addition to their purely mechanical defensive action, were capable of
destroying the micro-organisms by their microbicidal power. Bach[661]
submitted this question to a minute examination and came to the
conclusion that several species of bacteria, introduced _in vitro_ into
the tears of healthy persons or of those who were suffering from
conjunctivitis or certain other ocular diseases, disappeared somewhat
rapidly. Comparative experiments with tears previously heated to 58° and
even to 70° C., in most cases gave the same results, that is to say,
they caused a rapid disappearance of the organisms introduced. From
these facts the author concluded that it is probably to the salts
contained in the tears that their bactericidal action is due. Control
experiments made with physiological saline solution and with various
mixtures of mineral salts met with in the tears have been found by Bach
to cause a like disappearance of the same species of organisms. Well
water, and even distilled water, gave the same result. In all these
cases it is evident that, in the tears, there is no bactericidal cytase
comparable with that found in the serums and other body fluids which may
contain this phagocytic diastase. The experiments with heated tears
demonstrate this clearly. On the other hand, these same experiments lead
one to suppose that the diminution and even the disappearance of the
micro-organisms in the tears, is due to a large extent, and perhaps
completely, to an agglutinative action of the salts, a fact which has
been demonstrated by several observers.
In all these cases it is indisputable that the mechanical part played by
the tears is the most important of the defences offered by the
conjunctiva of the eye against the microbial invasion. That this defence
is not always sufficient is proved by the frequency of conjunctivitis,
as well as by the ease with which certain micro-organisms, inoculated
into the conjunctival sac, set up a general infection. This is specially
the case with the coccobacillus of human plague. When it is introduced
into the conjunctival sac of susceptible animals (rat, guinea-pig, &c.),
it passes thence into the nasal cavity and soon produces a generalised
and fatal infection. The conjunctival membrane, even when perfectly
intact, readily absorbs certain poisons. Everyone knows the rapidity
with which atropin, when introduced into the conjunctival sac, causes
dilatation of the pupil. But the mucous membrane may serve also as the
port of entry for toxins of microbial origin. Several observers, and
especially Morax and Elmassian[662], have demonstrated that the
diphtheria poison placed upon an unbroken conjunctival membrane, where
the epithelial layer is uninjured, sets up local lesions which progress
very slowly but which terminate in the formation of actual false
membranes. Nevertheless, it must be admitted that the intact epithelial
layer of the conjunctiva exerts a certain defensive action against the
penetration of toxins, although a very slight lesion of this layer will
allow of the ready absorption of the diphtheria poison and the formation
of false membranes.
The cornea likewise, so long as it is intact, exhibits a marked
resistance against the penetration of micro-organisms and of toxins.
When it becomes injured in any way its epithelium is repaired with great
rapidity, as has been well demonstrated by Ranvier[663], who has shown
that the walls of the wound close by a process of epithelial “soldering”
in a purely mechanical fashion, without the intervention of any
preliminary proliferation of the epithelial elements. Thanks to this
very rapid obliteration the micro-organisms are prevented from
penetrating not only into the interior of the cornea, but into the
anterior chamber of the eye.
[Sidenote: [430]]
It has already been pointed out that the ocular conjunctiva gets rid of
the introduced micro-organisms chiefly by removing them mechanically and
sending them through the lachrymal duct into the nasal cavity. This, in
turn, defends itself by making use of a similar method. In his
experiments on the Kiel red bacillus, inoculated into the conjunctival
sac of man, Bach demonstrated that in a very short time these
micro-organisms are carried into the nasal cavity. He showed also that
they do not remain long in the latter position and that their number
decreases hourly.
Twenty-four hours after the introduction of these bacilli into the
conjunctiva none, as a general rule, are to be found in the nasal mucus.
This expulsion of the micro-organisms likewise takes place by mechanical
means, aided by the movements of the vibratile cilia. It is evidently to
this process that the mucous membrane owes its relative freedom from
micro-organisms. Frequently, when examining the nasal mucus or when
making cultures therefrom, one is astonished at the small number of
micro-organisms found in the nasal cavities of persons in good health.
Thomson and Hewlett[664] have certainly gone too far when they affirm
that the upper regions [i.e. the Schneiderian membrane] of the nasal
cavity are, in almost 80% of cases, free from micro-organisms. But it is
certain that in these regions we do find a small number only of the
bacteria which exist in greater abundance in the lower (cutaneous)
passages of the nose.
[Sidenote: [431]]
To explain this paucity of micro-organisms in the nasal cavity, Wurtz
and Lermoyez[665] have assumed the existence of a bactericidal property
in the nasal mucus. They affirm that the anthrax bacillus, after contact
with this mucus for several hours, loses its virulence for the most
susceptible animals, and that several other micro-organisms—the
staphylococci, the streptococci, and the _Bacillus coli_—become
attenuated under the same conditions. Others who have studied this
question have come to a different conclusion. Thomson and Hewlett found
that the nasal mucus is not bactericidal, although it prevents the
multiplication of micro-organisms. F. Klemperer,[666] denies the
bactericidal property of the nasal mucus. He could never demonstrate the
destruction of micro-organisms by the mucus, and he also observed that
bacteria do not multiply at all readily in this medium. These results
confirm the hypothesis that the defensive action of the nasal mucous
membrane against microbial invasion is mainly effected by the mechanical
elimination of the numerous micro-organisms which continually reach it.
