PART II_Experiments on Animals

EXPERIMENTS IN PATHOLOGY,

MATERIA MEDICA, AND

THERAPEUTICS

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]

[12] See also the admirable Life of Pasteur, by M. Valléry-Radot.

Translation by Mrs. Devonshire, vol. ii. p. 20.

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.

[13] This account of Semmelweis, reprinted by permission from the

_Middlesex Hospital Journal_, is mostly taken from Dr. Theodore

Duka's excellent paper on "Childbed Fever." (_Lancet_, 1886.)

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'OEuvre Médicale de

Pasteur_. _Agenda du Chimiste_, 1896, p. 528.)

[14] See Pasteur's Life, vol. ii. p. 89.

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.)

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]

[15] Dr. Legge, in his Milroy Lectures, 1905, on Industrial

Anthrax (_Lancet_, March and April 1905), gives a full account of

Sobernheim's work up to March 1904, and a table of seventy-six

cases, treated with Sclavo's serum.

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.

[16] See Dr. Flexner's account of the disease, in volume xix. of

Stedman's _Twentieth Century Practice_.

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._

+------+-----------+--------+----------+------------------------+

| | | | Animals +-------+-------+--------+

+------+-----------+--------+----------+-------+-------+--------+

| 1882 | 270,040 | 112 | 243,199 | 756 | 847 | 1,037 |

| 1883 | 268,505 | 103 | 193,119 | 436 | 272 | 784 |

| 1884 | 316,553 | 109 | 231,693 | 770 | 444 | 1,033 |

| 1885 | 342,040 | 144 | 280,107 | 884 | 735 | 990 |

| 1886 | 313,288 | 88 | 202,064 | 652 | 303 | 514 |

| 1887 | 293,572 | 107 | 187,811 | 718 | 737 | 968 |

| 1888 | 269,574 | 50 | 101,834 | 149 | 181 | 300 |

| 1889 | 239,974 | 43 | 88,483 | 238 | 285 | 501 |

| 1890 | 223,611 | 69 | 69,865 | 331 | 261 | 244 |

| 1891 | 218,629 | 65 | 53,640 | 181 | 102 | 77 |

| 1892 | 259,696 | 70 | 63,125 | 319 | 183 | 126 |

| 1893 | 281,333 | 30 | 73,939 | 234 | 56 | 224 |

+------+-----------+--------+----------+-------+-------+--------+

| Total|3,296,815 | 990 |1,788,879 | 5,668 |4,406 | 6,798 |

+------+-----------+--------+----------+-------+-------+--------+

+------+-------+-----+-------+

| | | | |

| | | per |Vacci- |

+------+-------+-----+-------+

| 1882 | 2,640 | 1.08| 10% |

| 1883 | 1,492 | 0.77| " |

| 1884 | 2,247 | 0.97| " |

| 1885 | 2,609 | 0.93| " |

| 1886 | 1,469 | 0.72| " |

| 1887 | 2,423 | 1.29| " |

| 1888 | 630 | 0.62| " |

| 1889 | 1,024 | 1.16| " |

| 1890 | 836 | 1.20| " |

| 1891 | 360 | 0.67| " |

| 1892 | 628 | 0.99| " |

| 1893 | 514 | 0.69| " |

+------+-------+-----+-------+

| Total|16,872 | 0.94| 10% |

+------+-------+-----+-------+

VACCINATION AGAINST CHARBON (FRANCE).

