, wherever they are. The doses that they received were estimated in proportion to the dose that would kill a guinea-pig of 350-400 grammes weight; and the protective fluid contained no living bacilli:—

"The advantages which are associated with the use of such 'dead vaccines' are, first, that there is absolutely no risk of producing actual typhoid fever by our inoculations; secondly, that the vaccines may be handled and distributed through the post without incurring any risk of disseminating the germs of the disease; thirdly, that dead vaccines are probably less subject to undergo alterations in their strength than living vaccines."

The first use of the vaccine during an outbreak of typhoid was in October 1897, at the Kent County Lunatic Asylum. The treatment was offered to any of the working staff who desired it:—

"All the medical staff, and a number of attendants, accepted the offer. Not one of those vaccinated—84 in number—contracted typhoid fever: while of those unvaccinated and living under similar conditions, 16 were attacked. This is a significant fact, though it should in fairness be stated that the water was boiled after a certain date, and other precautions were taken, so that the vaccination cannot be said to be altogether responsible for the immunity. Still, the figures are striking." (Lancet, 19th March 1898; see also Dr. Tew's paper, in Public Health, April 1898.)

Certainly, they are striking; so is the story of the eight young subalterns on the Khartoum expedition, of whom six were vaccinated, and two took their chance. The six escaped typhoid, the two were attacked by it, and one died. But these figures are too small to be of much value.

The first anti-typhoid inoculations on a large scale were made among British troops in India (Bangalore, Rawal Pindi, Lucknow), when the Plague Commission, of which Professor Wright was a member, was in India, November 1898 to March 1899. These inoculations were voluntary, at private cost, and without official sanction; though the original proposal for them, in 1897, had come from the Indian Government. Pending official sanction, they were stopped. Then, on 25th May 1899, the Indian Government made application to the Secretary of State for India that they should be sanctioned, and should be made at the public cost. The application is as follows:—

"The annual admissions per mille for enteric fever amongst British troops in India have risen from 18.5 in 1890 to 32.4 in 1897, while the death-rate has increased from 4.01 to 9.01; and we are of opinion that every practicable means should be tried to guard against the ravages made by this disease. The anti-typhoid inoculations have been, we believe, on a sufficiently large scale to show the actual value of the treatment, while the results appear to afford satisfactory proof that the inoculations, when properly carried out, afford an immunity equal to or greater than that obtained by a person who has undergone an attack of the disease; further, the operation is one which does not cause any risk to health. In these circumstances, we are very strongly of opinion that a more extended trial should be made of the treatment; and we trust that your Lordship will permit us to approve the inoculation, at the public expense, of all British officers and soldiers who may voluntarily submit themselves to the operation."

On 1st August, the Secretary of State for India announced in Parliament that this treatment, at the public expense, had been sanctioned.

On 20th January 1900, Professor Wright published in the British Medical Journal an account of these 1898-99 inoculations in India. "They were undertaken under conditions which were very far from ideal. In particular, there is reason to suppose that the results obtained may have been unfavourably influenced by a weakening of the vaccine, brought about by repeated re-sterilisation." In no case was reinoculation done. The statistics were compiled from information furnished by officers of the Royal Army Medical Corps actually in charge of troops in the various stations; and were supplemented by reports received from the commanding officers of the various inoculated regiments. They are as follows:—

If the inoculated had been attacked equally with the uninoculated throughout the period of observation, they would have had 71 cases instead of 27.

These inoculations belong to the early part of 1899. During the rest of the year, inoculations were made in India, Egypt, and Malta: the results are given in an appendix to the Report of the Royal Army Medical Department, 1899. (See British Medical Journal, 21st September 1901.) The great majority of the troops tabulated were in India. Of the troops stationed at Malta, 61 were inoculated, 2456 not inoculated; among the former there were no cases, among the latter there were 17 cases and 5 deaths. In Egypt, of 4835 troops, 461 were inoculated; among these there were no cases, among the uninoculated there were 30 cases and 7 deaths. In India, of 30,353 troops, 4502 were inoculated, leaving 25,851 not inoculated; among the inoculated there were 44 cases and 9 deaths, among the non-inoculated 657 cases and 146 deaths. Taking the Indian statistics, and estimating percentage to strength, we find, amongst the inoculated, admissions 0.98, deaths 0.2; amongst the non-inoculated, admissions 2.5, deaths 0.56. The cases which occurred amongst the inoculated men were in the majority of instances of a mild character. Taking Malta, Egypt, and India together, it appears that the inoculated, if they had suffered equally with the non-inoculated, would have had 108 cases and 24 deaths, instead of 44 cases and 9 deaths.

At the end of 1899, this treatment, only just out of the hands of science, was suddenly demanded for the protection of a huge army at war in a country saturated with typhoid. Still, the South African results, and other results during 1899 to 1901, show a good balance of lives saved. The following paragraphs give all results published from the beginning of 1900 to May 1902. They are put in order of publication. Doubtless a few other reports have been overlooked in compilation; but the list includes all that were easily accessible.

1. Manchester, England. The British Medical Journal, 28th April 1900, contains a note by Dr. Marsden, Medical Superintendent of the Monsall Fever Hospital, Manchester, on the inoculation of 14 out of 22 nurses engaged in nursing typhoid patients. Of the remaining 8, 4 had already had typhoid. The inoculations were made in October 1899. The following table shows the subsequent freedom from typhoid of the nursing staff:—

2. Ladysmith, South Africa. The Lancet, 14th July 1900, contains a short note by Professor Wright, on the distribution of typhoid among the officers and men of the military garrison, during the siege of Ladysmith. The figures are as follows:—

The wide difference between the two groups, as regards the incidence of the disease, is well marked; but the case-mortality is practically the same in each group. (The statistics of the General Hospital, Ladysmith, also tell in favour of the preventive treatment: see Surgeon-Major Westcott's letter, British Medical Journal, 20th July 1901, in answer to Dr. Melville's letter, British Medical Journal, 20th April 1901.)

3. The Portland Hospital: Modder River and Bloemfontein. The British Medical Journal, 10th November 1900, contains an account by Dr. Tooth of the cases of typhoid in this hospital. Concerning the preventive treatment, he says: "The experience of my colleague Dr. Calverley and myself may be of interest, though we fear that the numbers are too few for safe generalisation.

"Personnel of the Portland Hospital. We take first the relation of disease and inoculation among the personnel of the hospital. Twenty-four non-commissioned officers, orderlies, and servants of the Portland Hospital, and 4 of the medical staff, were inoculated on the voyage out. All these showed the local symptoms at the time; that is, pain, stiffness, and local erythema; 17 also presented well-marked constitutional symptoms—general feeling of illness, fever, and headache. Of the orderlies, 9 had enteric fever subsequently. Two had refused inoculation, and both of these had the disease very severely; in fact one died. Of the inoculated cases, 5 had the disease lightly, and 2 fairly severely. One of the sisters had the disease rather severely, and she had not been inoculated.

"Officers and men admitted to the Portland Hospital. We had under treatment at the Portland Hospital 231 cases of enteric fever, most of which came under our care at Bloemfontein. We have not included in these figures a number of patients who came in convalescent for a short time only, and on their way to the base, and who would therefore appear in the admission and discharge book of the hospital. If we did so, of course our percentages would be lower. Of these 231 patients, 53 had been inoculated at home or on the voyage out, and of them 3 died, making a percentage of deaths among the inoculated of 5.6 per cent.; 178 had not been inoculated, of whom 25 died; that is, a mortality among the non-inoculated of 14 per cent. The general mortality in enteric fever with us was 28 deaths out of 231 cases; that is, 12.1 per cent., which seems to compare favourably with the experience of the London hospitals.

"It is interesting to record our experience among the officers taken separately. Thirty-three officers were admitted with enteric fever; 21 had been inoculated; that is, 63.6 per cent.; a much larger percentage than among the men. Only one of these officers died, and he had not been inoculated.

"These figures are small, but such as they are they are significant, and they dispose us to look with favour upon inoculation. So also does our clinical experience with our patients, for among the inoculated the disease seemed to run a milder course."

4. No. 9 General Hospital, Bloemfontein. The Medical Chronicle for January 1901 contains an account, by Dr. J. W. Smith, of the work of this hospital. He says: "The general impression amongst the medical officers in our hospital was that a single inoculation probably did not confer an immunity lasting very long—the lapse of time differing in individuals—and also that there was a tendency in the cases of enteric in inoculated patients to abort at the end of ten or fourteen days. I should say, however, that a very considerable number of our detachment who had been inoculated suffered from enteric, of whom 4 at least died. Of the medical staff, the only member of the junior staff who had not been inoculated died of enteric."

5. Scottish National Red Cross Hospital, Kroonstadt. The British Medical Journal, 12th January 1901, contains an account of the work of this hospital by Surgeon-Colonel Cayley, Officer in Charge. He says: "The first section of the hospital, consisting of 61 persons—officers, nursing sisters, and establishment—left Southampton on 21st April 1900. During the voyage out, all except 4 were inoculated twice, at an interval of about ten days; 2 were inoculated once; and 2 (who had had typhoid) were not inoculated. Immediately we reached the Cape, the hospital was sent up to Kroonstadt in the Orange River Colony, and remained there as a stationary hospital till the middle of October. During this period there were always many cases of enteric under treatment in hospital. Further, some of the medical officers and student orderlies had charge of the Kroonstadt Hotel temporary hospital, which was crowded up with enteric cases; and the nursing sisters, for three weeks, did duty in the military hospitals at Bloemfontein in May and June, when enteric fever was at its worst. There was not a single case of enteric among the personnel of this first section of the hospital.

"The second section of the hospital—medical officers, nurses, and establishment, 82 in all—left Southampton in May 1900. On board ship nearly all of them were inoculated, but many of them only once. The material for inoculation had been on board for some time, and was not so fresh as in the first instance. Of this second section, 1 nurse had enteric at Kroonstadt. She was the only one, out of a total of 36 nurses, who suffered from enteric; and she was the only nurse who was not inoculated, excepting the 2 who were protected by a previous attack of enteric. A third section of the hospital, consisting of 4 medical officers and 16 nurses, went out in July; they were all inoculated, and none of them had enteric.

