garrison at Malta immediately before and immediately after the
institution of the preventive measure of cutting off the supply of
unboiled goats’ milk. The figures of 1905--before the new regulation
came into force--are represented in black. The figures in the margin
refer to the number of cases per ten thousand of strength. The figures
for 1907 are represented in white on the same scale. There is a drop in
the maximum monthly incidence from 94 to 2. The size of the garrison
itself remained almost constant throughout the period. ]
Among the most anciently described diseases is the condition known as
_Tetanus_ or ‘Lockjaw’. There are unmistakable references to it in the
_Hippocratic Collection_ and notably in the _Aphorisms_. Two of these
references we have already quoted (p. 23). A general association
of Tetanus with wounds has long been recognized. In the eighties
the disease was shown to be transmissible from animal to animal. It
was, moreover, experimentally produced in animals by the inoculation
into them of garden mold. In 1889 Koch’s pupil, Kitasato, obtained
the Bacillus of Tetanus in pure culture and conveyed the disease to
animals. He found the organism would grow only in the absence of
Oxygen. It is, in fact, a type of a large and now well-known group,
the ‘anaerobic’ bacteria. The natural habitat of the Tetanus Bacillus
has been proved to be soil, and especially richly manured soil. The
knowledge of the bacillus, of its habitat, and of its mode of growth
has led to the development of a valuable protective process.
Looking backward from the standpoint of present-day knowledge we can
trace _Typhoid Fever_ far back in history. Nevertheless, it was not
till 1837 that the distinction between the two distinct conditions
known now as ‘Typhoid’ and ‘Typhus’ was first clearly made. This was
the work of an American physician, William Gerhard (1809-72), of
Philadelphia. The English were backward in adopting the distinction.
The organic cause of Typhoid Fever was first seen in 1880 by Karl
Joseph Eberth (1835-1927), a pupil of Virchow, and after him it is
known as ‘Eberth’s Bacillus’. It was not isolated, however, until some
years later. It is an inhabitant of the intestine, and its natural
history was obscured by confusion with certain other and very similar
organisms, which also dwell in the intestine. These have now been
fairly differentiated from each other, and in the course of this
process the ‘flora’, both normal and pathological, of the intestinal
canal has become well known. Moreover, it has been shown that typhoid
organisms are not always of the same species, but that several
closely allied forms produce several closely allied diseases. Lastly,
certain of the effects wrought by the typhoid group of organisms on
the body, which is their host, have been exactly investigated. These
investigations have led to improved methods of recognition of the
disease, that is to say, _diagnosis_, and also of prevention of its
incidence, that is to say, _prophylaxis_. To these methods of diagnosis
and of prophylaxis we now turn.
[Illustration:
FIG. 117. BACILLI OF TETANUS FROM A CULTURE. Highly magnified. The
drum-stick forms are very typical.
]
[Illustration:
FIG. 118. BACILLI OF TYPHOID FEVER FROM A CULTURE. Highly magnified.
The long flagellae, which are constantly in motion and are very
characteristic of these organisms, are well seen. ]
§ 12. _The Study of Immunity._
In the production of disease by living organisms two main factors
are involved. There is, firstly, the multiplication of the organisms
themselves, and there is, secondly, the production by the organisms
of poisonous substances or _toxins_. The former phenomena are spoken
of as _infection_, the results of the latter come under the title of
_intoxication_ or _toxic_ effects. The first toxins to be investigated
were those isolated from putrefying substance and named _ptomaines_
(1876, by false formation from Greek _ptoma_ ‘a corpse’). These are, in
fact, definite chemical substances of the group known to chemists as
‘alkaloids’ (p. 325). Later, toxins were prepared from actual disease
organisms such as those of Typhoid and Tetanus (1888). The method was
introduced of filtering the bacteria away from their fluid cultures
and thus obtaining a bacterium-free liquid containing the poisonous
bacterial products. This was the starting point of the scientific
study of toxins. These, it soon became clear, were either substances
which were normally sent out by the bacteria, _exotoxins_, or they
were normally retained within the bacteria and could only be obtained
in solution by breaking up the bodies of the bacteria, _endotoxins_.