_Cattle._

+------+-----------+--------+----------+------------------------+

| | | | Animals +-------+-------+--------+

+------+-----------+--------+----------+-------+-------+--------+

| 1882 | 35,654 | 127 | 22,916 | 22 | 12 | 48 |

| 1883 | 26,453 | 130 | 20,501 | 17 | 1 | 46 |

| 1884 | 33,900 | 139 | 22,616 | 20 | 13 | 52 |

| 1885 | 34,000 | 192 | 21,073 | 32 | 8 | 67 |

| 1886 | 39,154 | 135 | 22,113 | 18 | 7 | 39 |

| 1887 | 48,484 | 148 | 28,083 | 23 | 18 | 68 |

| 1888 | 34,464 | 61 | 10,920 | 8 | 4 | 35 |

| 1889 | 32,251 | 68 | 11,610 | 14 | 7 | 31 |

| 1890 | 33,965 | 71 | 11,057 | 5 | 4 | 14 |

| 1891 | 40,736 | 68 | 10,476 | 6 | 4 | 4 |

| 1892 | 41,609 | 71 | 9,757 | 8 | 3 | 15 |

| 1893 | 38,154 | 45 | 9,840 | 4 | 1 | 13 |

+------+-----------+--------+----------+-------+-------+--------+

|Total | 438,824 | 1,255 | 200,962 | 177 | 82 | 432 |

+------+-----------+--------+----------+-------+-------+--------+

+------+-------+-----+-------+

| | | | |

| | | per |Vacci- |

+------+-------+-----+-------+

| 1882 | 82 | 0.35| 5% |

| 1883 | 64 | 0.31| " |

| 1884 | 85 | 0.37| " |

| 1885 | 107 | 0.50| " |

| 1886 | 64 | 0.29| " |

| 1887 | 109 | 0.39| " |

| 1888 | 47 | 0.43| " |

| 1889 | 52 | 0.45| " |

| 1890 | 23 | 0.21| " |

| 1891 | 14 | 0.13| " |

| 1892 | 26 | 0.26| " |

| 1893 | 18 | 0.18| " |

+------+-------+-----+-------+

|Total | 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).

+------+-----------+--------+----------+------------------------+

| | | | Animals +-------+-------+--------+

+------+-----------+--------+----------+-------+-------+--------+

| |{ For these| | | | | |

| |{ two years| | | | | |

| 1886 |{ France | 49 | 7,087 | 91 | 24 | 56 |

| |{ and other| | | | | |

| |{ countries| | | | | |

| 1887 |{ are put | 49 | 7,467 | 57 | 10 | 23 |

| |{ together.| | | | | |

| 1888 | 15,958 | 31 | 6,968 | 31 | 25 | 38 |

| 1889 | 19,338 | 41 | 11,257 | 92 | 12 | 40 |

| 1890 | 17,658 | 41 | 14,992 | 118 | 64 | 73 |

| 1891 | 20,583 | 47 | 17,556 | 102 | 34 | 70 |

| 1892 | 37,900 | 38 | 10,128 | 43 | 19 | 46 |

+------+-----------+--------+----------+-------+-------+--------+

|Total | 111,437 | 296 | 75,455 | 534 | 188 | 345 |

+------+-----------+--------+----------+-------+-------+--------+

+------+-------+-----+-------+

| | | | |

| | | per |Vacci- |

+------+-------+-----+-------+

| | | | |

| 1886 | 171 | 2.41| 20% |

| | | | |

| 1887 | 90 | 1.21| " |

| | | | |

| 1888 | 94 | 1.35| " |

| 1889 | 144 | 1.28| " |

| 1890 | 254 | 1.70| " |

| 1891 | 206 | 1.17| " |

| 1892 | 108 | 1.07| " |

+------+-------+-----+-------+

|Total | 1,067 | 1.45| 20% |

+------+-------+-----+-------+

[17] "The reports for 1893 are at present too few to be utilised

for this table."

"_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]

[18] "In Zukunft wird man es im Kampf gegen diese schreckliche

Plage des Menschengeschlechtes nicht mehr mit einem unbestimmten

Etwas, sondern mit einem fassbaren Parasiten zu thun haben, dessen

Lebensbedingungen zum grössten Theil bekannt sind und noch weiter

erforscht werden. Es müssen vor allen Dingen die Quellen, aus

denen der Infektionsstoff fliesst, so weit es in menschlicher

Macht liegt, verschlossen werden."

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.

[19] At the British Congress on Tuberculosis, London, 1901, Koch

stated that bovine tuberculosis and human tuberculosis are not one

and the same disease, and that the risk of milk-infection is so

small that burdensome restrictions ought not to be enforced. In

the general judgment of men well qualified to study the subject,

he failed to prove his point.