"Of the second section, 5 orderlies had enteric fever at Kroonstadt, of whom 2 died. Of these 5, there were 2 inoculated (once) and 3 non-inoculated. Of the 2 who died, 1 had been once inoculated, the other had not been inoculated."

6. Meerut, India. The British Medical Journal, 9th February 1901, gives a short note by Professor Wright on inoculations in the 15th Hussars. He says: "Through the kindness of Lieutenant-General Sir George Luck, commanding the Bengal Army, I am permitted to publish the following officially compiled statistics, dealing with the effects of anti-typhoid inoculations in the case of the 15th Hussars:—

From 22nd October 1899 to 22nd October 1900.

It would thus appear that the incidence of enteric in the inoculated was represented by 0.55 per cent., and the mortality by 0.27 per cent.; while the incidence in the uninoculated was 6.14 per cent., and the death-rate 3.35 per cent."

If the inoculated had suffered equally with the uninoculated, they would have had 22 cases with 11 deaths, instead of 2 cases with 1 death.

7. The Edinburgh Hospital, South Africa. The Scottish Medical and Surgical Journal, March 1901, contains an account of the work of the Edinburgh Hospital, by Dr. Francis Boyd. Of the staff, 58 were inoculated (27 once, and 31 twice). Among these 58, there were 9 cases of typhoid fever, with I death, in a patient who had old mitral disease. "Our experience has been that, while inoculation appears to modify the disease, completely modified attacks are met with in the uninoculated. Again, very severe attacks, with complications and relapse, occur in those who have been inoculated. One cannot from this conclude that inoculation has been valueless, for had not the patient been inoculated, the attack might have been still more severe."

8. Egypt and Cyprus. The British Medical Journal, 4th May 1901, gives a short note by Professor Wright on inoculations during 1901 in Egypt and Cyprus. He says: "I am indebted to the kindness of Colonel W. J. Fawcett, R.A.M.C., Principal Medical Officer in Egypt, for the following statistics dealing with the incidence of enteric fever, and the mortality from the disease, for the year 1900, in the inoculated and uninoculated among the British troops in Egypt and Cyprus:—

These figures testify to a nineteen-fold reduction in the number of attacks of enteric fever, and to a threefold reduction in the number of deaths from that disease, among the inoculated.... The only case which occurred among the inoculated was that of a patient admitted to hospital on the thirty-third day after inoculation. It would seem that the disease was in this case contracted before anything in the nature of protection had been established by the inoculation."

9. Imperial Yeomanry Hospital, Pretoria. Dr. Rolleston, Consulting Physician to this hospital, writes in the British Medical Journal, 5th October 1901: "Among the personnel of the hospital (17 medical officers, 50 nursing sisters, 83 orderlies, etc.), total, 150, there were 22 cases of enteric fever, or an incidence of 14.6 per cent. Of the 150, 35 were inoculated, and of these, 6, or 17 per cent., suffered from enteric; while, of 115 non-inoculated members of the personnel, 16, or 13.9 per cent., suffered from enteric fever; the percentage is therefore higher among the inoculated. There were 2 deaths, both in non-inoculated patients. In 100 cases of enteric fever among non-commissioned officers and men, taken mainly from convalescent patients, only 8 had been previously inoculated; there were 3 fatal cases, all among non-inoculated patients. Among 42 officers who had enteric, no fewer than 19 had been previously inoculated; 6 of these 19 cases were severe in character, but none were fatal; of the 23 non-inoculated cases, 7 were severe, and of these 7, 3 ended fatally. The interval between inoculation and the subsequent incidence of enteric fever varied between one and twenty-one months, but in only four instances was the interval less than six months. The average interval between inoculation and the onset of enteric fever in these 19 cases was thirty-eight weeks.

"As far as these scanty figures go, they point to the conclusion (1) that anti-typhoid inoculation does not absolutely protect against a future attack of typhoid fever; (2) that when enteric occurs in an inoculated person, there is, as a rule, an interval of about six months; (3) that inoculation protects against a fatal termination to the disease."

10. Richmond Asylum, Dublin. The British Medical Journal, 26th October 1901, contains a note by Professor Wright on an outbreak of typhoid in this asylum during August to December 1900. Inoculations were begun on 6th September, by Dr. Cullinan, and by 30th November 511 persons were inoculated. After careful criticism of all doubtful cases, Professor Wright gives the following figures:—

Comparative Incidence of Typhoid Fever in Inoculated and Non-Inoculated, calculated upon the average strength of the representative groups during the period intervening between the commencement of the inoculations and the termination of the epidemic.

"It may be noted," he says, "that the result is in conformity with that of all the statistical returns of anti-typhoid inoculation which have reached me."

11. Deelfontein. The Lancet, 18th January 1902, contains a paper by Dr. Washbourn and Dr. Andrew Elliot, on 262 cases of typhoid fever in the Imperial Yeomanry Hospital at Deelfontein during the year March 1900 to March 1901. (See Dr. Washbourn's earlier letter, Brit. Med. Jour., 16th June 1900.) They say: "In 211 of our cases, it was definitely recorded whether the patient had been inoculated or not: 186 of these cases had not been inoculated, with 20 deaths, or a mortality of 10.7 per cent.; 25 had been inoculated, with 4 deaths, or a mortality of 16 per cent. The mortality was thus higher among the inoculated than among the non-inoculated." Of the personnel of the hospital, there were 59 inoculated, with 4 cases, and 25 not inoculated, with 4 cases.

12. Winburg. The Lancet, 5th April 1902, contains a short note by Professor Wright, on the 5th Battalion, Manchester Regiment. He says: "In view of the dearth of statistics bearing on the incidence of typhoid fever in South Africa in inoculated and uninoculated persons respectively, the following, for which I am indebted to Lieutenant J. W. West, R.A.M.C., Winburg, Orange River Colony, may not be entirely without interest. The statistics here in question give the results obtained in the case of the 5th Battalion, Manchester Regiment, for the six months which have elapsed since their landing in South Africa. The figures, which relate to a total strength of 747 men and officers under observation, are as follows:—

"The three attacks in the inoculated are reported to have been of exceptionally mild type, contrasting in a striking manner with the severe attacks which occurred in the uninoculated. At the time of sending in the report, some of the uninoculated patients were 'not yet out of danger.'"

Certainly, these instances show a good balance of lives saved, not only under the adverse conditions of the war, but also in Egypt, India, and the United Kingdom. But the bacteriological work on typhoid fever has been directed also to the working out of a very different problem: and that is the method of diagnosis which is called "Widal's reaction." The practical uses of this reaction are of the utmost importance. It is the outcome of work in different parts of the world—by Wright and Semple and Durham in England, Chantemesse and Widal in France, Pfeiffer and Kolle and GrÜber in Germany, and many more. The first systematic study of it was made by Durham and Pfeiffer; and Widal's name is especially associated with the application of their work to the uses of practice. Admirable accounts of the whole subject are given by Dr. Cabot in his book, The Serum-Diagnosis of Disease (Longmans, 1899), and by Mr. Foulerton in the Middlesex Hospital Journal, October 1899 and July 1901.

Widal's reaction is surely one of the fairy tales of science. The bacteriologist works not with anything so gross as a drop of blood, but with a drop of blood fifty or more times diluted; one drop of this dilution is enough for his purpose. Take, for instance, an obscure case suspected to be typhoid fever: a drop of blood taken from the finger is diluted fifty or more times, that the perfect delicacy of the test may be ensured; a drop of this dilution is mixed with a drop of nutrient fluid containing living typhoid bacilli, and a drop of this mixture of blood and bacilli is watched under the microscope:—

"The motility of the bacilli is instantaneously or very quickly arrested, and in a few minutes the bacilli begin to aggregate together into clumps, and by the end of the half-hour there will be very few isolated bacilli visible. In less marked cases, the motility of the bacilli does not cease for some minutes; while in the least marked ones the motility of the bacilli may never be completely arrested, but they are always more or less sluggish, while clumping ought to be quite distinct by the end of the half-hour."

The result of this clumping is also plainly visible to the naked eye, by the subsidence of the agglutinated bacteria to the bottom of the containing vessel: and thus an easy practical mode of diagnosis is afforded by it.

As with typhoid, so with Malta fever, cholera, and some other infective diseases. And the unimaginable fineness of this reaction goes far beyond the time of the disease. Months, even years, after recovery from typhoid, a fiftieth part of a drop of the blood will still give Widal's reaction: and it has been obtained in an infant whose mother had typhoid before it was born. A drop of dried blood, from a case suspected to be typhoid, may be sent a hundred miles by post to be tested; and typhoid, like diphtheria, may now be submitted to the judgment of an expert far away, and the answer telegraphed back. It would be difficult to exaggerate the practical importance of this reaction for the early diagnosis of cases of typhoid fever, especially those cases that appear, at the onset, not severe.

Malta Fever

The specific organism of Malta fever (Mediterranean fever), the bacillus Melitensis, was discovered in 1887 by Surgeon-Major David Bruce, of the Army Medical Staff. Its nature and action were proved by the inoculation of monkeys. The use of Widal's reaction is of great value in this disease:—

"The diagnosis of Malta fever from typhoid is, of course, a highly important practical matter. It is exceedingly difficult in the early stages." (Manson, loc. cit.)

