NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
23
Seasonal Prevalence.—Many and varied are the opinions regarding
the seasons at which rabies is supposed to be unduly prevalent in India,
and for many years we have held that no such season exists. But we
have been forced to modify this view. It will be seen from Table X,
in which the numbers of patients, Indian and European, treated during
the quinquennium are classified according to the month during which
they arrived that a rise occurs during the months of July and August.
The rise is of so slight a degree that it might at first sight be ascribed
to some cause other than a true increase in the prevalence of rabies.
It might be contended, for example, that the close of the harvest rendered
it possible for many of the agrarian population to attend who could not
have come during the period of harvesting. In order to investigate
whether increased facilities for attendance were responsible we have
classified in the second column mortalities relating to the respective
groups. Had the swelling of admissions in the early autumn been due
to increased facilities for attendance, one would have expected that the
population coming during the period of excessive influx would have been
either less at risk, which would evidence itself in a relatively lower
mortality, or at the same risk, in which case the mortality rate would
have remained steady. We see, however, that with this excessive influx of
patients there is an accompanying relative increase in mortality, and
we are forced to accept the indication that there is a slight rise in the
prevalence of human rabies in India during the monsoon period.
The Biting Animal.— I n T a b l e X I I I i t w i l l b e s e e n t h a t t h e
dog and the jackal account for 98.5 per cent of the cases which
have been treated at the Institute during the quinquennial period.
The relative proportions of persons bitten by dogs and jackals
respectively afford no evidence as to the animal which is res
-ponsible for the propagation of rabies in India, but they afford
an interesting indication of the method by which the sphere of
influence of the Institute is extending. For the quinquennium ending
1916 the proportion of persons bitten by jackals to the total was
18.47. In the previous quinquennium ending 1911 this proportion
was 12.93, and in the first six years of the Institute's working the
proportion was, with one exception, lower than 12 per cent and averaged
11.22. Thus as was to be expected there is a clear indication that cases
from rural areas are increasing more rapidly than those from towns and
cities. Although this point is of no scientific value, it is of great practical
importance, and it confirms the impression already held by us that,
although the sphere of influence of the Institute is large so far as towns
and cities are concerned, the area from which we draw rural patients is
comparatively small. It is from this source that the annual increments
in the number of patients are mainly being drawn, and we may conclude
that a large increase in the number of patients is still to be expected from
rural sources. We may add here that as the mortalities for dog and
jackal bites during the quinquennium were respectively 1.11 per cent . and
2.02 per cent, it is to be expected that with this increase amongst
patients from rural areas there will be a corresponding increase of
a small order in the general mortality.
2. THE INFLUENCE OF . VARIOUS FACTORS ON THE MORTALITY
OF RABIES.
It was with the object of determining the influence of such
factors that Tables V, VI, VII and VIII were designed by Major Harvey.
The factors which he set out to investigate were —
(1) Number of bites received.
(2) Depth of bites.
(3) The effect of interposition of clothing.
(4) The effect of cauterization of the wound.
(5) Position of bite.
(6) The effect of lateness of arrival.
The result has been satisfactory, for regarding each of the first five
factors a definite measurable result has been arrived at. We shall
consider these separately and leave the sixth for discussion in the section
dealing with the effects of treatment.
Numbers of Bites received.—It will be seen at a glance from the
total line at the bottom of Table V. C. that the mortality amongst
the treated increases more or less steadily with the number of. bites.
For the higher numbers of bites the percentage mortalities become
erratic, probably (as will be seen from Table V. A .) because the total
numbers involved are so small. If one confine oneself to bites up to 12,
one finds by the methods of least squares that the best fitting line to
express the relation between the respective factors is,—
Percentage mortality = 0 . 44 x number of bites — 0.37.
or the percentage mortality amongst the treated is roughly equal to half the
number of bites.
If one limit the examination to cases of persons who are bitten
deeply on the bare skin and whose wounds have not been cauterized
then the relation becomes—
Percentage mortality = 0.59 x number of bites + 0.17.
figs:;
25
This point may be examined in another way. If we calculate the
mean number of bites amongst non-fatal and fatal cases respectively
we find that the average for non-fatal cases is 3.90, whilst that for fatal
cases is 6.54. Thus there is no doubt that the mortality increases,
caeteris paribus, with the number of bites received.
Depth of Bite.—As would be expected the effect of depth of bite is
very marked. From Table VI it appears that amongst 13,777 persons
who were bitten deeply 256 died, or the mortality in this group was
1 . 86 per cent. On the other hand amongst 6,732 persons whose bites
were superficial 26 died, or the mortality was only 0.39 per cent. Thus
the mortality amongst persons bitten deeply as compared with that
amongst those whose bites were superficial is as 4.8 to 1.
Interposition of Clothing.
