NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
22
therefore to study a large series of cases treated by ordinary methods and by serum
side by side, in a strictly scientific manner, before a conclusion could be arrived
at. This has, I think, been to a large extent secured in the case of the trials
enumerated in Table I, and it is by a consideration of these alone, that a true
estimate of the worth of serum treatment for plague as at present practised can be
reached.
To take first the case of the Roux Yersin serum, it is seen that in all the
trials, save one, the case-mortality of those treated with serum is as high or
higher than that of the control patients. The one exception is in the series of
28 cases treated in Bombay by the Indian Plague Commission, in which one
patient fewer on the serum side died than among the controls. The element of
chance must be reckoned with here, as the numbers are small.
With regard to the trial of the serum sent personally by Dr. Roux and
dealt with fully in Dr. West's report, it is a matter for regret that permission to
employ the intravenous method was not obtained at an earlier stage of the
experiment, so that a greater number of patients might have been thus treated.
Dr. Roux maintains that subcutaneous injection, entailing as it does slow
absorption of the serum into the circulation, gives time for the formation in the
patient of anti-bodies to the serum anti-toxin so that the plague bacilli in the
blood are not affected by the serum. They may even, as Ainley Walker 34 has
pointed out, become accustomed to the presence of the anti-toxin and thereby
have their virulence increased. Roux maintains that the full dose of serum
should be injected straight into the blood stream, so that the bacilli may be
overwhelmed at once, by mass-action as it were.
If the patients dealt with in this trial be divided into three groups, according
as they were treated :
—
(a) by subcutaneous injection only ;
(b) by subcutaneous injection to begin with, followed by intravenous
injection ; and
(c) by primary intravenous injection, followed by similar injections, or in
some few cases by subcutaneous Medication ;
the following table can be constructed :—
SERUM CASES.
CONTROL CASES.
No.
Deaths.
Case-
mortality,
per cent.
No.
Deaths.
Case-
mortality,
per cent.
Patients treated according to ( a)
.
.
.
43
29
67.4
43
28
65.1
Patients treated according to ( b )
.
.
.
12
8
66.6
12
6
50.0
Patients treated according to ( c)
.
.
13
8
61.5
13
7
53.8
TOTAL
.
68
45
66.2
68
41
60.3
23
From a study of the case-mortality of the control cases corresponding to
those treated with serum as above divided, it is evident that the epidemic was
declining in severity as time went on. It is not therefore possible to say that
the lessened case-mortality shown by the 13 cases treated according to ( c) is
due to that treatment, for a corresponding and even greater lessening of the case-
mortality is exhibited by the 13 alternate control cases receiving the ordinary
treatment.
We must, therefore, reluctantly conclude that the serum treatment, as
judged by these figures, did not affect the case-mortality in the slightest
degree.
In three out of the four trials made with Lustig's serum we find that the
case-mortality of the serum-treated patients is higher than among those receiving
ordinary treatment.
The exceptional case is that treated at length in the report forming the first
of those published in this memoir. From Table II of this report we learn that of
the category showing the lowest mortality ( i.e ., those in whom both pulse and
respiration were slow) the serum group of patients had 46, while the control
group comprises only 24 such cases.
Table III of the same report shows that cases without buboes were "practi-
cally all fatal." Of these the controls had 29, while the serum-treated cases
had only 5. Table V shows that the sex distribution likewise is in favour of
the serum cases.
From a consideration of these tables and the details set forth in
Mr. Haffkine's report we must reluctantly arrive at the conclusion, that, judged
by these figures alone, there is no certain evidence that the serum is efficient.
The trial made with Terni's serum shows the difference in favour of the
injected patients to be 0.91 per cent. only, an amount which cannot be regarded
as of the slightest significance.
As regards Brazil's serum it seems highly problematical if the 2.85 per cent.
of the life-saving shown amongst the treated cases can be credited to the effects
of the treatment. For in one hospital we find that of the serum-treated patients
ten per cent. more died, while in the other, eight per cent. fewer of the cases
had a fatal termination.