As with typhoid, so with Malta fever, Netley led the way to the discovery of an immunising serum. In the course of the work, one of the discoverers was by accident infected with the disease:—

"He was indisposed when he went to Maidstone to undertake anti-typhoid vaccination, and after fighting against his illness for some days, he was obliged to return to Netley on 9th October. Examination of blood-serum (Widal's reaction) showed that he was suffering from Malta fever. It appears that he had scratched his hand with a hypodermic needle on 17th September, when immunising a horse for the preparation of serum-protective against Malta fever; and his blood, when examined, had a typical reaction on the micrococcus of Malta fever in 1000-fold dilution. The horse, which has been immunised for Malta fever for the last eight months, was immediately bled, and we are informed that the patient has now had two injections, each of 30 cub. cm. of the serum. He is doing well, and it is hoped that the attack has been cut short." (British Medical Journal, 16th October 1897.)

About fifty cases had up to September 1899 been treated at Netley "with marked benefit: whereas they found that all drug-treatment failed, the antitoxin treatment had been generally successful."[36] A good instance of the value of the serum-treatment of Malta fever is published in the Lancet, 15th April 1899. For a later account of this treatment and of its efficacy, see the Philadelphia Medical Journal, 24th November 1900.

Another point is noted by Sir Patrick Manson, in his recent Lane Lectures (Constable, 1905). "For some time back," he says, "a commission of experts, working under the direction of the Royal Society, has been studying this disease in Malta. The commission has accumulated much detailed information; but the most important observation it has published is the fact that a large percentage of the goats in Malta are infected with Micrococcus melitensis, and that the milk of the infected goats contains the bacterium. May not this account for the great prevalence of Mediterranean fever there and in other places having perhaps a similar milk-supply?"

X
THE MOSQUITO: MALARIA, YELLOW
FEVER, FILARIASIS

Within the last few years, it has been proved that the mosquito is an intermediate host, between man and man, of malaria, yellow fever, and filariasis (elephantiasis).[37] Just as the grosser parasites, the tapeworms, must alternate between man and certain animals, and cannot otherwise go through their own life-changes and reproduce their kind, so the micro-parasites that are the cause of malaria alternate between man and the mosquito, having the mosquito as an intermediate host. These organisms, once they get into the mosquito, pick out certain structures, and there carry out a definite cyclical phase of their lives, whereby their progeny make their way into the stylets of the mosquito, and so get back to man, who is their "definite host." Thus, malaria is not, strictly speaking, a disease of man; it is one phase in man of micro-organisms that have another phase in mosquitoes. So also with filariasis; the filariÆ in man, their ova, and their embryo-worms, are one phase of filariasis; and the embryo-worms in certain structures of the mosquito are another phase. The plasmodium malariÆ and the filaria are instances of a law of animal life that holds good also of plant life:—

"All plants and animals possess parasites, and thousands of different species of parasites have been closely studied by science; we therefore know much about their general ways of life. As a rule, a particular species of parasite can live only in the particular species of animal in which, by the evolution of ages, it has acquired the power of living. It is therefore not enough for the parasites of an individual animal—say a man—to be able to multiply within that individual, but they must also make arrangements, so to speak, for their progeny to enter into and infect other individuals of the same species. They cannot live for ever in one individual; they must spread in some way or other to other individuals.

"The shifts made by parasites to meet this requirement of their nature are many and various, and constitute one of the wonders of nature. Some scatter their spores and eggs broadcast in the soil, water, or air, as it were in the hope that some of them will alight by accident on a plant or animal suitable for their future growth. Many parasites employ, in various ways, a second species of animal as a go-between. Thus, some tapeworms, and the worms which cause trichinosis, spend a part of their lives in the flesh of swine, and transfer themselves to human beings when the latter eat this flesh. To complete the cycle, the parasites return to swine from human offal; so that they propagate alternately from men to swine, and from swine to men. The blood-parasites which cause the deadly tsetse-fly disease among cattle in South Africa are transferred from one ox to another on the proboscis of the ox-biting or tsetse-fly. The progeny of the flukes of sheep enter a kind of snail, which spreads the parasites upon grass. The progeny of the guinea-worm of man enter a water-flea. The progeny of the parasites which cause Texas cattle-fever, and which are very like the malarial parasites, live in cattle-ticks, and are transferred by the young of these ticks into healthy cattle." (Ross, Malarial Fever, 1902.)

1. Malaria

The plasmodium malariÆ was discovered by Laveran in 1880, in the blood of malarial patients. For many years his work stopped there, because it was impossible to find the plasmodium in animals: "the difficulties surrounding the subject were so great that this discovery seemed to be almost hopeless." In 1894, Sir Patrick Manson—who had proved mosquitoes to be the intermediate host in the case of the parasitic nematode filaria—suggested, as a working theory of malaria, that the plasmodium was carried by mosquitoes. This belief, not itself new, he made current coin. He observed that there is a flagellate form of the plasmodium, which only comes into existence after the blood has left the body: and he suggested that the flagella might develop in the mosquito as an intermediate host, a halfway-house between man and man. Then, in 1895, Ross set to work in India, keeping and feeding vast numbers of mosquitoes on malarial blood; and for two years without any conclusive result. About this time came MacCallum's observations, at the Johns Hopkins University, on a parasitic organism, halteridium, closely allied to the plasmodium malariÆ; he showed that the flagella of the halteridium are organs of impregnation, having observed that the non-flagellated form, which he regarded as the female, after receiving one of the flagella, changed shape, and became motile. In August 1897, Ross found bodies, containing pigment like that of the malarial parasite, in the outer coat of the stomach of one kind of mosquito, the grey or dapple-winged mosquito, Anopheles maculipennis, that had been fed on malarial blood. In February 1898, he was put on special duty under the Sanitary Commissioner with the Government of India, to study malaria, and started work again in Calcutta:—

"Arriving there at a non-fever season, he took up the study of what may be called 'bird malaria.' In birds, two parasites have become well known—(1) the halteridium, (2) the proteosoma of LabbÉ. Both have flagellated forms, and both are closely allied to the plasmodium malariÆ. Using grey mosquitoes and proteosoma-infected birds, Ross showed by a large number of observations that it was only from blood containing the proteosoma that pigmented cells in the grey mosquito could be got; therefore that this cell is derived from the proteosoma, and is an evolutionary stage of that parasite. Next, Ross proceeded to find out its exact location, and found that it lay among the muscular fibres of the wall of the mosquito's stomach. It grows large (40-70 micro-millimetres) and protrudes from the external surface of the stomach, which under the microscope appears as if covered with minute warts." (Manson, at Edinburgh meeting of British Medical Association, 1898.)

These pigmented spherical cells give issue to innumerable swarms of spindle-shaped bodies, "germinal rods"; and in infected mosquitoes Ross found these rods, in the glands that communicate with the proboscis. Thus the evidence was complete, that the plasmodium malariÆ, like many other parasites, has a special intermediate host for its intermediate stage of development; and that this host is the dapple-winged mosquito. It is impossible to over-estimate the infinite delicacy and difficulty of Ross's work; for instance, in his "Abstract of Recent Experiments with Grey Mosquitoes," he says that "out of 245 grey mosquitoes fed on birds with proteosoma, 178, or 72 per cent., contained pigmented cells; out of 249 fed on blood containing halteridium, immature proteosoma, &c., not one contained a single pigmented cell." Another time (April 1898) he counted these pigment-cells under the microscope:—

"Ten mosquitoes fed on the sparrow with numerous proteosoma contained 1009 pigmented cells, or an average of 101 each. Ten mosquitoes fed on the sparrow with moderate proteosoma contained 292 pigmented cells, or an average of 29 each. The mosquitoes fed on the sparrow with no proteosoma contained no pigmented cells."

Finally, he completed the circle of development by infecting healthy sparrows by causing mosquitoes to bite them.

In 1899, there went out a German Commission to German East Africa, a Royal Society's Commission to British Central Africa, and an expedition from the Liverpool School of Tropical Medicine; in 1900, another German Commission, this time to the East Indies, and another expedition from the Liverpool School; by July 1901, the Liverpool School was organising its seventh expedition. Italy, of course, has given infinite study to the disease:—

"It has been decided that, in addition to the stations of observation and experiment in the provinces of Rome, Milan, Cremona, Mantua, Gercara, Foggia, Lecce, others shall be established in the provinces of Udine, Verona, Vicenza, Padua, Ravenna, Pisa, Basilicata, and Syracuse. Besides epidemiological researches, applications on a large scale will be made of preventive measures for the protection of the agricultural population against the scourge. Another extensive experiment on the prophylaxis of malaria will be made on the Emilian littoral. Moreover, in all the malarious regions of the Italian peninsula the provincial and communal administrations and many private persons will co-operate in the application of preventive measures. From all this it may be gathered that during the summer and autumn the war against malaria will be carried on in Italy with great vigour and thoroughness." (British Medical Journal, 6th July 1901.)

In India, the work started in 1900 by the Royal Society Commissioners, and by the Nagpur Conference, has been widely extended; especially by such researches as those of Major Buchanan, I.M.S., Superintendent of the Central Jail, Nagpur. The following paragraph, from the report of the Sanitary Commissioner with the Government of India, refers to Major Buchanan's published work, Malarial Fevers and Malarial Parasites in India:—

"A remarkable note is struck at the outset, in the acknowledgment made, by the author, of the capable assistance rendered in these researches by several of his Burmese prisoners, whom he trained to the use of the microscope, and who soon became expert in detecting and distinguishing the various kinds of parasites.... Besides a systematic clinical account of the different forms of fever and the associated parasites, which is the first attempt of the kind in India, there are a summary of the facts showing the relation of the seasonal prevalence of Anopheles to the incidence of attacks; experiments exhibiting the protective effects of mosquito-curtains; inoculation-experiments; researches on the blood-parasites of birds; and many other points.... Nor can we pause to notice the many attempts now being made by health officers and others to pursue the methods of prophylaxis indicated; these efforts are necessarily in the tentative stage, but, so far, and especially where carried out in connection with small communities and institutions, they are giving promise of gratifying success."

