Chapter VII: Part II (2)

Of course there will still be bad diphtheria years and good diphtheria years: for example, the death-rate of the population of England, from diphtheria, was higher during the years 1893-1899 than during the years 1889-1892. Antitoxin can no more prevent a bad diphtheria year than an umbrella can prevent a wet day. But in limited outbreaks of diphtheria, such as occur in a village, an asylum, a school, or a large family of young children, it can be used, and is used, as a prophylactic, and with admirable results. The example of Dr. Kármán, just quoted, is one of the earliest instances of this preventive use of antitoxin: other instances, of equal importance, are given in the _Boston Medical and Surgical Journal_, December 1897 and March 1898; and in the _Lancet_, 2nd April 1898, and 28th January 1899. A summary of later experiences of this preventive use of antitoxin in different countries is given by Dr. Wilcox of New York, and Dr. Stevens of Philadelphia, in Gould's _Year-Book_ for 1902:--

"At a meeting of the Société de Pédiatrie (Paris), held June
1901, a resolution was adopted affirming that preventive
inoculations present no serious dangers, and confer immunity in
the great majority of cases for some weeks, and recommending
their employment in children's institutions and in families in
which scientific surveillance cannot be exercised. Netter stated
that he had collected 32,484 observations (cases) of
prophylactic injections, and after eliminating cases in which
the disease developed in less than twenty-four hours after
injection, or more than thirty days after, there were 6 per
cent. of failures. On the other hand, the author stated that he
had recently made ninety preventive injections with but 2.17 per
cent. of failures. Potter reports a series of twenty-four
families in which preventive injections were used. Only one case
of diphtheria occurred. In another series of cases, in which no
prophylactic injections were given, the disease occurred
secondarily in one-third of the houses, and one-sixth of the
inmates contracted the disease, in spite of the fact that a
large number of the primary cases were removed to the hospital.
Blake reports a series of thirty-five prophylactic injections.
The treatment was instituted after three cases of diphtheria had
developed in a children's home. No secondary cases developed.
Voisin and Guinon describe an epidemic of diphtheria in the
Salpetrière Hospital among idiots and epileptics. Prophylactic
injections were given to all those exposed to the contagion.
After that, but four cases appeared, all mild in character. One
severe case developed, however, two weeks later, ending fatally
in twenty-four hours, showing that the prophylactic action of
the antitoxin, while efficacious, is not of very long duration."

It would be easy to prolong _ad infinitum_ the proofs of the curative and preventive efficacy of the antitoxin: it would be impossible to find any evidence to be weighed for one moment against these proofs. There are three early records that ought to be quoted more fully: the 1894 report from the Hospital for Sick Children, Paris; the 1896 report of the American Pædiatric Society; and the 1898 report of the Clinical Society of London.

I

The report from the Hospital for Sick Children, Paris, is contained in a memoir, _Sérum-Thérapie de la Diphtérie_, the joint work of MM. Roux, Martin, and Chaillon (_Annales de l'Institut Pasteur_, September 1894). It gives the results of the serum-treatment during February to July 1894. The cases were not selected: the antitoxin was given in every case that was proved, by bacteriological examination, to be diphtheria--with the exception of 20 cases where the children were just dying when they were brought to the hospital. No change was made either in the general treatment or in the local applications to the throat; these were the same that had been used in former years: _le sérum est le seul élément nouveau introduit_.

In 1890-1893, before the serum-treatment, 3971 children were admitted to the diphtheria wards, and 2029 of them died. The percentage of these deaths was--

In 1890 55.88 }
" 1891 52.45 } 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.

II

Report of the American Pædiatric Society's Collective Investigation into the use of Antitoxin in the treatment of diphtheria in private practice. (Eighth Annual Meeting, Montreal, May 1896.) From the _New York Medical Record_, 4th July 1896.

This vast collection of cases is of special interest, because they occurred in private practice. In most of them the nature of the disease was proved by bacteriological examination; in the rest, the clinical evidence was decisive: "It is possible that among the latter we have admitted some streptococcus cases, but the number of such is certainly very small." All other doubtful cases, 244 in number, were excluded.