From the stand-point of clinical evidence, however, there is more hope in the
outlook. Almost all the clinicians who have reported on the use of serum in their
hospitals or in private practice are emphatic that it acts favourably on the course
of the disease.
It seems, for instance, that the serum-treated cases live longer than the
control cases.
24
The following statement brings this out :—
Kind of serum used.
AVERAGE NUMBER OF
DAYS IN HOSPITAL IN FATAL CASES IN
Advantage in
favour of serum-
treated cases.
Serum Cases.
Control Cases.
Roux.
. . . . .
7 . 5 7
4.19
3.38
Lustig
3.89
2.76
1.13
Terni
3 . 2 7
2.93
0 . 3 4
Maratha Hospital ..
.
2.56
2.25
0 . 3 1
Brazil
Modikhana „
2.06
4.61
- 2 . 5 5
It is a curious circumstance, as noted by Mr. Haffkine, that serum should
have the effect of prolonging life, and yet be apparently powerless to affect the
case mortality of hospital cases. Perhaps the proper method of administration
has not yet been arrived at; for undoubtedly in the case of animals artificially
infected with plague the serum proves efficacious when given within a reasonable
time after infection. It is therefore a matter for regret that more cases were not
treated intravenously as suggested by Dr. Roux. Time is everything when
treating such a virulent and rapidly fatal disease as plague, and it is well to
remember the results obtained by Martin when working with snake venom. He
found that the proportion of toxine to anti-toxine necessary for neutralisation was
approximately the same whether they were allowed to act on one another in a test
tube before injection, or were injected separately but simultaneously in different
parts of the body, provided the serum was given intravenously . When however
the serum was injected subcutaneously, at least twenty times the quantity was
required to save the life of the animal. The reason for the failure of
the anti-toxic serum used by Martin35 when given subcutaneously, was its
slow absorption into the system of the experimental animal, due to the
large size of the molecular molecule of the anti-toxine. Starling 36 has shown that
the walls of the capillaries are relatively impermeable to proteids, and Martin
has proved that antivenene is a body "of great molecular size " compared with
proteids. It is, therefore, reasonable to suppose that antivenene and other anti-
toxines will also be very slowly taken up by the capillaries.
Other effects attributed to the serum by those who have used it are
(a ) lowering of the temperature, ( b ) lessening of rate of pulse and respiration,
( c ) a general improvement in the patient's condition as to physical comfort, and
a diminution of delirium and restlessness, and ( d ) disappearance of the buboes
and lessening of pain in them.
25
In such a virulent disease as plague is in India, these are no small gains, but
it must be remembered that 60 per cent. of all bubonic cases are at the time of
admission to hospital septicae mic. It has been urged by certain competent
authorities ( e.g., Roux) that it is quite out of the question to expect to get any
results with cases far advanced in the disease 3 7
a n d t h a t t h e r e f o r e t h e a l t e r n a t e
method hitherto tried in Indian hospitals is not one to bring out the true value
of serum treatment.
But perhaps it would be possible to get an experienced clinician to select
such cases as he deemed suitable for serum treatment and to admit them to a
separate ward where they could be submitted to the alternate method of treatment
by an independent observer.
When comparing the effects of the various sera as described in this memoir,
it is necessary to remember that they differed much as regards freshness. Thus
Lustig's serum being made locally was often used within a few days of separa-
tion from the blood ; Brazil's serum had been kept for six months in the ice chest
after receipt in India, and so on. Particulars as to date of receipt and use will be
found in the detailed reports.
In view of the somewhat discouraging results obtained among hospital
patients in India, it seems necessary to commence anew the study of the serum
therapy of plague.
This, as suggested by the Indian Plague Commission, should be done by
studying the action of plague toxines on animals and the blood changes taking
place in men and animals injected with living plague or its toxines.
It would be necessary also to find out whether the insusceptible horse is the
best manufacturer of plague curative serum. Brazil and Haffkine seem to have
been the only experimenters with serum from animals other than the horse.
Judged by the effect of serum on rabbits it appears 38 that the toxicity of serum
from various species of animals may be arranged in the following order of
decreasing virulence, viz.,—bullock, dog, calf, sheep, ass, and horse serum ; but
it does not follow that this order of toxicity would be maintained in the case of
man.