The famous experiment made by Dr. Sambon and Dr. Low in 1900, must be recalled here:—

A similar "experiment," of the utmost importance, was made in 1900 by Professor Grassi. It concerned the workmen and their families along the Battipaglia-Reggio railway, 104 in all, including 33 children. The great majority of them had suffered from malaria in the preceding year; and only 11, including 4 children, had never suffered from it. Pending the arrival of the malarial season, quinine was given to all who needed it. The first Anopheles with its salivary glands infected was found on 14th June. Twelve days later came a case of malaria outside the "zone of experiment," in a person who had never had malaria before. The twelve days correspond to the incubation-period after infection. Anopheles having come, and the malarial season with him, the experiment was begun. The houses were carefully protected with wire netting, chimneys and all; the siesta was taken under wire netting; the workmen, if they were out in the evening or at night, wore veils and gloves; and Anopheles was to be killed wherever he was found. Quinine was altogether given up and forbidden, except for three workmen who had escaped or evaded its use before June, and had, indeed, never before been treated with quinine; one of them, moreover, had been sleeping outside the zone of experiment in July. Except these three, all the 104 and their doctors remained absolutely free from malaria up to 16th September, the date of Professor Grassi's report:—

"Rightly to estimate the value of these facts, it is necessary briefly to describe the surroundings of the protected area. Towards the north, coming from Battipaglia, three railway cottages are situated, at a distance of 1, 2, and 3 kilometres respectively. The 25 inhabitants of these cottages, although they were put under the tonic and quinine treatment in the non-malarial season, all without exception were taken ill with malarial fevers, in many cases obstinate."

Experiments of voluntary exposure to bite from an infected mosquito were made at or about this time, in London, New York, Italy, and India. The London "consignment" of mosquitoes had been allowed to bite a malaria-patient in Rome. The experiment had to be very carefully planned:—

"To have sent mosquitoes infected with malignant tertian parasites might have endangered the life of the subject of the experiment; and quartan-infected insects might have conferred a type of disease which, though not endangering life, is extremely difficult to eradicate. The cases, therefore, on which the experimental insects were fed had to be examples of pure benign tertian—a type of case not readily met with in Rome during the height of the malarial season; the absolute purity of the infection could be ascertained only by repeated and careful microscopic examination of the blood of the patient." (British Medical Journal, 29th September 1900.)

The mosquitoes were forwarded, through the British Embassy in Rome, to the London School of Tropical Medicine. The two brave gentlemen who let themselves be bitten by some thirty of the mosquitoes were in due time attacked by malaria, and the tertian forms of the parasite were found in their blood. Nine months later, one of them had a relapse, and the parasite was again found in his blood.

It is not possible to sum up the wealth of work on malaria published in 1900-1901. Good accounts of it are in the Transactions of the Section of Tropical Diseases, at the Annual Meeting of the British Medical Association (Cheltenham, 1901), and in the Thompson Yates Laboratories Reports, vol. iii., pt. 2, 1901. Everything had to be studied: not only the nature and action of the plasmodium in all its phases, but also the whole natural history and habits of the Anopheles of different countries; and, above all, the incidence of the disease on natives and on Europeans in China, India, and Africa. All that can be done here is to try to indicate the principal lines followed in the present world-wide campaign against malaria. The following paragraphs are taken mostly from the accounts given by Dr. Christophers and Dr. Annett, in the Thompson Yates Laboratories Report, 1901:—

1. Elimination of the Infection at its Source. This is the method employed with success by Professor Koch in New Guinea, viz., to search out all cases of malaria (the concealed ones in particular), and to render them harmless by curing them with quinine. At Stephansort, by thus hunting up all infected cases, and as it were, sterilising them by the systematic administration of quinine, he was able to achieve a great reduction of the disease in the next malarial season, even under adverse conditions. He says, in his report to the German Government: "The results of our experiment, which has lasted nearly six months, have been so uniform and unequivocal that they cannot be regarded as accidental. We may assume that it is directly owing to the measures we have adopted that malaria here has, in a comparatively short time, almost disappeared."

This method, of course, is applicable only in small communities; and, within these limits, it may become one of the most valuable of all methods, being, like the quality of mercy, a blessing both to him who gives and to him who taketh. But it cannot be practised on a vast scale. This difficulty is well put by Sir William MacGregor, K.C.M.G., Governor of Lagos, West Africa:—

"In all probability, the day will come before long, when newly-appointed officers for places like Lagos will have to undergo a test as to whether they can tolerate quinine or not. A man that cannot, or a man that will not, take quinine, should not be sent to or remain in a malarial country, as he will be doing so at the risk of his own life, and to the danger of others.... The great difficulty is how to extend this treatment beyond the service, more particularly to the uneducated masses of the natives. It is simply impossible to protect the whole population by quinine administered as a prophylactic. In the first place, the great mass of natives would not take the medicine; and, in the second place, the Government could not afford to pay for the 70 tons of quinine a year that would be required to give even a daily grain dose to each of 3,000,000 of people."

2. Segregation of Europeans from Natives. This method is strongly advocated by the members of the Nigeria Expedition of the Liverpool School (1900). The distance of removal to half a mile is considered sufficient: "Considerable evidence has now been accumulated to prove that the distance which is traversed by a mosquito is never very great, and extremely rarely reaches so much as half a mile." The arguments in favour of this method of "segregation" are of so great interest that they must be put here at some length. The drawback is that the method cannot be followed everywhere to its logical issue without some risk of giving offence, of seeming to abandon the native, of damaging commerce, and so forth. But, short of this, much might be done for the protection of Europeans in Africa:—

It is plain, from these and other instances given by the members of the Nigeria Expedition, that a modified sort of "segregation" can be effected in many places, without any injury either to native feelings, or to politics, or to commerce; and that by such segregation the risk of malaria among Europeans in Africa would be diminished.

3. Protection against Anopheles. Manson, in his Tropical Diseases (1905), says, "The question is often asked, Is there any other way by which malaria can be contracted than through a mosquito-bite? For many reasons, I believe not. It is difficult to prove a negative; but, so far, there is no observation capable of bearing investigation that would lead us to suppose that malaria can be acquired, under natural conditions, except by mosquito-bite," All authorities are agreed that, practically, the fight against malaria and the fight against Anopheles are one and the same thing; and the experiments by Sambon, Low, and Grassi, show what can be done, in this war against the mosquito, by way of defence. But what is practicable in Italy might not be generally practicable on the West African coast; as Sir William MacGregor says of Lagos:—

"It is not likely that in a place like Lagos as good results can be obtained from the use of mosquito-proof netting as in Italy. One great objection to it here is the serious and highly disagreeable way it checks ventilation. This is a difficulty that cannot be fully brought home to one in a cold climate. But, in a low-lying, hot, and moist locality like Lagos, it comes to be a choice of evils, to sit inside the netting stewed and suffocated, or to be worried and poisoned by mosquitoes outside. The netting is hardly a feasible remedy as regards native houses. It is not possible to protect even European quarters completely by it. Few officers or others are so occupied that they could spend the day in a mosquito-proof room. Certain it is that any man that suffers from the singular delusion that mosquitoes bite only during the night, would have a speedy cure by spending a few days, or even a few hours, in Lagos. Operations here (September 1901) are being limited to supplying one mosquito-proof room to the quarters of each officer. In this he will be able to spend the evening free from mosquitoes if he chooses to do so. The European wards of the hospital are similarly protected."

The European in Africa, as Ross says, is generally neglectful of his health; and the "unhealthiness" of the African coast is to some extent due to the life that men lead there:—

"Let us compare the habits of a European in a business-house in Calcutta with the habits of a European in West Africa. In Calcutta he sleeps under a punkah or mosquito-net, or both; he dresses and breakfasts under a punkah; in the evening he takes vigorous exercise, and he dines under a punkah. He wears the lightest possible clothing, he lives in a solid, cool, airy house, and he obtains very good food; once in five or six years, he returns to Europe for leave.... In Africa, the houses are frequently very bad; in Freetown, for instance, they are the same as the houses of natives, and are mingled with them. The Anglo-African seems to imagine that he can live in the tropics in the same manner as he lives in England. He seldom uses a punkah, except perhaps for an hour at dinner-time, and, not seldom, he neglects even the mosquito-net. The food is often, or generally, execrable. Owing to the frequent absence of gymkhanas and clubs, the exile obtains little suitable exercise."

But whatever risks the old resident may choose to take, the newcomer can at least use a proper and efficient mosquito-net at night, and avoid sleeping in a native house, and protect himself in these and the like ways against malaria.

4. The keeping down of Anopheles. The breeding places of Anopheles are ponds, swamps, and puddles, roadside ditches, tanks, and cisterns, old disused canoes, and the like collections of stagnant water: also the smaller receptacles that are more generally occupied by Culex, such as broken bottles, old tins, pots, and calabashes, and barrels, whatever will hold water—all the dÉbris and broken rubbish round huts or houses. In all these places, Anopheles' eggs or larvÆ are found; and, with practice, it is easy to detect them. Of course, it is not easy to wage war against the adult mosquito: the work is, Venienti occurrere morbo, to organise gangs of workmen, or of prison labour, and "mosquito brigades"; to clear the ground of cartloads of old biscuit-tins, broken gin-bottles, and other dust-heap things, in and around the place; to cover-in the cisterns, rain-barrels, and wells; to clean pools and duck-ponds of weed, and stock them with minnows; to put a film of kerosene to the puddles, or sweep them out, or fill them up and turf them over; everywhere, to drain, and level, and clean-up the surface soil; and everywhere, by these and the like methods, to break the cycle of the life of the plasmodium malariÆ:—

"Draining and cultivation where the land will repay the expenditure, permanent and complete flooding where it will not, and such flooding is possible; proper paving of unhealthy towns, and the filling-in of stagnant, swampy pools; these—in other words, all measures calculated to keep down mosquitoes—are the more important things to be striven for in attempting the sanitation of malarious districts. In England, in Holland, in France, in Algeria, in America, and in many other places, enormous tracts of country, which formerly were useless and pestilential, have been rendered healthy and productive by such means." (Manson.)