Three thousand three hundred and eighty-four cases were reported by 613 physicians from 114 cities and towns, in 15 different States, the District of Columbia, and the Dominion of Canada. To these 3384 cases were added 942 cases from tenement-houses in New York, and 1468 cases from tenement-houses in Chicago. The New York and Chicago cases were, most of them, treated by a corps of inspectors of the Health Board of the city; and the municipal surveillance was very strict at Chicago:--

"There are very few hospitals in America that receive diphtheria
patients.... It was the custom in Chicago to send an inspector
to every tenement-house case reported, and to administer the
serum unless it was refused by the parents. These cases were
therefore treated much earlier, and the results were
correspondingly better than were obtained in New York, although
the serum used was the same in both cities, viz., that of the
New York Health Board."

The sum total of results was 5794 cases, with 713 deaths = 12.3 per cent., including every case returned; but 218 were moribund at the time of injection, or died within twenty-four hours of the first injection. "Should these be excluded, there would remain 5576 cases in which the serum may be said to have had a chance, with a mortality of 8.8 per cent.

Of 996 cases injected
on the first day of the disease, 49 died = 4.9%
" 1616 " on the second " 120 " = 7.4"
" 1508 " on the third " 134 " = 8.8"
" 758 " on the fourth " 147 " = 20.7"
" 690 " on or after the fifth " 244 " = 35.3"

And in 232 cases, where the day of injection was unknown, there were 19 deaths = 8.2 per cent.

"No one feature of the cases of diphtheria treated by antitoxin has excited more surprise among the physicians who have reported them than the prompt arrest, by the timely administration of the serum, of membrane which was rapidly spreading downward below the larynx. Such expressions abound in the reports as 'wonderful,' 'marvellous,' 'in all my experience with diphtheria, have never seen anything like it before,' etc.

"Turning now to the operative cases, we find the same remarkable effects of the antitoxin noticeable. Operations were done in 565 cases, or in 16.7 per cent. of the entire number reported. Intubation was performed 533 times, with 138 deaths, or a mortality of 25.9 per cent. In the above are included 9 cases in which a secondary tracheotomy was done, with 7 deaths. In 32, tracheotomy only was done, with 12 deaths, a mortality of 37.4 per cent. Of the 565 operative cases, 66 were either moribund at the time of operation or died within twenty-four hours after injection. Should these be deducted, there remain 499 cases operated upon, by intubation or tracheotomy, with 84 deaths, a mortality of 16.9 per cent.

"Let us compare the results of intubation, in cases in which the serum was used, with those obtained with this operation before the serum was introduced. Of 5546 intubation cases in the practice of 242 physicians, collected by M'Naughton and Maddren (1892), the mortality was 69.5 per cent. Since that time, statistics have improved materially by the general use (in and about New York, at least) of calomel fumigations. With this addition, the best results published (those of Brown) showed in 279 cases a mortality of 51.6 per cent.

"But even these figures do not adequately express the benefit of antitoxin in laryngeal cases. Witness the fact that over one-half the laryngeal cases did not require operation at all. Formerly, 10 per cent. of recoveries was the record for laryngeal cases not operated upon. Surely, if it does nothing else, the serum saves at least double the number of cases of laryngeal diphtheria that has been saved by any other method of treatment."

III

In 1898, the Clinical Society published the Report of their Special Committee, based on 633 cases (_Trans. Clin. Soc._, xxxi., 1898, pp. 1-50). The whole report should be read carefully; but there is room here for nothing more than the latter part of it. This is given at length.

A

_Table showing the General Mortality of cases treated, on the same day of the disease, with and without Antitoxin._

+----------------------------++---------------------------++----------+
| ||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 |
+----------+-----+-----+-----++---------+-----+-----+-----++----------+

B

_Summary and Conclusions of the Committee's Report_

"The material for the investigation of the clinical value of the
antitoxin serum in the treatment of diphtheria was not obtained
from selected, but from consecutive, cases, reported from the
general hospitals and the fever hospitals of the Metropolitan
Asylums Board; all were made use of which fulfilled the
requirements of the Committee.