—As was to be expected the effect of the
interposition of clothing is a very marked one. Again from Table VI
it will be seen that amongst 15,013 persons who were bitten on the
bare skin 267 died, whilst amongst 5,496 who were bitten
through clothing only 15 died. The mortalities in the two groups
were 1.78 and 0.27 respectively, or in the ratio of 6.6 to 1.
It must be remembered in this connection that Indians are much
more liable to being bitten on the bare skin than are Europeans. For
example, among the latter a bite on the leg without the interposition
of clothing is of very rare occurrence. In comparing the general
mortality amongst patients treated at this Institute with the mortalities
amongst those treated in European countries this must be borne in mind.
At this Institute the Indian element forms 91 per cent of the total.
Effect of Cauterization.—It must be remembered in considering this
point that the only criteria employed as to the fact of cauterization
are the nature of the caustic and the time of its application.
' C a u t e r i z e d ' a s u s e d i n t h e t a b l e s c o m p r i s e s s u c h p e r s o n s a s h a v e h a d
their wounds treated within two hours by one of the recognized methods
of physical or chemical cauterization. The thoroughness of its
application is not considered. This naturally reduces the apparent
effect of such treatment, as in many cases without doubt, the
manner of application has been very imperfect.
The figures from Table V are as follows :
—
Amongst 12,044 persons uncauterized 183 (or 1.52 per cent) died,
whilst amongst 8,465 cauterized 99 (or 1.17 per cent) died. It would
appear then that the effect of cauterization as above defined is to reduce
the percentage mortality from 1.52 to 1.17, or in the proportion of
4 to3.
26
Position of Bite .—It will be seen from Table VII that the
mortalities vary widely in relation to the position of the bite.
That this is not due to variations in the multiplicity of bites in the
respective positions will be evident from the following table in which
both factors are tabulated:—
Part bitten.
Mortality.
Mean number
of bites.
Face. . .
7 . 6 7
4.11
Arm
. . .
1.15
5.84
Leg . . .
0.69
5.14
Multiple
. . .
2.75
9.2
Multiple face
. . .
7.52
11.35
Summary.
It will be seen then that each of the first four factors which we
have examined has a very definite effect on the mortality. This was to
be expected, as each and all of them influence the dose of virus received.
The first is the measure of the number of possible doses, the second
depends on the thoroughness of the injection of each dose separately,
the third depends on the reduction of that dose during injection, and the
fourth on its neutralization after injection.
Putting aside the number of bites received which is measured on a
different basis and which as we have shown has a profound influence
on the mortality, we find that of the latter three the most important
is the interposition of clothing, next comes superficiality of bite, and last
comes the effect of cauterization.
It is over the last alone that the medical practitioner has any control,
and there seems to be no reason to suppose that with care and thorough-
ness a great improvement in this direction might not be achieved.
3. THE INCUBATION PERIOD OF RABIES AMONGST THE TREATED.
During the quinquennial period 282 patients have died of rabies.
It is to be understood that these figures include all deaths without
regard to whether a full course of treatment had been received or not.
For example, they include the case of one man in whom symptoms were
recognized two hours after be received his first dose. This course was
adopted originally by Major Harvey in recognition of the difficulty of
defining a satisfactory limit beyond which the effects of treatment might
27
be considered as having been completely established. That this method
of classification has its advantages will appear when we come to discuss
the effects of the treatment.
In each case the date of commencement of symptoms and the date
of death are recorded in the annual reports. The first of these figures
is much less reliable than the second, and in a number of cases cannot
be ascertained. We have therefore dealt with the interval between bite
and death only in the following analysis. This figure could not be
ascertained in two instances. We have for convenience called it the
incubation period.
The Incubation Period in relation to Position of Bite .—Out of the
280 cases of which there is a full record the mean incubation period
was 49.40 days with a "probable error" of 1.58. The results obtained
under this head are confirmatory of those usually accepted, but it
may be of interest to record them.
The following figures give the mean periods obtained from the
figures under review:—
Part bitten.
Number
of fatal
cases.
Mean interval
between bite and
death.
Mean number of
bites.
Face. . .
55
38.85 ±3.2
4.11±0.19
Trunk . . .
2
48.5
5.5
Arm. . .
62
52.27 ±4.0
5.84±0.30
Leg . . .
81
59.64 ±2.3
5.14±0.36
Multiple . . .
40
48.75 ±4.7
9.2 ±1.06
Multiple face . . .
40
39.375±3.7
11.35±1.02
In general then the farther the bite is from the central nervous
system the longer is the interval of time before symptoms develop. This
fact is generally accepted as indicating that the virus travels by the nerves.
Before proceeding to a discussion of the further results which we
have obtained let us consider the nature of the problem which we have
to investigate.