And, short of such great enterprises as Government works of drainage, much has already been done, in many African towns, and in India, by the work of a few men and women: not only by practical sanitary improvements, but by insistent teaching and lecturing. For the admirable results recently obtained in Ismailia, Algeria, Formosa, and the Malay States, see the Medical Annual, 1905 and 1906.[39]

Before leaving the subject of malaria, it must be added that the discovery and study of the parasite which causes it have cleared up the mystery of the specific action of quinine upon the disease. It operates simply by its germicidal effect upon the microbe. But, beyond this, we have now a clue which we never had before to guide us to the most advantageous manner of administering the drug.

2. Yellow Fever

The specific organism of malaria may become active again and again in the blood, causing relapses twenty years or more after the original infection. The specific organism of yellow fever expends itself at once, in one acute attack; and, if the patient recovers, he is thenceforth more or less immune against infection. That the inoculation of the disease, by the application of a single mosquito recently contaminated, is calculated to produce a mild or abortive attack less dangerous than the average attack among the non-acclimatised, was known to Finlay, and was confirmed in 1899 by the Army Commission of the United States.

Of the mortality of the disease, Sir Patrick Manson, in 1900, wrote as follows:—

"It is better for women and children than for men; better for old residents than for newcomers; worst of all for the intemperate. According to a table of 293 carefully observed cases given by Sternberg, the mean mortality in the whole 293 cases was 27.7 per cent. This may be taken as a fairly representative mortality in yellow fever among the unacclimatised, something between 25 and 30 per cent., although in some epidemics it has risen as high as 50 or even 80 per cent. of those attacked.... Some of these epidemic visitations bring a heavy death-bill; thus, in New Orleans, in 1853, 7970 people died of yellow fever; in 1867, 3093; in Rio, in 1850, it claimed 4160 victims; in 1852, 1943; and in 1886, 1397. In Havana, the annual mortality from this cause ranges from 500 to 1600 or over."

The earlier attempts to reproduce the disease, by inoculation with its products, failed altogether:—

"In 1816, Dr. Chervin, of Point-À-Pitre (Antilles), drank repeatedly large quantities of black vomit without feeling the least disturbance. Some years before, other North American colleagues, Doctors Potter, Firth, Catteral, and Parker, did everything possible to inoculate themselves with yellow fever. After having uselessly attempted experiments on animals, they experimented on themselves, inoculating the black matter at the very moment in which the moribund patient rejected it, placing this matter in their eyes, or in wounds made in their arms, injecting it more than twenty times in various parts of their body ... in short, devising every sort of daring means for experimentally transmitting yellow fever. All these experiments were without result, and in the United States during many years it was believed that this terrible malady was non-contagious." (British Medical Journal, 3rd July, 1897.)

The history of the subject, from 1812 to 1880, is given by Dr. Finlay of Havana, in the New York Medical Record (9th February 1901). In 1880, two very important reports on the disease were published; one by a Havana Commission of the National Board of Health of the United States, the other by the United States Navy Department. They tended to show that yellow fever is a "germ-disease"; that it is not wind-borne; and that there may be some change, outside the body of the patient, whereby the virulence of the active principle of the disease is heightened. From these reports, Dr. Finlay advanced his doctrine that the mosquito receives and transmits the germs of the disease:—

"It was upon the above line of reasoning (in these reports), that I conceived the idea that the yellow-fever germ must be conveyed from the patient to the non-immunes by inoculation, a process which could be performed in nature only through the agency of some stinging insect whose biological conditions must be identical with those which were known to favour the transmissibility of the disease."

In 1881 he inoculated himself and six soldiers with infected mosquitoes, and obtained, as he had calculated, mild attacks and subsequent immunity. During the years 1881-1900 he inoculated by this method 104 persons:—

"In these inoculations, be it remembered, my principal object was rather to avoid than to seek the development of a severe attack; in point of fact, only seventeen showed any appreciable pathogenic effects after their inoculation. I felt sure, however, that severe or fatal result might follow an inoculation either with several mosquitoes contaminated from severe cases of the disease, or from a single insect applied several days or weeks after its contamination, having come to this last conclusion in view of the facts connected with the Anne Marie, and the epidemic of Saint Nazaire."

Dr. Finlay's discovery that the mosquito can convey yellow fever, and that the germ of the disease is more virulent after a prolonged sojourning in the mosquito, was proved beyond all question by the work of 1889-1901. But, so far as immunisation is concerned, few people would submit themselves to be bitten by an infected mosquito, even with perfect assurance that the germs contained in it were of a low degree of virulence: the urgent need, therefore, was for an immunising serum. In 1896, at Flores, Sanarelli discovered the bacillus icteroides; and by October 1897, he had prepared an immunising serum which was able to give a considerable amount of protection to animals.[40] Next year (Annales de l'Institut Pasteur, May 1898) came the news that he had advanced against yellow fever with its own weapons—PremiÈres expÉriences sur l'emploi du sÉrum curatif et prÉventif de la fiÈvre jaune. Of the first 8 cases (Rio de Janeiro), 4 recovered. Then came the 22 cases at San Carlos do Pinhal, in Saint-Paul au BrÉsil (January 1898), with 16 recoveries, and only 6 deaths. And it is to be noted that he submitted his method of treatment to the utmost test that was possible; he chose the bad cases, and the country where the fever was most fatal:—

"Chaque cas Était choisi de commun accord entre nous, dans le but de mettre bien en Évidence l'action thÉrapeutique du sÉrum, mettant toujours de cÔtÉ tous les cas qui se prÉsentaient avec des symptÔmes vagues ou attenuÈs ou en forme lÉgÈre ou fruste. On ne conservait donc que des cas oÛ, d'aprÈs la violence des phÉnomÈnes d'invasion, on devait considÉrer comme trÈs peu probable une crise spontanÉe de la maladie...."

Furthermore, Sanarelli was able to show the preventive value of the serum. At the end of February 1898, yellow fever broke out in the jail at San Carlos:—

Every prisoner, except one who had already had the fever, was therefore given the preventive treatment. At once the outbreak stopped; no more cases occurred, though only a weak serum was used, though the state of the prison and its occupants was unhealthy, though the fever, two months later, was still raging round the prison, in the town.

In October 1900, the United States Commission on Yellow Fever published a preliminary report on 11 cases of mosquito-inoculation. Of these, the majority gave a negative result, and were found susceptible to infection, at a later date, from the blood of a yellow-fever patient. Two gave a positive result. In the course of these experiments, Dr. Lazear, a member of the Commission, died of the disease. In February 1901, and again in July, the Commission published further reports, emphasising the fact that the mosquito conveys the disease, and denying that the disease can be conveyed in clothing, bedding, and so forth:—

In February 1901, Dr. H. E. Durham published an abstract of an interim report of the Liverpool School Yellow Fever Commission. He and Dr. Walter Myers, the two Commissioners, had both of them been attacked by the disease, and Dr. Myers had died of it. The report gives evidence that the disease is due to a bacillus which is not the bacillus icteroides; and it does not wholly favour the earlier report (1900) of the American Commission. A later Commission to New Orleans, September 1901 to January 1902, reported an extensive series of investigations, which seem rather to support the belief that the bacillus icteroides is the cause of the disease. Later still, this belief is again denied; and, as in rabies, so in yellow fever, the good work has gone on without waiting for the identity of this or that micro-organism.

Immunisation, by the direct use of an infected mosquito, may be compared with the old custom of inoculation against smallpox. The use of Sanarelli's serum-treatment has not gone far. There remains for consideration the method of keeping down infection by keeping down Culex.

Three reports, in 1901-1902, come from Dr. GuitÉras (Havana), Surgeon-Major Gorgas, chief sanitary officer (Havana), and the Commission at New Orleans. Dr. GuitÉras reports that 6 cases of yellow fever (inoculation) were treated in a large "mosquito-proof" building, which also contained cases of other diseases. No prophylaxis was enforced, save the exclusion of mosquitoes; non-immunes visited the yellow fever cases, non-immunes nursed them, and most of the attendants and labourers about the place were non-immunes; but not a single case of infection occurred. The New Orleans Commission reports that, of 200 cisterns, &c., examined in the city for the presence of larvÆ, the larva of Culex (Stegomyia) predominated in more than 60 per cent.

The report of Surgeon-Major Gorgas is very pleasant reading. For two centuries, Cuba had been cursed with yellow fever; then, after the war with Spain, America took it over:—

"The army took charge of the health department of Havana, when deaths (from all causes) were occurring at the rate of 21,252 per year. It gives it up, with deaths occurring at the rate of 5720 per year. It took charge, with smallpox endemic for years. It gives it up, with not a case having occurred in the city for over eighteen months. It took charge, with yellow fever endemic for two centuries—the relentless foe of every foreigner who came within Havana's borders, which he could not escape, and from whose attack he well knew every fourth man must die. The army has stamped out this disease in its greatest stronghold."

Make fair allowance for the wide variation, from year to year, of the number of yellow fever cases in any town within the geographical belt of the disease; admit that a town may, in the course of nature, have many hundred cases in one year, and only half a dozen in another year. Again, make fair allowance for all other good influences of the American occupation of Cuba, beside those that were concerned with the stamping out of Culex; admit that the general death-rate of Havana, in the last February of Spanish rule (1898), was 82.32 per thousand, and in February 1901, was 19.32. Still, there is an example here, in the 1901 work in Havana, for the world to follow, wherever yellow fever exists. The following abstract of Surgeon-Major Gorgas' results was published in the Practitioner, May 1902, by Professor Hewlett, one of the foremost of English bacteriologists:—

"Commencing in February 1901, orders were issued that every suspected case of yellow fever should be screened with wire gauze at the public expense, so as to render the room or rooms mosquito-proof. All mosquitoes in the infected house and in contiguous houses were destroyed. After the middle of February, 100 men were employed in carrying out the destruction of the mosquito-larvÆ in their breeding places, putting oil in the cesspools of all houses, clearing the streams, draining pools, and oiling the larger bodies of water. Up to June, quarantine was enforced, together with disinfection of the house and fomites. After that, however, rigid quarantine of the patient was stopped, and disinfection of fabrics and clothing ceased. It was merely required that the patient should be reported, his house placarded and screened, and a guard placed over each case to report how general sick-room sanitation was carried out, to see that the screen-door communicating with the screened part of the house was kept properly closed, and to see that communication with the sick-room was not too free, four or five non-immunes only being allowed in. By the end of September, the last focus of the disease had been got rid of, and since then, up to the beginning of January, there has not been a single case. Whereas, for the years since 1889, from 1st April to 1st December, yellow fever caused an average of 410.54 deaths, with a maximum of 1175 for 1896, and a minimum of 79 for 1899, it caused in 1901 5 deaths only. In the months of October and November, when the disease has hitherto been exceedingly rife in Havana, there has not been a single case. For the first time in 150 years, Havana has been free from yellow fever."