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.

[20] For references to this paper, and to evidence put forward

against the validity of the test, and for criticism of such

evidence, see Gould's _Year-Book of Medicine and Surgery_, 1902

(Philadelphia, W. B. Saunders & Company).

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.

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.

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 } Average = 51.71.

" 1892 47.64 }

" 1893 48.47 }

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 } Average = 33.94.

" 1892 38.8 }

" 1893 32.02 }

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 } Average = 73.49.

" 1892 74.6 }

" 1893 73.45 }

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.

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.

_Table showing the General Mortality of cases treated, on the same day

of the disease, with and without Antitoxin._

+----------------------------++---------------------------++----------+

| ||METROPOLITAN ASYLUMS BOARD || |

| ANTITOXIN COMMITTEE: || 1894: ||Difference|

| 633 Cases treated ||3042 Cases treated without || of |

| with Antitoxin. || Antitoxin. || Per- |

+----------------------------++---------------------------++ centage. |

|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 |

+----------+-----+-----+-----++---------+-----+-----+-----++----------+

_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]

[21] After childhood, the disease is much less fatal.

"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."

[22] For an exhaustive and wise study of the diphtheritic

paralyses, see Dr. Woollacott's essay in the _Lancet_, 26th August

1899: "The use of antitoxic serum in the treatment of diphtheria

has, up to the present time, in the London fever hospitals, had

two main results--the death-rate has fallen, while the

paralysis-rate has risen. In the hospitals of the Metropolitan

Asylums Board, the former has been reduced from 29 per cent. to

15.3 per cent., while the latter has risen from 13 per cent. to as

high as 21 per cent. in 1896. This increase of paralysis is

chiefly due to the fact that many more patients now recover from

the primary disease, and live long enough for paralysis to show

itself. _During the last two years, however, the occurrence of

paralysis has begun to diminish in frequency.... The earlier

antitoxin is given in diphtheria, the less likely is paralysis to

follow._" It is to be borne in mind that post-diphtheritic

paralysis, in the great majority of cases, affects only a very

small group of muscles; of Dr. Woollacott's tabulated cases, 377

were of this kind, and 97 were severe. And "the type of paralysis

has, on the whole, become less severe, or at all events less

dangerous to life."

* * * * *

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._

+--------+------------------------+------------------------+

| | Antitoxin Cases, | All Cases, |

| | 1895. | 1895. |

| Ages. +------+-------+---------+------+-------+---------+

+--------+------+-------+---------+------+-------+---------+

|Under 5 | 1013 | 379 | 37.4 | 1453 | 497 | 34.2 |

| " 10 | 1829 | 575 | 31.4 | 2720 | 744 | 27.3 |

| " 15 | 2056 | 606 | 29.4 | 3144 | 779 | 24.7 |

|All ages| 2182 | 615 | 28.1 | 3529 | 796 | 22.5 |

+--------+------+-------+---------+------+-------+---------+

+--------+------------------------+------------+

| | All Cases, | Diff. in |

| | 1894. |Mortalities,|

| Ages. +------+-------+---------+ 1894 |

| | | |per cent.| 1895. |

+--------+------+-------+---------+------------+

|Under 5 | 1171 | 556 | 47.4 | 13.2 |

| " 10 | 2246 | 836 | 37.2 | 9.9 |

| " 15 | 2609 | 877 | 33.6 | 8.9 |

|All ages| 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._

+-----+------+-------+----------+

+-----+------+-------+----------+

|1894 | 466 | 289 | 62.0 |

|1895 | 468 | 196 | 41.8 |

+-----+------+-------+----------+

2. _Comparative Results in Tracheotomy Cases at all Hospitals,

except the Fountain._

+-----+------+-------+----------+

+-----+------+-------+----------+

|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._

+-----+------+--------------+--------------+

+-----+------+--------------+--------------+

|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||Year. |Percentage|

| |Mortality.|| |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.

[23] This, of course, does not apply to two instances, in 1901, of

accidental contamination of serum. See, for an account of these,

_The British Medical Journal_, November 1901.

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.)

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.