"The Committee rejected all cases in which satisfactory proof of
the existence of true diphtheria was not shown, either by the
presence of the _Bacillus diphtheriæ_ upon bacteriological
examination, or by the occurrence of paralysis in the course of
the illness. All were also rejected in which the amount of
antitoxin administered was stated in cubic centimetres and not
in normal units, the Committee having no means by which the
strength of the antitoxin could in these cases be determined.

"Six hundred and thirty-three cases form the basis on which the
report is drawn up; 549 were treated with antitoxin obtained
from the laboratory of the Royal Colleges of Physicians and
Surgeons; the remainder, 84 in number, were injected with
antitoxin obtained from other sources. In nine instances,
antitoxin from two different sources was injected into the same
patient.

"Statistics of the disease before the use of antitoxin are
introduced as control series; these were obtained from the fever
hospitals of the Metropolitan Asylums Board, and from the
general hospitals; and, like the antitoxin series, are compiled
from consecutive and not from selected cases.

"The general mortality, under the antitoxin treatment, was 19.5
per cent.; a reduction of 10 on the percentage mortality of the
cases treated in the hospitals of the Metropolitan Asylums Board
in 1894. If 15 fatal cases, in which death took place within
twenty-four hours of the first injection, be deducted, the
mortality falls to 15.6 per cent.; which is very little more
than half the mortality during 1894 under other forms of
treatment.

"The lessened mortality is especially noticeable in the earlier
years of life, the percentage mortality of children under five
being 26.3, as opposed to 47.4. In the next period of five
years, the percentage of mortality is 16.0, as opposed to 26.0;
whilst after ten years of age the difference in the mortality is
slight.[21]

[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. +------+-------+---------+------+-------+---------+
| |Cases.|Deaths.|Mortality|Cases.|Deaths.|Mortality|
| | | |per cent.| | |per cent.|
+--------+------+-------+---------+------+-------+---------+
|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 |
| |Cases.|Deaths.|Mortality| and |
| | | |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._

+-----+------+-------+----------+
|Year.|Cases.|Deaths.|Percentage|
| | | |Mortality.|
+-----+------+-------+----------+
|1894 | 466 | 289 | 62.0 |
|1895 | 468 | 196 | 41.8 |
+-----+------+-------+----------+

2. _Comparative Results in Tracheotomy Cases at all Hospitals,
except the Fountain._

+-----+------+-------+----------+
|Year.|Cases.|Deaths.|Percentage|
| | | |Mortality.|
+-----+------+-------+----------+
|1894 | 261 | 184 | 70.4 |
|1895 | 219 | 108 | 49.3 |
+-----+------+-------+----------+

3. _Comparative Number of Laryngeal Cases which required
Tracheotomy at all Hospitals, except the Fountain._

+-----+------+--------------+--------------+
|Year.|Cases.|Tracheotomies.|Percentage of |
| | | |Tracheotomies.|
+-----+------+--------------+--------------+
|1894 | 466 | 261 | 56.0 |
|1895 | 468 | 219 | 46.8 |
+-----+------+--------------+--------------+

"On these tables further comment seems unnecessary.

_Summary_

"The improved results in the diphtheria cases treated during the
year 1895, which are indicated by the foregoing statistics and
clinical observations, are--

1. A great reduction in the mortality of cases brought under
treatment on the first and second day of illness.

2. The lowering of the combined general mortality to a point
below that of any former year.

3. The still more remarkable reduction in the mortality of the
laryngeal cases.

4. The uniform improvement in the results of tracheotomy at each
separate hospital.

5. The beneficial effect produced on the clinical course of the
disease.

_Conclusions_

"A consideration of the foregoing statistical tables and
clinical observations, covering a period of twelve months, and
embracing a large number of cases, in our opinion sufficiently
demonstrates the value of antitoxin in the treatment of
diphtheria.

"It must be clearly understood, however, that to obtain the
largest measure of success with antitoxin it is essential that
the patient be brought under its influence at a comparatively
early date--if possible, not later than the second day of
disease. From this time onwards, the chance of a successful
issue will diminish in proportion to the length of time which
has elapsed before the treatment is commenced. This, though
doubtless true of other methods, is of still greater moment in
the case of treatment by antitoxin.