Sir Patrick Manson, lecturing in America, last year, on tropical diseases, summed up the work as follows:—

3. Filariasis

These same lectures contain an admirable account of the life-history of Filaria. It is not necessary here to describe the loathsome deformities which occur in the later stages of filariasis. These deformities (elephantiasis, Barbadoes leg), which may attain colossal size, are due to the blocking of the lymphatic vessels with filarial worms. Cases of the disease are hardly ever seen in this country; but it is very frequent in some parts of the tropics. In the endemic areas, says Manson, 10 per cent. is not an uncommon proportion of the population to be found affected with filariasis. Thirty and even 50 per cent. may be affected. In many of the Pacific Islands—the Samoa group for instance—I believe that even this proportion is exceeded.

That Culex (fatigans) can carry the parasite, has been proved past all doubt. Neither does anybody doubt, that the keeping down of this mosquito would keep down filariasis. A report of great interest, from Barbadoes, was published in the British Medical Journal for 14th June 1902. It is written by Dr. Low, whose experiment on himself in the Campagna has already been noted in this chapter. Dr. Low reports that there is no indigenous malaria in the island, and that neither he nor Mr. Lefroy could find a single Anopheles larva, though they hunted diligently in the swamps and other likely places. But filariasis is terribly common, and so is Culex fatigans. Dr. Low examined the night-blood of 600 cases of all kinds in the General Hospital, the Central Almshouse, and elsewhere, and found the filaria-embryos in no less than 76 = 12.66 per cent. He caught and dissected a hundred mosquitoes (Culex fatigans) from the wards and corridors of the General Hospital, and found that no less than 23 of them were infected. If it were not for Culex, and for men's indifference and apathy, filariasis could be kept down all over the island:—

"There is a perfect water supply, and people can get their water fresh from the standpipes at their doors. Old wells ought to be filled up; no water-barrels or tubs should be allowed, or, if kept, they should be emptied every week or so. Tanks and collections of water in gardens should all be periodically treated with kerosene, or be furnished with closely-fitting covers to prevent mosquitoes getting in. These methods are simple and inexpensive, and each householder should see that they are applied in his garden and grounds. The difficulty begins when one has to take into account the inability of the negro to grasp anything of a hygienic nature. The only way to get over this, would be a system of sanitary inspection by a few competent men. For individual prophylaxis, mosquito-nets ought always to be used; but many, even educated people, still persist in sleeping without them; of course, nothing in this line can be expected of the native population.

"If such means were adopted for Barbadoes, the presence of filarial disease, which at present is quite alarming, could easily, with little trouble and expense, be greatly diminished, and thus save much suffering, as well as loss of time, hideous deformity, and doubtless in not a few instances loss of life."

Thus, in a few years, from experiments on mosquitoes, sparrows, and men, has come the present plan of campaign against malaria, yellow fever, and filariasis; that is, against Anopheles and Culex. He who would know what is being done to check these diseases in Italy, India, China, Africa, and America, must read Prof. Ross' Malarial Fever, its Cause, Prevention, and Treatment (1902), and Mosquito Brigades, and how to organise them (1902). There has been nothing like it since Pasteur died. Far and wide, from Staten Island to Cuba, from Hong Kong to Lagos, the work of keeping down the larvÆ of Anopheles and Culex is going on. Henceforth we have to reckon not with a nameless something, but with a definite parasite, whose conditions of life are known. Before all things, we must shut off the sources of the infection. For centuries, men had believed in exhalations and miasmata lying all over the land: and, behold, the agents of malaria are in the puddles round a man's house, and the agents of yellow fever are in the water-butt and the broken bottles and old sardine-tins. Science has given the word, and now there are Anopheles brigades and Culex brigades set going; labourers with brooms and rubbish-carts, sweeping out the stagnant pools, draining the surface soil, and carrying off the odd receptacles that serve to hold mosquito eggs and larvÆ. The job, like all sanitary jobs, must be steady, year in, year out: it must be limited to infected places, a whole continent cannot be treated. But there the work is, and will grow; and saves, by unskilled labour, and at a trivial expense, those "non-acclimatised" lives that have hitherto been thrown away as recklessly as the larvÆ that are now swept out of the puddles and ditches round African settlements.

XI
PARASITIC DISEASES

The foregoing chapters are concerned with bacteriology alone, and with those curative or preventive methods of treatment that have come out of inoculation-experiments on animals. The lives that are saved, or safeguarded, by these methods, even in one year, must be many thousands in each country of the civilised world. And, beside human lives, there is the protection of sheep and cattle against anthrax, swine against rouget, horses against tetanus, cattle against rinderpest. In Cape Colony alone, so far back as 1899, about half a million cattle had received preventive treatment against rinderpest; and the sum total of human and animal lives saved or safeguarded, in all parts of the world, must be reckoned in millions by this time.

The present chapter, and the next two chapters, are concerned with methods that have come out of experiments on animals, but not out of bacteriology.

It is plain that the grosser parasites of the human body, tapeworms and the like, could not be explained or understood without the help of feeding-experiments on animals. By this method, and by this alone, their life-history was discovered. They were known to Aristotle and to Hippocrates; but nothing was understood about them. They were never studied, for this among other reasons, that men believed in spontaneous generation; and the presence of lower forms of life inside human bodies was attributed to the fault of the patient, or the work of the devil. Then, at last, Redi (1712), and Swammerdam (1752) in his Bibel der Natur, struck at the doctrine of spontaneous generation, saying that it did not apply to insects; and in 1781 Pallas boldly declared that the internal parasites of man came out of eggs, like insects, and not "of themselves." It would be a good theme for an essay—The paralysing effect, on medicine and surgery, of the doctrine of spontaneous generation. Rudolphi (1808) and Bremser (1819) opposed Pallas; and von Siebold (1835) and Eschricht (1837) supported him. Then came the great students of this part of biology—Cobbold, Busk, Davaine, van Beneden, Leuckart, KÜchenmeister. In 1842, Steenstrup had discovered, in certain insects, the alternation of generations; in 1852, KÜchenmeister proved that the generations of internal parasites are similarly alternate. By feeding carnivorous animals with "measly" meat, he produced tapeworms in them; and by feeding herbivorous animals with the ova of tapeworms, he made their muscles "measly."

The feeding of animals was the only possible way to understand the bewildering transformations and transmigrations of the thirty or more entozoa to which flesh is heir. This chapter of pathology makes up in tragedy what it lacks in romance; for these animal parasites have killed whole hosts of people. Take, for instance, the trichina spiralis, a minute worm discovered in 1835 encysted in countless numbers in the muscles of the human body; it was studied by Virchow, Leuckart, and others, by feeding-experiments on animals, and was proved to come from infected half-cooked ham and pork, and to make its way from the alimentary canal all over the body. The name of trichiniasis or trichina-fever was given to the acute illness that came of the sudden dissemination of these myriad parasites into the tissues. Trichiniasis had killed hundreds of people by a most painful death; outbreaks of it, in Germany and elsewhere, had swept through villages like cholera or plague: then Leuckart and Virchow traced it to its source, and it was stopped there—Above all things, we must shut off the sources of the infection—the butchers' shops were kept under sanitary inspection, people were warned against half-cooked ham and pork, and there was an end of it.

Or take hydatid disease, which occurs in all parts of the world, and in some countries (Australia, Iceland) is terribly common. The nature of this disease—that it is an animal parasite transmissible between men and dogs—was proved by feeding-experiments on animals. In Iceland, where men and dogs live crowded together in huts, there is an appalling number of deaths from hydatid disease; Leuckart, in 1863, of it:—

"At present, almost the sixth part of all the inhabitants annually dying in Iceland fall victims to the echinococcus epidemic."

Before KÜchenmeister's experiments in 1852, there was no general knowledge of the exact pathology of entozoic disease. The advance was not made by the experimental method alone; other things helped: but among them was neither clinical experience, nor what Sir Charles Bell called "the observation of the just facts of anatomy and of natural motions."

Beside the entozoa, there are also vegetable parasites. Of these, the most important is the streptothrix actinomyces, the cause of actinomycosis in man and cattle. Israel, in 1877, gave the first accurate account of it in man; and BÖllinger, the same year, studied it in cattle. Ponfick, in 1882, recognised the identity of the disease in man and animals. In 1885, Israel published the collected records of 37 cases in man, tabulated according to the site of the primary infection. BostrÖm, about this time, made cultures of the fungus: but all the earlier attempts at inoculation failed; and it was not till 1891 that Wolff and Israel published their successful inoculations, and thus completed the evidence that actinomycosis is a parasitic infection, a growth of vegetable threads and spores, transmissible between men and animals, and able to keep its vitality outside its host; so that men who are employed with cattle, or have the habit of chewing straws or ears of corn, incur some slight risk of infection. Before 1877, the disease was hardly suspected in man, and was not understood in cattle.