The use of these toxins has been essential for the scientific study of
Immunity.
The word _Immunity_ is derived from a Latin word which means ‘exemption
from military service’. In Medicine it indicates an exemption, relative
or absolute, from the incidence of a disease. Immunity in the medical
sense is of various kinds. There is ‘species immunity’, some species
not being liable to diseases to which others fall victims. There is
relative and there is absolute immunity. There is innate and acquired
immunity. Of acquired immunity there is a natural immunity resulting
from the ordinary contraction of a disease, and there is an ‘artificial
immunity’. It is only artificial immunity that is in the hands of the
physician.
Artificial immunity itself is of two kinds, and both kinds are of use
and of importance in Medicine. There is an _Active Immunity_, which is
produced directly by injection of disease organisms or their products.
It is found, however, that if a high degree of active immunity be
attained the blood serum of the immunized animal, when injected into a
second animal, may itself produce a state of immunity. The state thus
indirectly produced is described as _Passive Immunity_.
The early observers found that when organisms are cultivated outside
the body they lose their virulence to a greater or less degree. Pasteur
found this for Chicken Cholera (p. 234). He found, moreover, that such
‘attenuated cultures’, when inoculated, protect against the disease.
By the use of attenuated cultures he succeeded in establishing a state
of ‘Active Immunity’ against Chicken Cholera. But there are many other
ways of attenuating the virulence of an organism. Thus, in 1882,
Pasteur showed that to grow Anthrax bacilli at a high temperature would
reduce their virulence. These bacilli of reduced virulence could be
injected into a sheep. They would give the animal the disease in a mild
form and protect it against further attacks of the disease. They acted,
in fact, in the same way as did the old ‘Inoculation’ of Small-Pox (p.
183).
It has been found, however, that the same kind of immunity which is
produced by administering attenuated cultures is sometimes given even
by dead cultures. Nearly all active immunization is therefore done by
inoculating such killed cultures. These are usually called ‘Vaccines’
from the analogy which they bear to vaccination. The most familiar and
effective ‘vaccine’ is that against Typhoid. Moreover, it has been
found that in certain cases the principle of the induction of Active
Immunity may be applied directly in the treatment of disease. The
conditions that respond best to this line of treatment are those which
present some localized infection, such as a boil or carbuncle. In such
cases we must suppose that, while the local capacity for resistance
is lowered, yet reserves of resistance in other parts of the body can
be brought into play. These reserves are called up by the signal that
reaches them by the reaction of the body against the Vaccine.
It has been shown that, for the production of Active Immunity, the
actual bodies of the disease organisms are not always necessary. In
some cases, toxins obtained from these disease organisms are themselves
sufficient to induce Active Immunity. The matter may become of great
medical importance in the future and is already applied for Diphtheria
(p. 265).
We turn to ‘Passive Immunity’. The fact that Immunity can be
transferred from one animal to another via the serum proves that the
immunizing serum contains substances antagonistic to the bacterium
or toxin against which immunity is conveyed. These antagonistic
substances are spoken of as _Antibodies_. A series of very important
observations on Antibodies has been made, and may in time profoundly
modify not only our views of Disease but also our whole conception
of the workings of the living body. We find that it is not only
toxins that stimulate the formation of antibodies. Antibodies can be
elicited also by the introduction into the tissues of the living body
of red blood corpuscles, of embryonic tissue, and of various soluble
tissue-constituents of animal or vegetable origin. We are still only
on the threshold of the investigation of this subject, which may be as
important philosophically as it is therapeutically.
§ 13. _Some Practical Applications of Immunity._
We may now consider a few special applications of our knowledge of the
defences against bacterial action.