In a disease of which the causative agent is a multiplying organism
(and this is true of rabies) and to counteract which antibodies are
formed in the host two factors are active: On the one hand, the organisms
multiply at a rate depending upon the number of parent organisms;
on the other the organisms are killed off at a rate proportional to their
28
own number and also to the quantity of antibodies present. The quantity
of these antibodies again depends upon some function of the number of
organisms and of the time during which they have acted, for antibodies
are produced by a reaction of the host against the organisms invading it.
Thus, during the course of an infection, the number of organisms will in
most cases increase up to a maximum and subsequently decrease. If
this maximum be above the 'limen' at which symptoms appear, we
say that the patient has suffered from the disease, but if the maximum
be below the ' limen,' symptoms willi n
ordinary circumstances never
appear. It is thus wrong to consider the incubation period of an animal
which has escaped the disease as infinite. If the number of organisms
attain a maximum which is below the 'limen' and subsequently
decreases, then the term incubation period has no meaning.
Now there are two main ways in which the course of such a disease
may be modified, and these depend upon the two factors which we have
mentioned.
In the first place the initial dose of the infecting organism may
vary, thus influencing the initial number of parent organisms ; and in
the second place the number of antibodies, or the rate of their production,
may vary. The first means of modification is obvious ; the second
requires some further discussion. In the case of an untreated disease
variations in antibody formation will depend on what we may call the
reactivity of the host.
In the case of an infection occurring in an animal which has previously
been immunized by doses of a dead specific vaccine it is generally accepted
that the reactivity of the animal has been raised to a higher level, and
that the rate of antibody formation depends on this increased reactivity
of the tissues.
Thus in both these cases we have simply to deal with what we have
called reactivity. The case of the effects of post infectional immunization
is much more complicated, and we shall leave its discussion until
later.
The problems which we have to investigate are then—
(1) Is there any relation between the incubation period and the
infecting dose ?
(2) Is there any relation between the incubation period and the
degree of reactivity ?
So far as we are aware these questions have not been answered in
the case of any microbic disease. It does not of course of necessity
follow that results obtained in the case of rabies from the very favourable
29
statistics at our disposal will be generally applicable ; but an interesting
line of investigation will have been opened up, for answers to these
questions will give us a very deep insight into the nature of the processes
which are operative during an infection.
Let us now examine the evidence. We have seen that we have no
Is there a relation
between incubation period
and the dose of the infect
-
ing organism ?
direct measure of the dose received, but that
in number of bites, depth of bite, the effect of
interposition of clothing, and the effect of
cauterization we have indications of its degree.
None of these indications is perfect in itself, but a study of their effects
should afford sufficient evidence on which to base an answer to our
question—
(1) In the first place the figures show that the correlation between
number of bites and incubation period is negligible (0·055±
0·04), and this in spite, as we have previously shown, of
a marked increase in the mortality with the number of
bites. This apparent absence of a correlation between
number of bites and incubation period is difficult to explain ;
for if instead of considering the number of bites
as an indication of a cumulative dosage, one adopts the
alternative theory that each bite acts independently and
that the incubation period depends not on the bites as
a
whole but on the particular bite which acts most rapidly ;
then clearly, with increasing numbers of bites, there would
be an increasing chance of the inclusion of a rapidly acting
one. In this case then the answer to our first question is
in the negative.
(2) As regards the effects of depth of bites the result is con
-
tradictory, for we find that the mean incubation period
for deep bites is 50 . 27 days, whereas for superficial it is
39·19 days. When one remembers that the ratio of the
mortalities of deep to superficial were as 5 to 1, one recog
- n i z e s t h e c o n t r a d i c t i o n . F o r i f b o t h t h e r e s u l t s w e r e t r u e ,
one would be forced to accept the conclusion that a higher
mortality rate was accompanied by a longer incubation
period, and this cannot be true. The probable explanation
lies in the small number (26) of superficial cases regarding
which data were available.
(3) Regarding the effects of the intervention of clothing we find
that the mean incubation period amongst those bitten on the
30
bare skin is 43.93, whereas that amongst those bitten through
clothing is 79.2. In this case then we have what appears to
be a direct relation between incubation period and dosage,
but here again we are dealing with very small numbers,
for the mean incubation period amongst those bitten through
clothing is calculated from a total of only 15 cases.
( 4 ) T h e e f f e c t o f c a u t e r i z a t i o n i s t o i n c r e a s e t h e m e a n i n c u b a t i o n
period from 47.24 days to 53.46 days whereas the
mortality is reduced in the proportion of 4 to 3.
( 5 ) W e m a y a l s o a d d i n t h i s c o n n e c t i o n t h a t t h e m e a n i n c u b a t i o n
periods amongst persons bitten by dogs and jackals were
49.9 and 48.4 days respectively, whilst their mortalities
were 1.11 and 2.02 per cent. We recognize, however,
that this result may not be dependent on dosage per se,
but may be influenced by variations in position, etc.