W. B. BANNERMAN, M.D., B. SC.,
Lieutenant-Colonel, I.M.S.,
Director, Plague Research Laboratory.
26
REFERENCES TO INTRODUCTION.
1 Report of the Indian Plague Commission, Vol. III, p. 382, Note 1. Vide also
La Peste Bubonique, Par M. M. Yersin, Calmette et Borrel, Annales de l' Institut Pasteur,
1895, p. 591.
2 Gatacre's Report, pp. 145-6. "Times of India" Press, Bombay, 1897.
3 Report of the Indian Plague Commission, Vol. I, p. 395, also vide The Bombay
Plague, Condon, 1900, p. 85, and General Gatacre's Report, 1897, pp. 78 and 80.
4 Indian Plague Commission Report, Vol. V, p. 308.
5
Ibid,
Vol. V, p. 298, and Vol. III, p. 380.
6
Ibid,
Vol. V, p. 299.
,7 Ibid, Vol. V, p. 300.
8
Ibid,
Vol. V, p. 301.
9
Ibid,
Vol. III, p. 136 and V, p. 303.
10
Ibid,
Vol. V, p. 306.
11
Ibid,
Vol. V, p. 307.
12
Ibid,
Vol. III, pp. 593—643, and Vol. V, pp. 289—298.
13
Ibid,
Vol. V, p. 290.
14
Ibid,
Vol. V, p. 291.
15
Ibid,
Vol. V, p. 292.
16 Jennings, Indian Plague Commission Report, Vol. V, p. 310.
17 Clemow, Lancet, Vol. I, 1899, p. 1212.
18 Mr. Haffkine's evidence ; Indian Plague Commission Report, Vol. I, para. 115.
19 Ibid,
para. 135.
20 Colonel J. Wilkins, I.M.S., in Report of Municipal Commissioner on the Plague
in Bombay for the year ending 31st May 1899. Appendix E, p. 374.
21 Memo. by Professor Lustig, to Health Officer, Bombay, Ibid. Appendix E, p. 376.
22 Indian Plague Commission Report, Vol. V, p. 314.
23
Ibid, p. 315.
24
Ibid,
p. 316.
25 The Treatment of Plague with Prof. Lustig's Serum, page 110, by N. H. Choksy,
M.D., Honoris causâ, Freiburg, Germany, Cor. Mem. Med. Soc. Munich, Special Assistant Health
Officer, in charge of Arthur Road and Maratha Plague Hospitals, Bombay. "Eagle"
Printing Office, Dalai Street, Fort, Bombay, 1903.
26 Loc. cit., p. 111.
27 The Serum Treatment of Plague; by Frank G. Clemow, M.D., Edin., D.P.H.,
Cantab. Lancet, May 6, 1899, p. 1215.
28 Report on cases treated with Professor Lustig's Serum in 1899-1900, by Drs.
Polverini and Mayr. Appendix IV, p. 378 of Report of the Municipal Commissioner on
the Plague in Bombay for the year ending 31st May 1900. Bombay "Times of India"
Press, 1901.
29 Report of Municipal Commissioner for 1900, p. 378.
27
30 In a letter to the writer.
31 Vide Appendix B, Epitome of Greig's unpublished paper.
32 Vide pages 113—115 of No. 25 of this list.
33 Bombay Government Resolution, General Department (Plague), No. 2869-P.,
dated Bombay Castle, 30th October 1902. (Accompaniment.)
34 Berliner Klinische Wochenschrift, 1901, Nos. 21 and 22.
35 C. J. Martin, M.D., D.Sc., F.R.S., Director, Lister Institute. Proceedings, Royal
Soc., 1898, Vol. LXIV, p. 88, and British Medical Journal, Vol. II, 1904, p. 901.
36 Starling. Journal of Physiology, Vol. XIX, 1895-96, p. 311.
37 Cf. Dr. Choksy. The treatment of Plague, p. 122.
38 Serum Therapy, Bacterial Therapeutics and Vaccines, by R. T. Hewlett, M.D., p. 37.
Note giving Salter's results. London, J. & A. Churchill, 1903.