_Diphtheria_ is a disease in which the characteristic organisms are
found only locally, and in artificially produced cases only at the
site of inoculation. It therefore seemed probable from the first that
the symptoms were due not to the organisms themselves but to poisons
that they threw off, that is to their ‘exotoxins’. This was given
demonstrational form in 1889 by two pupils of Pasteur, Pierre Roux
(1853-) and Alexandre Yersin (1863-), who investigated many of the
properties of these toxins. In the following year (1890) Emil von
Behring (1854-1917), a Prussian Army Surgeon, and Kitasato showed that
it was possible to produce a Passive Immunity against Tetanus by a
serum from an infected animal, the immunity being efficient against 300
times the fatal dose of Tetanus. Their paper contains for the first
time the word _antitoxic_. Immediately after, von Behring showed that
against Diphtheria, too, immunity could be obtained by injecting serum
from an animal that had been previously injected with living cultures
of the Diphtheria bacillus. This epoch-making discovery of von Behring
was soon given a practical application. It was found possible to induce
a degree of immunity even after the onset of the disease. The first
human case was a child in a clinic at Berlin in 1891. Antidiphtheritic
serum was placed on the market in 1892. In a few years’ time its
administration had become a routine part of the treatment of the
disease. Diphtheria antitoxin is one of the greatest additions to
therapeutics. With competent administration the case mortality of
Diphtheria is one-half or one-quarter of what it is without the use of
Antidiphtheritic serum. (Fig. 119.)
[Illustration:
FIG. 119. DEATH-RATE OF CASES OF LARYNGEAL DIPHTHERIA IN PUBLIC
HOSPITALS IN LONDON. Antitoxic serum came into use in London in 1895
and into full use in 1896. As its application became more general and
as the method of administration improved the death-rate from this very
grave condition progressively fell. ]
An important aspect of the reaction of the body to the Diphtheria toxin
was revealed by B. Schick of Vienna in 1908. The technique of inducing
it was perfected by him in 1913, and the test is known by his name.
He showed that susceptibility to the disease could be detected by the
behavior of the skin after injection of minute doses into it. It has
thus been found that new-born infants are seldom susceptible and that
the proportion of susceptibles increases up to two years of age, but
that then it diminishes. The actual proportions of susceptibles, as
estimated in a large number of cases in New York City in 1919, are as
follows:
Of those under 3 months 15% are susceptible
Of those between 3 months and 6 months 30% are susceptible
Of those between 6 months and 1 year 60% are susceptible
Of those between 1 year and 2 years 70% are susceptible
Of those between 2 years and 3 years 60% are susceptible
Of those between 3 years and 5 years 40% are susceptible
Of those between 5 years and 10 years 30% are susceptible
Of those between 10 years and 20 years 20% are susceptible
Of those over 20 years 15% are susceptible
These figures show why Diphtheria is mainly a disease of childhood
and is relatively seldom encountered in adults. They also make it
evident that steps for protecting individuals against contracting the
disease--‘prophylactic measures’ as they are called--need only be taken
with a fraction of the population. The useful term _Prophylaxis_ is
derived from a Greek word meaning a watchman or guard. It is used to
describe preventive measures against disease in general, but is more
specially applied to that form of protection which is achieved through
the artificial production of Immunity.
Such prophylactic measures are now available against Diphtheria.
They differ from those in use against any other disease, since the
substance injected is neither the living infective material as in
vaccination against Small-pox (p. 184), nor is it a killed culture of
the organisms as in immunization against Typhoid (p. 268), nor is it
the serum of an immunized animal as in the protective measures against
Tetanus (p. 267). The Toxin itself (mixed with an experimentally
determined proportion of its antitoxin) is now in wide and effective
use as a prophylactic against Diphtheria. The method was proposed by
von Behring (cp. p. 264) in 1913. The details, however, have since
been worked out in the laboratories of the New York City Department
of Public Health and have been mainly the work of W. H. Park (1863-).
The susceptibles are first determined by the Schick test and are then
immunized against the disease. The immunization reduces the likelihood
of contracting the disease to about one quarter.