"Certain secondary effects not unfrequently arise as a direct
result of the injection of antitoxin in the form in which it has
at present to be administered, and even assuming that the
incidence of the normal complications of diphtheria is greater
than can be accounted for by the increased number of
recoveries, we have no hesitation in expressing the opinion that
these drawbacks are insignificant when taken in conjunction with
the lessened fatality which has been associated with the use of
this remedy.

"We are further of the opinion that in antitoxic serum we
possess a remedy of distinctly greater value in the treatment of
diphtheria than any other with which we are acquainted."

* * * * *

Now let us take the whole record of all the hospitals together. The disease was first admitted in 1888; this year is therefore to be reckoned as incomplete.

+--------------------------+----------++--------------+----------+
|Year. |Percentage||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.)

V

TETANUS

Before bacteriology, the cause of tetanus (lock-jaw) was unknown, and men were free to imagine that it was due to inflammation travelling up an injured nerve to the central nervous system. This false and mischievous theory was abolished by the experimental work of Sternberg (1880), Carle and Rattone (1884), and Nicolaier (1884), who proved, once and for all, that the disease is an infection by a specific flagellate organism. Their work was of the utmost difficulty, for many reasons. First, because tetanus, in some tropical countries, is so common that it may fairly be called endemic; and many of these tropical cases, there being no record of any external infection, had been taken as evidence that the disease can occur "of itself." Of this frequency of tetanus in tropical countries, Sir Patrick Manson, in his book on _Tropical Diseases_ (1898), says:--

"Tetanus is an exceedingly common disease in some tropical
countries. In Western Africa, for example, a large proportion of
wounds, no matter how trifling as wounds they may be, if they
are fouled by earth or dirt, result in tetanus. The French in
Senegambia have found this to their cost. A gentleman who had
travelled much in Congoland told me that certain tribes poison
their arrows by simply dipping the tips in a particular kind of
mud. A wound from these arrows is nearly sure to cause tetanus.
In many countries, so general and so extensive is the
distribution of the tetanus-bacillus that trismus neonatorum
(tetanus of newly-born infants) is a principal cause of the
excessive infant mortality."

Next, because the tetanus-bacillus has its natural abode in the superficial layers of the soil: here it is associated with a vast number of other organisms, so that its identification and isolation were a work of immeasurable complexity. What mixed company it keeps, is shown by Houston's estimate of the number of microbes per gramme in twenty-one samples of different soils. This number ranged from 8326 in virgin sand, and 475,282 in virgin peat, to 115,014,492 in the soil from the trench of a sewage-farm. In all rich and well-manured soil the tetanus-bacillus may possibly be present; but it was the work of years to dissociate it from the myriads of organisms outnumbering it.

Next, because it cannot be got to grow in cultures exposed to the air: its proper place is below the surface of the soil, away from the air; it is "strictly anaërobic," and the attempts to cultivate it by ordinary methods failed again and again. It had to be cultivated below the surface of certain nutrient media, or in a special atmosphere of nitrogen or hydrogen.

These and other difficulties for many years delayed the final proof of the true pathology of tetanus. The success of the work was mainly due to Nicolaier. He started from the well-known fact that tetanus mostly comes of wounds or scratches contaminated with particles of earth--such mischances as the grinding of dirt or gravel into the skin, or the tearing of it by a splinter of wood or a rusty nail; as Dr. Poore says, in his Milroy Lectures (1899), "Every child who falls on the ground and gets an abrasion of the skin, all tillers of the soil who get accidental wounds in the course of duty, and every horse which 'breaks its knees' by falling in the London streets, runs potentially a risk of inoculation with tetanus." Nicolaier therefore studied the various microbes of the soil, and made inoculations of garden-mould under the skin of rabbits. He was able, by these inoculations, to produce tetanus in them; and the discharge from the points of inoculation, put under the skin of other rabbits, produced the disease again. He also identified the bacillus, and cultivated it; but in these cultures it was mixed with other organisms, and he failed to isolate it from them. Carle and Rattone, and Rosenbach, were able to produce tetanus in animals by inoculating them with discharge from the wounds of patients attacked by the disease. Finally, Kitasato, in 1889, found a way of obtaining pure cultures of the bacillus. Beginning with impure cultures such as Nicolaier had made, he kept these at a temperature of 36° C. till the bacillus had spored; then, by repeated exposures of the cultures to a temperature of 80° C. for three-quarters of an hour at a time, he killed-off all organisms except the spores of the tetanus-bacillus; then he kept these in an atmosphere of hydrogen, at a temperature of 20° C., and thus got pure cultures.