XII
MYXŒDEMA

On 4th October 1873, Sir William Gull read a short paper before the Clinical Society of London, "On a Cretinoid State supervening in Adult Life in Women." This famous first account of myxoedema was based on five cases: it is less than five pages long, it does not suggest a name for the disease, and it says nothing about the thyroid gland. Four years later (23rd October 1877), Dr. Ord read a paper before the Medico-Chirurgical Society of London, "On Myxoedema; a term proposed to be applied to an essential condition in the 'Cretinoid' Affection occasionally observed in Middle-aged Women." His work had begun so far back as 1861; and in this 1877 paper he gave not only clinical observations, but also pathological and chemical facts; and he noted, as one among many changes, wasting of the thyroid gland. He also pointed out the close resemblance between cases of myxoedema and cases of sporadic cretinism.

In 1882, Reverdin stated before the Medical Society of Geneva that signs like those of myxoedema had been observed in some cases of removal of the thyroid gland on account of disease (goÎtre). In April 1883, Kocher of Berne read a paper on this subject, before the Congress of German Surgeons; but he attributed this myxoedema after removal of the gland (cachexia strumipriva) not directly to the loss of thyroid-tissue, but rather to some sort of interference with free respiration, due to operation. On 23rd November, Sir Felix Semon brought the subject again before the Clinical Society; and on 14th December 1883, the Society appointed a Committee of Investigation to study the whole question.

Their report, 215 pages long, with tabulated records of 119 cases of myxoedema, was published in 1888. It is a monument of good work, historical, clinical, pathological, chemical, and experimental. Twenty years ago, the purpose of the thyroid gland was unknown: a few experiments had been made on it, by Sir Astley Cooper and others, and had failed; and Claude Bernard, in his Physiologie OpÉratoire (published in 1879, soon after his death), makes it clear that nothing was known in his time about it. He is emphasising the fact that anatomy cannot make the discoveries of physiology:—

"The descriptive anatomy, and the microscopic characters, of the thyroid gland, the facts about its blood-vessels and its lymphatics—are not all these as well known in the thyroid gland as in other organs? Is not the same thing true of the thymus gland, and the suprarenal capsules? Yet we know absolutely nothing about the functions of these organs—we have not so much as an idea what use and importance they may possess—because experiments have told us nothing about them; and anatomy, left to itself, is absolutely silent on the subject."

Therefore, in 1882-83, things stood at this point—that the removal of a diseased thyroid gland had been followed, in some cases, by a train of symptoms such as Sir William Gull had recorded in 1873. Would the same symptoms follow removal of the healthy gland? The answer was given by Sir Victor Horsley's experiments, begun in 1884. He was able, by removal of the gland, to produce in monkeys a chronic myxoedema, a cretinoid state, the facsimile of the disease in man: the same symptoms, course, tissue-changes, the same physical and mental hebetude, the same alterations of the excretions, the temperature, and the voice. It was now past doubt that myxoedema was due to want of thyroid-tissue, and to that alone; and that "cachexia strumipriva" was due to the loss, by operation, of such remnants of the gland as had not been rendered useless by disease.

The advance had still to be made from pathology to treatment. Here, so far as England is concerned, honour is again due to Sir Victor Horsley. On 8th February 1890, he published the suggestion that thyroid-tissue, from an animal just killed, should be transplanted beneath the skin of a myxoedematous patient:—

"The justification of this procedure rested on the remarkable experiments of Schiff and von Eisselsberg. I only became aware in April 1890, that this proposal had been in fact forestalled in 1889 by Dr. Bircher, in Aarau. (The date of Dr. Bircher's operation was 16th January 1889.) Kocher had tried to do the same thing in 1883, but the graft was soon absorbed; but early in 1889 he tried it again, in five cases, and one greatly improved."

The importance of this treatment, by transplantation of living thyroid-tissue, must be judged by the fact that in 1888 no practical use had yet been made of the scientific work that had been done. The Clinical Society's Report, published that year, gives but half a page to treatment, of the old-fashioned sort; and not a word of hope.

Then, at last, in 1891, came Dr. George Murray's paper in the British Medical Journal, "Note on the Treatment of Myxoedema by Hypodermic Injections of an Extract of the Thyroid Gland of a Sheep." Later, hypodermic injections of thyroid-extract gave way to sandwiches, made with thyroid gland (Dr. Hector Mackenzie, and Dr. Fox of Plymouth), and these in their turn were eclipsed by tabloids.

It is a strange sequence, from 1873 onward: clinical observation, post-mortem work, calamities of surgery, experimental physiology, transplantation, hypodermic injections, sandwiches, and tabloids. And far more has been achieved than the cure of myxoedema. Even if the discovery stopped here, it would still be a miracle that little bottles of tabloids should bring men and women back from myxoedema to what they were before they became thick-witted, slow, changed almost past recognition, drifting toward idiocy. But it does not stop here. The same treatment has given good results in countless cases of sporadic cretinism, restoring growth of body and of mind to children that were hopelessly imbecile. It is of great value also for certain diseases of the skin. Moreover, physiology has gained knowledge of the purpose of the thyroid gland, and a clearer insight into the facts relating to internal secretion.

XIII
THE ACTION OF DRUGS

Long after the Renaissance, the practice of medicine was still under the influence of magic. Whatever things were rare and precious were held to be good against disease—gold, amber, coral, pearls, and the dust of mummies; whatever took strange forms of life—toads, earthworms, and the like; whatever looked like the disease, after the doctrine of signatures—pulmonaria for the lungs, because the spots on its leaves were like tubercle, a kidney-shaped fruit for the kidneys, a heart-shaped fruit for the heart, and yellow carrots for the yellow jaundice. Among the drugs in the 1618 Pharmacopoeia are cranium humanum, mandibula lucii, nidus hirundinum, sericum crudum, linum vivum, and pilus salamandrÆ. In the Pharmacopoeia of 1667 are exuviÆ serpentis, telÆ aranearum, saliva jejuni, cranium hominis violent morte extincti, and worse obscenities.

Soon after the publication of this Pharmacopoeia, on 14th February 1685, King Charles II. died; and in the Library of the Society of Antiquaries there is a manuscript account in Latin, by Dr. Scarbrugh, how the case was treated. The King had sixteen physicians, and nine consultations in five days; and to say "everything was done that was possible" gives no idea of the vigour of the treatment. Finally, the day he died, they gave him, eleven of them in consultation—totus medicorum chorus ab omni spe destitutus—they gave him, as more generous cardiacs, the lapis GoÆ, and the Bezoar-stone. The lapis GoÆ was a dust of topaz, jacinth, sapphire, ruby, pearl, emerald, bezoar, coral, musk, ambergris, and gold, all made into a pill and polished; and the bezoar is a calculus found in the intestines of herbivorous animals. Half a century later, the Pharmacopoeia of 1721 still included ants' eggs, teeth, lapis nephriticus, and other horrors; and in the Pharmacopoeia of 1746, though the dust of Egyptian mummies was ruled out, vipers and wood-lice were retained.

Certainly these "last enchantments of the Middle Ages" were slow to depart. Clinical observation, anatomy, and pathology, had all failed to bring about a right understanding of the actions of drugs. It was the physiologists, not the doctors, who first formulated the exact use of drugs; it was Bichat, Magendie, and Claude Bernard. That is the whole meaning of Magendie's work on the upas-poison and on strychnine, and Claude Bernard's work on curari and digitalis. Of these four substances, two only are of any use in practice; yet Magendie's study of strychnine[41] was of immeasurable value, not so much because it gave the doctors a "more generous cardiac," though that was a great gift, but because it revealed the selective action of drugs. Contrast his account of strychnine with Ambroise ParÉ's story how they tested the bezoar-stone on the thief instead of hanging him; contrast Bernard's chapter on curari with Dr. Scarbrugh's notes on the King's death, with all the Crown jewels inside him: you are in two different worlds. The selective action of drugs—the affinity between strychnine and the central nerve-cells, between curari and the terminal filaments of the motor nerves—that was the revolutionary teaching of science: and it came, not by experience, but by experiment.

Take Professor Fraser's address on "The Action of Remedies, and the Experimental Method" at the International Medical Congress in London, 1881:—

"The introduction of this method is due to Bichat; and, by its subsequent application by Magendie, pharmacology was originated as the science we now recognise. Bichat represents a transition state, in which metaphysical conceptions were mingled with the results of experience. Magendie more clearly recognised the danger of adopting theories, in the existing imperfections of knowledge; and devoted himself to the supplementing of these imperfections by experiments on living animals. The advantages of such experiments he early illustrated by his investigation on the upas-poison; and afterwards by a research on the then newly-discovered alkaloid, strychnia.... He demonstrated the action of this substance upon the spinal cord, by experiments upon the lower animals, so thoroughly, that subsequent investigations have added but little to his results."

Or take Professor Fraser's account of digitalis:—

"It was introduced as a remedy for dropsy; and, on the applications which were made of it for the treatment of that disease, a slowing action upon the cardiac movements was observed, which led to its acquiring the reputation of a cardiac sedative. Numerous observations were made on man by the originators of its application, by Dr. Sanders and many other physicians, in which special attention was paid to its effects upon the circulation; but no further light was thrown upon its remarkable properties, with the unimportant exception that in some cases it was found to excite the circulation. It was not until the experimental method was applied in its investigation, in the first instance by Claude Bernard, and subsequently by Dybkowsky, Pelikan, Meyer, Boehm, and Schmiedeberg, that the true action of digitalis upon the circulation was discovered. It was shown that the effects upon the circulation were not in any exact sense sedative, but, on the contrary, stimulant and tonic, rendering the action of the heart more powerful, and increasing the tension in the blood-vessels. The indications for its use in disease were thereby revolutionised, and at the same time rendered more exact; and the striking benefits which are now afforded by the use of this substance in most (cardiac) diseases were made available to humanity."