Plague differs from Diphtheria in that the organisms, instead of
being local, pullulate throughout the body of the victim. As in the
case of most diseases of this type, the toxins of Plague are chiefly
_endotoxins_, unlike those of Diphtheria, which are _exotoxins_
(p. 263). Thus, the filtrate of a culture of Plague Bacilli is but
little toxic and confers little or no immunity. Protective vaccines
of a killed culture of Plague Bacilli are, however, prepared, and
these confer considerable immunity. It is claimed that they reduce
the liability to the disease by about three-quarters, and the case
mortality by about one-half. Prophylactic inoculation against Plague
is associated especially with the name of the Russian investigator
Waldemar Haffkine (1860-), a pupil of Pasteur, who was for many years
in the service of the British Government in India, the Plague center of
the world.
After Diphtheria one of the earliest diseases of which the toxins were
investigated was _Tetanus_. Kitasato found in 1891 that the filtrates
of pure cultures injected into animals are very toxic. A peculiar
feature is the incubation period of some days that occurs between
the inoculation and the advent of the symptoms. This fact had been
referred to, more than two thousand years earlier, in the _Aphorisms_
of Hippocrates (p. 23). Moreover, it has been found that, soon after
inoculation, the Tetanus toxin disappears from the blood-stream. This,
it has been shown, is due to its affinity for nervous tissue, with
which it rapidly enters into some sort of combination. The fact is of
clinical significance and of therapeutic application.
By injection of small and progressively increasing doses of Tetanus
toxin into animals, a high and long-lasting degree of immunity to
the disease is produced. The serum of such immunized animals has the
capacity to protect animals susceptible to the disease against an
injection of a fatal dose. It is now a routine treatment to inject
serum derived from an immunized horse into those who have wounds likely
to result in Tetanus. Owing to the rapid disappearance of the Tetanus
toxin from the blood-stream, and owing to its tendency to unite with
nervous tissue, it is important to inject the serum as soon as possible
after the infliction of the wound. In some cases it is advisable to
inject the serum into the sheath that surrounds the spinal cord in
order to give it as rapid access to the nervous centers as possible.
During the Great War prophylactic doses of Antitetanic Serum were given
to every wounded man after 1914. Before the practice was adopted, the
incidence of Tetanus among the wounded was 16 per 1,000. After the
introduction of this line of treatment as a routine, the incidence fell
to 2 per 1,000. Countless lives were thus saved. Antitetanic serum
should be injected as early as possible in every case of a large ragged
wound, especially if contaminated with soil.
_Typhoid Fever_ differs from Diphtheria, Plague, and Tetanus in that
it can hardly be conveyed to animals. It has thus proved impracticable
to produce anything in the way of passive immunity in man. On the other
hand, there is no disease in which the production of active immunity
by means of Vaccines of dead cultures has been attended with more
favorable results. The researches which led up to the introduction
of active immunization against Typhoid Fever are bound up with
investigations concerning the diagnosis of the disease which are of
wide importance in connection with several other diseases.
The discovery of Antibodies (p. 262) gave rise to great activity in
their investigation. Among the most interesting and important of the
antibodies is a group which will cause ‘agglutination’ or clumping
of the disease organisms with which they are specially associated.
This reaction is specific for the corresponding organisms, within
certain limitations. Given, therefore, (1) a pure culture of an
organism, and (2) the knowledge of the highest degree of dilution of
the serum containing such an antibody that will cause agglutination of
that particular organism, the physician has in his hands a means of
detecting or excluding infection with that organism. The method was
especially studied by the Parisian investigator Fernand Widal (1862-),
who in 1896 succeeded in making it practicable for Typhoid Fever, and
his name is attached to the test. It is now universally applied in that
disease. Similar tests have been devised for Malta Fever and for other
conditions.
There are other groups of antibodies that have been investigated. Some
of these possess the power of dissolving the corresponding organism.
They are, therefore, known as _Bacteriolysins_. Their existence
gives a certain insight into the defensive mechanism of the animal
body against bacterial invasion. They are sometimes of practical use
in distinguishing types of disease-producing bacteria. The method
is applicable, for example, in detecting certain types of dysentery
organisms.