Brieger, Fränkel, Cohen, Sidney Martin, Kanthack, and others, have studied the chemical products of the disease, have obtained them from cultures and from infected tissues, and have been able with these toxins to produce the disease in animals. As with the other infective diseases, so with tetanus, there have been two main lines of researches; the one, toward a fuller knowledge of the chemical changes in the blood and in the central nervous system; the other, toward a fuller knowledge of the nature and ways of the bacillus, and its method of invasion. Before any study of immunity or immunisation, or of neutralisation of the toxins in man by an antitoxin, came the study of the toxins and of the bacillus. It was proved, by an immense quantity of hard work, that the bacillus does not tend to invade the blood, or to pass beyond the lymphatic glands in the immediate neighbourhood of the site of inoculation; that it stays in and about the wound, and there multiplies, and from this site pours into the blood the chemical products which cause the disease; and that these chemical substances have a selective action on certain nerve-cells in the brain and the spinal cord. This is the bare outline of the facts; and no account can be given here of the intricate problems of bacteriology and animal chemistry that have been answered, or are still waiting an answer. At least, it is evident that the whole pathology of tetanus was found, proved, and interpreted by the help of experiments on animals; and that these alone did away with the old false doctrine that the disease was due to rapid extension of inflammation up a nerve to the brain.

In 1894 came the use of an antitoxin in cases of the disease, and, in 1895, 42 cases were reported, with 27 recoveries. It cannot be said that any one of the diverse preparations of tetanus-antitoxin, up to this present time, has triumphed over the disease. Tetanus is of all diseases the hardest to reckon with: the first sign of it is the last stage of it; there is no warning, nothing, it may be, but a healed scratch, till the central nervous system is affected with sudden and rapidly advancing degeneration of certain cells. These and other difficulties have stood in the way of an antitoxin treatment; and there is no less difficulty in estimating the efficacy of that treatment. The recovery, under antitoxin, of a "chronic" case cannot always or altogether be attributed to the treatment; and in a very acute case, antitoxin, like everything else, has but small chance of success. Various reports on the antitoxin treatment, published during 1897-1899, give the following figures:--

26 cases, with 12 recoveries.
98 " 57 "
36 " 25 "
22 " 11 "
51 " 36 "
10 " 7 "

Probably the paper by Dr. Lambert of New York, in the _Medical News_, July 1900, gives fairly the general opinion of the treatment, so far as the subcutaneous administration of antitoxin is concerned:--

"The following cases of tetanus, treated with antitoxin,
comprise published and unpublished cases. We have a total of 279
cases, with a mortality of 44.08 per cent.: but of these we must
rule out 17 cases--4 deaths from intercurrent diseases, 8 deaths
in cases in which the antitoxin was given but a few hours before
death, and 5 recoveries in which antitoxin was not given until
after the twelfth day (as they probably would have recovered
without it). We have left 262 cases, with 151 recoveries, and
111 deaths, a mortality of 42.36 per cent. Dividing the cases
into acute and chronic, we have 124 acute cases, with 35
recoveries and 89 deaths, a mortality of 71.77 per cent., and
138 chronic cases, with 116 recoveries and 22 deaths, a
mortality of 15.94 per cent. In interpreting critically these
statistics, we see that in acute cases the mortality is but
slightly reduced, being but 72 per cent. instead of 88 per cent.
But, in the less acute cases, there is a decided improvement,
from 40 per cent. to 16 per cent. Taking the statistics as a
whole, there is a distinct improvement in the mortality of
tetanus since the introduction of antitoxin."