Or take Sir T. Lauder Brunton's account of the action of nitrite of amyl in angina pectoris:—

Of course it would be easy to lengthen out the list. Aconite, adrenalin, belladonna, calcium chloride, colchicum, cocain, chloral, ergot, morphia, salicylic acid, strophanthus, the chief diuretics, the chief diaphoretics—all these drugs, and many more, have been studied and learned by experiments on animals. Then comes the answer, that drugs act differently on animals and on men. The few instances, that give a wise air to this foolish answer, were known long ago to everybody: they do not so much as touch the facts of daily practice:—

It would be strange indeed, if experts who work in micromillimetres and decimal milligrammes, and study the vanishing-point of microscopic structures, and measure and ordain infinitesimal changes in invisible organisms, were blind to such gross and palpable differences as exist between men and pigeons in their susceptibility to a dose of opium.

AnÆsthetics must be reckoned among the drugs that have been studied on animals: but, for the discovery of them, men experimented on themselves. The first use of nitrous oxide (laughing gas) in surgery was 11th December 1844, when Horace Wells, of Connecticut, had it administered to himself for the removal of a tooth. The first use of ether was made by Dr. Long, of Athens, Georgia; but he did not publish the case, or follow up the work: and the honour of the discovery of ether went to Morton, of Boston, who made repeated experiments, both on animals and on himself. The date when he first rendered himself absolutely unconscious for seven or eight minutes, is 30th September 1846; and the first operation under ether was done on 16th October, in the Massachusetts General Hospital. The first use of chloroform was 4th November 1847, that famous evening when Simpson, George Keith, and Matthews Duncan took it together. The whole history of anÆsthesia is to be found in the Practitioner, Oct. 1896.

It is sometimes said that the men who make experiments on animals ought to make them on themselves. But they do, hundreds of them, and suffer for it: Heaven knows the list is long enough—the discoverers of anÆsthesia, Hunter, GarrÉ, Koch, Klein, Moor, Haffkine, Grassi, Bochefontaine, Quesada, Sanarelli, Pettenkofer—these and hosts more, here or abroad, have done it, as part of the day's work; and some—by accidental infection, like Chabry and Villa, or by deliberate self-inoculation, like Carrion—have been killed:—

"Dr. Angelo Knorr, Privat-docent in the Veterinary School of Munich, died on 22nd February from acute glanders, contracted in the course of an experimental research on mallein. Helmann, the Russian investigator who discovered mallein, himself fell a victim to accidental inoculation of the glanders virus. Some time afterwards another Russian, Protopopow, died of glanders contracted in a French laboratory. An Austrian physician, Dr. Koffman-Wellenhof, died of the same disease, contracted in the Institute of Hygiene at Vienna. On 17th January of the present year Dr. Guiseppe Bosso, of the University of Turin, died of infection contracted in the course of cultivations of tubercle-bacilli made in his laboratory. Not long before, Dr Lola, assistant in the maternity department of the Czech University Hospital of Prague, died of tetanus caused by an experimental inoculation made on himself. Some fourteen or fifteen years ago, a medical student of Lima proved that 'verruga Peruana' is an infectious disease by inoculating himself with it, an act of scientific devotion which cost him his life.[42] Besides those who have died, there are many who have only escaped with their lives after long and painful illness. Professor Kourloff contracted anthrax in a laboratory at Munich, and was saved only by vigorous surgery. Dr. Nicolas supplied, in his own person, the first example of tetanus produced in man by inoculation of the pure toxin of the bacillus of Nicolaier." (Brit. Med. Journal, 18th March 1899.)

This list is seven years old now; it is twice the length by this time. Typhoid, malaria, yellow fever, have all taken toll of those who study them. It is a long record of the men who fell ill, or died, or killed themselves over their work; and the deaths of Barisch, Dr. MÜller, and Nurse Pecha, from plague at Vienna (October 1898) are another instance that there is danger in the constant handling of cultures. But these deaths at Vienna were due to the great carelessness of one man. In laboratories in all parts of the world there are stored cultures of all sorts of organisms, yet no harm comes of it. "More cases of infection occur amongst young medical men attending fever cases, whether in private practice or hospital wards, in a single month, than have occurred in the whole of the laboratories in the world since they were established." (British Medical Journal, 29th October 1898.) Outside the laboratory, outside the fever hospitals, the risk is something less than a negligible quantity:—

"Apart from plague and cholera, in all the big laboratories studies are uninterruptedly pursued, from one end of the year to the other, upon anthrax, glanders, influenza, Malta fever, various tropical diseases which do not exist at all or are rare in the countries where they are being studied. The laboratories in question are situated in the largest and most important towns of their respective countries; and, within those towns, very often in the most fashionable or most populous centres.... On no occasion was there even a suspicion aroused of an epidemic having been produced by any of the above-mentioned institutes, or by those tens of thousands of operations against cholera performed in India." (Haffkine, Madras Mail, 8th December 1898.)

XIV
SNAKE-VENOM

The Report of the 1875 Commission said:—

"It is not possible for us to recommend that the Indian Government should be prohibited from pursuing its endeavours to discover an antidote for snake-bites; or that, without such an effort, your Majesty's Indian subjects should be left to perish in large numbers annually from the effects of these poisons."

Certainly it was not possible; and the numbers are large indeed. During 1897, 4227 persons were killed by wild animals in India, and 20,959 by snakes. (British Medical Journal, 5th November 1898.)

Sir Joseph Fayrer's name must be put in the highest place of all those who have studied the venomous snakes of India.

Sewell, in 1887, showed that animals could be rendered immune, by repeated inoculation with minute quantities of rattlesnake-venom, to a dose seven times as large as would kill an unprotected animal. Kanthack, in 1891, immunised animals in the same way against cobra-venom. He also made experiments to ascertain whether the blood-serum of these animals acted as an antidote to the venom. Then came the work of Calmette, Fraser, Phisalix, Bertrand, Martin (Australia), Stephens, and Meyers. Professor Fraser's observations on the antidotal properties of the bile are, of course, of the utmost importance; not only in preventive medicine, but also in physiology. The results obtained by Calmette are a good instance of the fineness and accuracy of the experimental method. It is to be noted that the animals were inoculated with a fine needle, not thrust into cages with snakes, as at zoological gardens; and that an animal thus poisoned has a painless death. The different venoms were measured in decimal milligrammes, and their potency was estimated according to the body-weight of the animal inoculated. As with tetanus, so with snake-venom, there must be a standard, or "unit of toxicity."

By experiments in test-tubes, Calmette studied these venoms under the influences of heat and various chemical agents. He found how to attenuate their virulence, and how to diminish the local inflammation round the point of inoculation; and it was in the course of these test-tube experiments and inoculations that he discovered the value of calcium hypochlorite as a local application. Working, by various methods, with attenuated venoms, he was able to immunise animals:—

By 1894 he had found that the serum of an animal, thus immunised by graduated doses of one kind of venom, neutralised other kinds of venom:—

"If 1 mgr. of cobra-venom, or 4 mgr. of viper-venom, be mixed, in a test-tube, with a small quantity of serum from an immunised rabbit, and a fresh rabbit be inoculated with this mixture, it does not suffer any discomfort. It is not even necessary that the serum should come from an animal vaccinated against the same sort of venom as that in the mixture. The serum of a rabbit immunised against the venom of the cobra or the viper acts indifferently on all the venoms that I have tested."

In 1894 he had prepared enough serum for the treatment to be tried by his own countrymen practising in some of the French colonies. In April 1895, he gave the following account of his work:—

In 1896 four successful cases of this treatment in the human subject were reported in the British Medical Journal. In 1898 Calmette made the following statement of his results:—

"It is now nearly two years since the use of my antivenomous serum was introduced in India, in Algeria, in Egypt, on the West Coast of Africa, in America, in the West Indies, Antilles, &c. It has been very often used for men and domestic animals (dogs, horses, oxen), and up to now none of those that have received an injection of serum have succumbed.... A great number of observations have been communicated to me, and not one of them refers to a case of failure." (British Medical Journal, 14th May 1898.)

Good accounts of Fraser's and Calmette's work are given by Dr. Stone in the Boston Medical and Surgical Journal, 7th April 1898, and by Staff-Surgeon Andrews, R.N., in the British Medical Journal, 9th September 1899. For other cases see the Pioneer, 10th August 1899, the Lancet, 25th November 1899, and the British Medical Journal, 23rd December 1899. In one of these cases, recorded by Dr. Rennie, the patient was, literally, at the point of death, but recovered after the serum had been injected. Two cases have also been recorded of cobra-bite during work in the laboratory: both of them recovered after injection. "Every Government or private dispensary," says Surgeon Beveridge, "should be supplied with antivenene, which is certainly the best remedy for snake-bite available." The cases are few at present; but it does not appear that the treatment has failed in any case; and, with a new remedy of this kind, it is fairly certain that failures would be published.

From all these instances in physiology, pathology, bacteriology, and therapeutics, we come to consider the Act relating to experiments on animals in the United Kingdom. Many subjects have been left out; among them, the work of the last few years on the suprarenal glands and adrenalin, and Dr. William Hunter's admirable work on pernicious anÆmia. No attempt has been made to describe the researches of experts in many countries into the nature of malignant disease, or to guess what may come of the discovery that mice can be immunised against that form of cancer which occurs in mice and is inoculable from mouse to mouse. Nothing has been said of the discovery that the African sleeping-sickness is due to a blood-parasite carried by flies from man to man. Nothing has been said about those discoveries in bacteriology that have not yet been applied to practice, or of the many inventions of medical and surgical practice that owe only an indirect debt to experiments on animals. Artificial respiration, the transfusion of saline fluid, the hypodermic administration of drugs, the use of oxygen for inhalation, the torsion of arteries, the grafting of skin, the transplantation of bone, the absorbable ligature, the diagnostic and therapeutic uses of electricity, the rational employment of blood-letting—all these good methods have been left out of the list; only some facts have been presented, those that mark most clearly the advance of knowledge and of practice, and stand up even above the rest of the work. There they will stand, when we are all dead and gone: and by them, as by landmarks, all further advance will be guided.