Another group of antibodies act not against bacteria but against
certain specific substances. Antibodies of this type were first
detected by the Belgian workers Jules Bordet (1870-) and Octave Gengou
(1875-) in the year 1900. The physician avails himself of the existence
of such an antibody in the test that is applied for Syphilis, which was
introduced in 1904 by Ehrlich’s pupil, August von Wassermann (1866-),
and is known by his name.
Of late years a special aspect of Immunity has come into view in
connection with the so-called ‘Carrier Problem.’ With many diseases,
acquisition of Immunity on the part of the patient implies the death
within his body of the organism that has been causing the disease.
There are conditions, however, in which the organisms may lurk in some
individuals long after the symptoms have subsided. These persons may
even contract the disease so lightly that they are unconscious of it,
but nevertheless they become capable of conveying it. Such individuals
are known as _carriers_. Evidently the existence of carriers introduces
special difficulty into attempts to delimit an infective disease in any
population.
Among the diseases of known bacterial origin that are sometimes
conveyed by carriers are Typhoid Fever, Diphtheria, and Spotted Fever
or Cerebrospinal Meningitis. A special case of the Carrier Problem is
afforded by Infantile Paralysis, a disease due to ‘ultra-microscopic’
organism--since the virus is ‘filtrable’ (p. 274). This disease, like
that of Cerebrospinal Meningitis, is probably transmitted by carriers
who do not themselves suffer.
Typhoid Fever, Diphtheria, Influenza, Scarlet Fever, and many other
conditions are often conveyed by ‘ambulant’ cases. This term is applied
to those cases which, while definitely suffering from a disease, do
not regard themselves as ill enough to take to their beds but continue
their ordinary avocations. Such ambulant cases are not less but more
dangerous to their neighbors than those more severely stricken.
The whole study of the Carrier Problem is in its infancy. It is beset
with extraordinary difficulties. In the case of Diphtheria and Typhoid
Fever, however, the demonstration that a suspected individual is or is
not a ‘carrier’ is easy. The difficulty is to trace him in the first
instance!
§ 14. _The Conquest of the Tropics._
Nowhere in Medicine has the rational spirit been more triumphantly
vindicated than in connection with the diseases peculiar to hot
countries. The increase in the habitability of the Tropics may be
traced to two main causes. First is the application of the ordinary
laws of Hygiene. Second is the increasingly exact knowledge of the
microbic origin of tropical diseases, leading to a more complete
apprehension and a stricter application of the laws of Hygiene.
We have glanced at the great changes wrought in the social
organization of temperate countries by the rise of modern Hygiene (pp.
172-78), which commenced to be felt about the middle of the eighteenth
century. The death-rate then began to fall, and has fallen steadily
ever since. The mid-eighteenth century marks, for temperate countries,
the end of the ‘Middle Ages’ of Hygiene. But with the advent of the
modern period the fall in the death-rate in temperate countries has not
been the only change in the public health. Even more significant is a
change in the _causes_ of death.
Certain diseases have gradually receded from the more civilized and
settled temperate countries, and are now almost unknown there. Thus,
Malaria, Plague, Typhus, Leprosy and Dysentery, once of world-wide
distribution, have come to be regarded as more or less distinctively
‘tropical’ diseases. A time is approaching when we shall be able
to place other diseases with which temperate countries are still
afflicted, such as Typhoid Fever, in the same category. The ultimate
exclusion of Typhoid as a disease of civilized communities is suggested
by the death-rates of England and Wales.
_Average Annual Death-rate in England and Wales from Typhoid per
million living._
1871-80 1881-90 1891-1900 1901-10 1911-20 1921-26
332 198 174 91 35 24
In the category of such removable diseases which, being excluded from
temperate countries, are regarded as tropical are Malaria, Plague,
Typhus, Leprosy, and certain forms of Dysentery. These diseases are
‘tropical’ only in the sense that it is in the Tropics that the general
hygienic conditions most favorable to their development are still
found. If the hygienic conditions of the Tropics could be raised to
those of the civilized temperate countries--a task, it is true, of very
great difficulty--these particular diseases might become as rare there
as they are with us. Indeed, it is possible to foresee a world in which
a number of these so-called tropical diseases will have disappeared
altogether.