It would be foreign to the present purpose to pursue this matter further: for the other treatments, used by Baccelli and by Krokiewicz, and the sub-dural use of antitoxin, are also founded on experiments on animals; and the same will be true of any better method that shall be developed out of them.

The _preventive_ use of the tetanus-antitoxin, for the immunisation of human beings or of animals, has given excellent results. Horses are very apt to be infected by tetanus; and the antitoxin has been used in veterinary practice, both for prevention and for cure. The curative results are not, at present, very good. But, as regards protection against the disease, there is evidence that horses can be immunised against tetanus by the antitoxin with almost mechanical accuracy. In some parts of the world, the loss of horses by tetanus is so common that their immunity is a very important matter; and that the antitoxin does confer immunity on them is shown by statistics from France and from the United States:--

1. _France._--"The results of Nocard's method of preventive
inoculations in veterinary practice are most striking. Among 63
veterinarians, there have been inoculated 2737 animals with
preventive doses of antitoxin, and not a single case of tetanus
developed; while during the same period, in the same
neighbourhoods, 259 cases of tetanus developed in non-inoculated
animals." (_Med. News_, 7th July 1900.)

2. _United States._--"Joseph MacFarland and E. M. Ranck, in
addition to a synopsis of the method of manufacture of
tetanus-antitoxin, give some facts of interest and importance in
regard to its use for prophylaxis and treatment. The studies
were made upon several hundred horses used for the production
of various immunised serums in one of the large laboratories of
the United States. The horses, because of the constant
manipulations, frequently became infected with tetanus, and in
1897 and 1898, when scrupulous cleanliness and disinfection were
the only precautions employed to prevent the disease, the
death-rate varied from 8 to 10 per cent. During 1899 nearly two
hundred horses were subjected to systematic immunisation with
tetanus-antitoxin; and, in spite of otherwise similar
conditions, the death-rate descended to 1 per cent." (_Medical
Annual_, 1901.)

The preventive use of the antitoxin has, of course, a very limited range outside veterinary surgery. Tetanus, thanks to the use of antiseptic or aseptic methods, not only in hospital surgery but also in amateur and domestic surgery, has become a very rare disease, except in tropical countries. It is no longer a "hospital disease"; and, even in war, it no longer has anything like the frequency that it had, for instance, in the War of the Rebellion. A student may now go all his time at a large hospital without seeing more than a very few cases. But, now and again, attention is called to some wholly unsuspected risk of the disease. For example, certain cases of tetanus occurred in Dundee among workers at the jute-mills there:--

"The last victim was a female worker in the jute-mill, who, six
days after a crushed and lacerated wound of the foot, developed
tetanus and died within twenty-four hours. Some of the dust,
taken from under the machine in which the foot was crushed, was
found to contain an unusually large number of tetanus-bacilli.
The source of the jute used is India." (_Medical News_, August
1900.)

Again, at the Gebaer Anstalt at Prague, in 1899, an outbreak of tetanus occurred, with several deaths; but it was stopped when a preventive dose of the antitoxin was given to the new patients on admission.

Again, an amazing number of deaths from tetanus, in the United States, are due to wounds of the hands with toy-pistols. It is said that after the Fourth of July festivities in 1899, no less than 83 cases of tetanus were reported, 26 of them in and around New York. Almost all of them were due to gunshot wounds of the hand with toy-pistols: the unclean wad of the cartridge, made of refuse paper picked up in the streets, penetrates deep into the tissues of the hand, taking the germs of the disease with it, out of the reach of surgical disinfection. These cases of tetanus in the United States from toy-pistol wounds are so frequent, that immunisation has been recommended for them. The _Medical News_, 1st June 1901, has the following note:--"H. G. Wells states that tetanus is endemic in Chicago, the specific organism being present in the dirt of the streets. Every Fourth of July an epidemic occurs, because these bacilli are carried deeply into wounds before wads from blank cartridges.... The writer thinks that such cases should receive a prophylactic dose, say, 5 c.c. of tetanus-antitoxin, as soon as possible after the wound is first seen. It seems certain that if antitoxin prophylaxis were adopted, there would be no further Fourth of July epidemics, and this end would justify the means."

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

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

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

VI

RABIES