We may now classify such answers to question 1 as have been
obtained from our results, as follows:—
Increase of dosage as indicated by— Incubation period.
Mortality.
(1) Number of bites . . . Unaffected . . . Increased.
(2) Depth of wound . . . Increased ? . . .
Ditto.
(3) Intervention of clothing . . . Decreased
? . . . Ditto.
(4) Effect of cauterization . . . Decreased (slightly)
Ditto.
(5) Nature of animal . . . Unaffected . . .
Ditto.
In the main then we may conclude that the evidence tends to show
that there is no relation between the incubation period and the infecting dose.
Let us now pass to the second question.
A direct answer to this question can, as we have shown, only be
obtained from the study of the untreated, or
Is there a relation
between incubation period and reactivity?
of cases which have been subjected to pre
-
infectional immunization. Neither of these
conditions is fulfilled in the statistical material which we are reviewing.
But an experiment carried out by us in this Institute with the aid
of Dr. A. C. Lankester, to whom our thanks are due, is of interest in this
connection.
Three different groups of rabbits received three different degrees of
vaccinal treatment. After a convenient period each animal amongst
the three groups received an identical test dose of street virus
administered intramuscularly in the back of the neck.
31
The results were as follows :—
Received.
Number of
rabbits.
Per cent
mortality.
Mean incubation
period in days.
No treatment. . .
4 9
97.9
15.83 ±
0.3
Treatment A...
47
76.6
15.0
±
0.4
Treatment B . . .
48
65.3
16.84 ±
0.9
Here then we have a very definite reduction in mortality with an
increase in incubation, which is practically negligible. It is possible that
with a lighter test dose a more definite increase might have been observed.
This remains for further investigation. But it would appear that if
there be any relation between incubation period and reactivity, it must
be of a much lower order than that which exists between mortality and
reactivity.
The case of post-infectional immunization is, as we have said above,
a much more complex problem. Here we are not measuring the simple
relation of incubation to reactivity. For in this case an animal
commences its course of infection under one set of conditions, and then
by successive doses of a dead vaccine it is brought gradually under a
different set of conditions.
The statistical material is available, and its examination is worthy
of study, even though it does not afford a direct answer to our question.
In comparing the incubation periods of fatal cases occurring
amongst those who arrived for treatment during the first, second, and
third weeks after the bite was inflicted we recognize that we are
comparing the effects of changes of conditions of reactivity which
commenced during these three different periods.
The results are as follows
:—
Mean incubation amongst those arriving during first week, second week,
and third week.
1st week.
2nd week.
3rd week.
Face . . .
42.13
31.5
26.8
57.39
50.45
31.5
Arm . . .
65.04
51.68
63.5
Leg . . .
39.64
68.15*
32.6
Multiple . . .
43.89
35.17
37.5
Multiple face . . .
All cases . . .
51.9
47.1
40.4
* Includes periods of 177 and 211 days amongst 13 cases.
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It will be seen that both in the total and in the divided figures there
is a definite tendency towards lengthening of the incubation periods
among those who have arrived early and who have consequently been
afforded the full benefits of treatment. The cases of pre-infectional and
post-infectional immunization are not, as we have said, analogous, and
consequently the results which we have obtained are not necessarily
contradictory, but all the same they are of such a nature as to make
one hesitate regarding their interpretation, and the second question must
remain unanswered.
Summary.
Whilst then we are unable to state definitely whether there is a
relation between the period of incubation and reactivity, the balance of
the evidence which we have put forward is in favour of the conclusion that
the period of incubation is independent of the degree of the infecting dose.
If we accept this conclusion tentatively a problem of great interest
discloses itself, for we naturally are led to consider in what circum
-stances such an independence is possible. The problem is analogous to
that of tautochronous motion, which engages the attention of the physi
-cist. A motion is defined as tautochronous when the period after which
the body in question arrives at some point is independent of the initial
position of the body. The problem as it presents itself to us is one in
which the period after which the number of organisms attains a particular
value (the limen) is independent of the initial number of organisms.
We note also that on the assumptions stated on page 28 the occurrence
of a considerable proportion of 'escapes' will indicate that the limen
is not far distant from the maximum.
A full discussion of the question would be out of place in this report,
but we may state that we have found that the conditions are fulfilled
when the effect, as evidenced by antibody production, depends upon the
logarithm of the stimulus, i.e., upon the logarithm of the number of
organisms present.
That this is analogous with the laws of psychology is at once apparent,
and that such an analogy should exist is not to be wondered at, for in
this, as in the case of psychological processes, we are dealing with
reactivities and with perceptions in the shape of symptoms, which may
or may not be subliminal.
To generalize as to the nature of the laws which control antibody
formation on the basis of such slender evidence gained from the study
of one particular and rather peculiar disease would be unwarranted,