E 3
28
REPORT ON A SERIES OF 484 CASES OF PLAGUE TREATED WITH
LUSTIG'S ANTI-PLAGUE SERUM.
BY W. M. HAFFKINE, C.I.E.,
Director-in-Chief, Plague Research Laboratory, Bombay.
THE patients were those received into the Bombay Municipal Plague
Hospital at Arthur Road, which is under the care of Khan Bahadur N. H.
Choksy, M.D. (Hon. causâ, Freiburg), L.M.&S., Special Assistant Health
Officer of the Bombay Municipality. The patients were treated by this officer
and by Professor Lustig's assistants, who made the serum in Bombay.
Those to whom the serum was administered were selected from the patients
proved to be suffering from plague, who were admitted to the Arthur Road Muni-
cipal Plague Hospital between the 1st of May 1899 and the 31st of July 1900.
After the diagnosis had been made in the hospital, every second plague
patient was at once injected with the serum, while the alternate individuals were
kept without this treatment and observed as "controls."
In this way 484 cases diagnosed by competent medical men as plague were
treated with this serum, while 484 cases similarly diagnosed and admitted alter-
nately with them were observed for comparison, and not given serum at any time.
All these 968 plague patients were treated in the ordinary symptomatic way,
the only difference being the injection of serum in the case of half the number.
The following report is compiled from an examination of the temperature
charts kept in the hospital and submitted to me for this purpose by order of
Government.
The actual clinical data submitted to analysis are those in which the
personality of the observer plays no part, viz., the temperature, the pulse-rate,
the number of respirations, the situation of the buboes and the ultimate issue
of each case.
The general results may be formulated as follows:
—
Among the 484 cases treated with serum there were 55 fewer deaths than
among the similar number of control cases.
The first point to ascertain, then, is whether the 484 control patients were
from the first, comparable in their main features with the 484 serum cases, and
whether the latter would have had more deaths if the serum had been omitted.
There are some indications that this may not have been entirely the case,
as the following illustration will show:
—
From the first table it appears that the mortality in ordinary plague cases
is greatest among those admitted with a high temperature. The higher the
29
temperature on admission, so much the greater is the mortality. The number
of serum treated patients, however, is slightly less in the graver categories, and
more in the milder forms ; though indeed, the difference is not great.
From Table II, it is seen that the lowest mortality occurred among patients
in whom both pulse and respiration were slow. Of these, the serum cases had
46 ; the control cases 24. On the other hand, patients in whom the pulse or
respiration, or both, were so imperceptible or irregular that they could not be
recorded, showed the highest mortality ; of these, the control cases had a very
considerable preponderance.
Plague cases without buboes, i.e., septicæmic and pneumonic cases, are
practically all fatal. From Table III it will be seen that the controls had 29
such cases, while the serum treated cases had only 5. It is evident then that
among the serum patients there must have existed a group of 24 cases of a
type milder than these cases without buboes.
It is found from Table V that the highest mortality occurs in both sexes
between the ages of 21 and 40 ; but it is seen that the control group had 20 more
such cases than the serum group ; the numbers being 264 and 244, respectively.
From the same table we learn that the lowest mortality was in males
below 15 years of age, and of these the treated cases had more than those not
treated ; the numbers being 63 and 52, respectively.
As the same individuals figure afterwards in other columns and tables where
they are considered from other points of view, the effect of the unequal gravity
of the cases will be seen in the form of a lower mortality in each of the cate-
gories and sub-divisions in which they are grouped.
It is impossible to maintain that this uneven distribution of cases, which in
most instances was quite unavoidable, accounts for the preponderance of deaths
observed in the control group, for in certain other sub-divisions showing a
lessened but still high mortality, there was a considerable though less prepon-
derance of serum cases. But it is impossible also to say with certainty how
many of the excess survivals, if any, are due to the serum. In my original plan
of investigation into the efficiency of plague anti-toxic sera, I had foreseen difficul-
ties of this kind, and, as a corrective, added the postulate that in every instance
in which a choice has to be made between two patients admitted to hospital at
the same time, the more severe case be taken for serum treatment and the
milder one for the purposes of control observations.*
If the mortality is influenced favourably in these circumstances, a proof is
obtained à fortiori of the beneficial action of the treatment applied. In the case
under consideration this postulate has not been complied with.
* NOTE .—This method was actually carried out by Mr. Haffkine at Poona in 1897 in some 200 cases,
vide Indian Plague Commission Report, Vol. I, p. 14, para. 140 ; also introduction, page 10, supra. — (Ed.)
30
If we admit that the distribution of patients between the control and serum
groups was sufficiently uneven to influence, at least partially, the mortality rates,
we must be prepared to find that it played also a part in the difference shown by
the two groups in regard to the duration of life in the fatal cases (vide Table 1,
columns 7 and 11).
It was expected that the favourable effect of a serum injection would
manifest itself in an immediate or early reduction of the fever temperature. In
a number of cases this expectation was not fulfilled ; in a large number of others
the temperature began to go down after admission to hospital without any serum
injection ; but when we compare the proportions, we find a favourable difference
attributable to the serum, but perhaps partially also to the better condition of the
serum cases (Table VI).
This initial favourable effect of the serum was unfortunately not maintained,
for when we consider the temperature chart throughout the patients' illness we
do not find that the fever left the treated cases sooner than the controls (Table
VII), or that in the recovery cases the normal temperature was reached sooner
by the serum cases than by the controls (Table VIII).
A paradoxical result is observed in many of the facts recorded. Thus,
for instance, femoral buboes gave to the controls a mortality of 79.74 per
cent. ; serum would seem to have "reduced" it to 55.05 per cent. Cervical
glands appear somewhat less fatal (75.86 per cent.), still the serum was much
less "successful" here, the serum cases having had a mortality of 73.52 per
cent. (Table III).
Similarly patients with multiple neighbouring glands seem to die more
frequently (mortality of controls 82.44 per cent.) than those with multiple
scattered and opposite glands. Still the serum would seem to have "reduced"
the mortality in the first and "increased" it in the two other categories (Table
III).
Males are shown in the group under study to recover more frequently
than females (Table V) ; but under the serum treatment a higher proportion of
the latter than of the former recovered.
Among the male control cases the highest mortality is found among those
between the ages of 21 and 40, while those below 15 years of age show the lowest
death-rate. The serum would appear to have been very successful with the first,
and to have failed entirely with the second.
The temperature of a plague patient has a natural tendency to go down
towards the morning and to rise towards the evening ; one might therefore
expect that if the serum injection had the virtue of bringing down the temperature,
this would be more often manifested in the morning temperatures after evening
injections than in the evening temperatures after morning injections. Indeed in
31
the recovery cases this was so ; in the fatal cases it would seem, on the contrary,
as if the serum had interfered with the natural morning fall of the fever (Table
VI). And so on.
The above paradoxical cases seem to suggest that in the facts observed
there were, apart from the serum injections, other factors which influenced the
course of the disease and the recovery or death of the patients very powerfully.
Were clinical symptoms actually and effectively improved by the serum, and
this improvement maintained for the greater part of the illness, this need not
necessarily have led to an improved mortality rate. I may illustrate my meaning
by the fact that the injection of water in cholera has a most striking effect on the
symptoms, probably such as no other operation has in the case of any other
disease ; the effect on the mortality appears, however, so absolutely negative
that the injections have been abandoned in practice.
Similarly, from the analysis of the plague cases treated with Dr. Terni's
curative serum in the Modikhana and Maratha Municipal Plague hospitals, it
will be seen that the facts recorded present indications of an improvement
effected by the serum in the clinical features of the disease. Notwithstanding
this, the mortality rate was 90 deaths in 110 serum cases and 89 deaths in
110 controls.
Considering that the cost of the serum is something like Rs. 60 per patient
treated (not patient saved), the results obtained so far from the Lustig, Terni
and Brazil sera are not favourable to a general adoption of the treatment.
I beg to acknowledge the able assistance given me by Dr. E. S. Winter of
this Laboratory in the laborious task of compiling from the hospital documents
the figures reproduced in the tables attached.