Amongst these organisms are some which are conspicuous for the ease with
which they multiply in the body, taking the nasal cavity as a starting
point, e.g. the micro-organisms of influenza, the plague bacillus,
which, according to several observers, is very virulent when introduced
by the nostrils[667], and the leprosy bacillus. This last, according to
Goldschmidt[668], Sticker[669], and Jeanselme[670] often enters the
human body by way of the nose.
It is certain that the olfactory apparatus deprives the inspired air of
a large number of the micro-organisms which it carries. These organisms
deposited on the mucous membrane are expelled with the nasal mucus. A
number of the foreign organisms, carried by the air, may, however,
surmount this first barrier and penetrate further into the trachea and
bronchi, whence, helped by the movements of the vibratile cilia, they
are usually expelled along with the mucus.
[Sidenote: [432]]
[Sidenote: [433]]
In spite of this double defence it has been recognised that very minute
corpuscles and, amongst others, micro-organisms may overcome every one
of these obstacles and reach the pulmonary alveoli. Here, under the name
of “dust-cells” (“cellules à poussière”)—“Staubzellen” of the German
writers—located in the alveoli, are described certain large
mononucleated elements which contain granules of foreign origin, usually
deposits of soot, of a deep black. This permeability of the normal lung
tissue for dust particles and pigmented corpuscles has been closely
studied and clearly demonstrated by J. Arnold[671] and his pupils.
Several observers have tried to determine whether micro-organisms,
introduced by the respiratory channels, behave like other bodies.
Animals were made to inhale, or there were introduced into the trachea,
cultures of bacteria pathogenic for the animals experimented upon. The
results so obtained have been very contradictory. Morse[672],
Wyssokowitch[673], and Hildebrandt[674], never succeeded in inducing
anthrax by the introduction of anthrax bacilli into the lungs of normal
animals. They concluded, therefore, that the uninjured pulmonary tissue
was impermeable by virulent micro-organisms. H. Buchner[675] with his
collaborators and pupils maintaining the opposite view, declare that
rabbits that have inhaled anthrax bacilli or their spores always succumb
to a fatal attack of anthrax. These contradictory results were
attributed to differences in the methods employed, and an attempt was
made to perfect the methods of research, especially to prevent the
penetration of the anthrax bacilli by lesions of the trachea or by any
channel other than that of the pulmonary tissue. Gramatschikoff[676],
under Baumgarten’s direction, undertook a series of experiments in order
to determine whether it was possible for the anthrax bacillus to
traverse the pulmonary tissue. He introduced through the trachea of
rabbits and guinea-pigs an anthrax culture, afterwards washing the
respiratory passages with a large quantity of broth or of physiological
saline solution. Several of the animals so treated did not succumb to
the inoculation, and Gramatschikoff concluded that it was impossible for
the anthrax bacillus to make its way through the wall of the normal
pulmonary tissue. He was satisfied that some of the injected organisms
were destroyed in the lung, although he was unable to see how this
bactericidal action was determined. In these experiments a large
quantity of fluid was introduced after the bacilli; this might wash away
the bacilli and convey them to situations where they could exert no
morbific action; moreover the anthrax bacilli used were of doubtful
virulence (the injections made to control the virulence in the
subcutaneous tissue were in nearly every instance made with quantities
of fluid greater than those introduced by the trachea), and
Gramatschikoff’s results could not be accepted as deciding the question.
On the other hand, H. Buchner’s inhalation experiments made with spores,
and the study of the organs of animals so treated, leave no doubt as to
the possibility of the invasion of an animal by the respiratory channels
by the anthrax bacillus. Furthermore, the “rag-picker’s disease” and the
“wool-sorter’s disease,” or pulmonary anthrax, developed in man as a
result of the inhalation of dust charged with anthrax spores,
demonstrate most clearly that it is possible for the anthrax bacillus to
enter the body by the respiratory channels. The pulmonary mycoses,
produced by the penetration of the _Aspergillus fumigatus_ in the human
subject, offer confirmatory evidence.
[Sidenote: [434]]
In spite of the fact that the pulmonary tissue is not impermeable to
pathogenic micro-organisms, it is none the less true that it exhibits a
very marked resistance to infection by this channel. It is, however,
neither the thickness of the wall, as in the case of the skin and the
mucous membranes, nor the mechanical elimination with the help of the
vibratile cilia or of the secretions, that constitute the means of
defence in the respiratory alveoli. Here the cell elements are charged
with the duty of ridding the lungs as much as possible of the
micro-organisms which enter. Ribbert[677] and his Bonn pupils,
Fleck[678] and Laehr[679], observed this fact long ago. They showed that
the spores of _Aspergillus flavescens_ and the staphylococci, injected
into the veins or into the trachea, penetrate into the pulmonary
alveoli, where they are soon seized by the “epithelial cells” and the
leucocytes. Laehr observed that this phenomenon is produced at the end
of a few hours, and that the ingested cocci within the phagocytes
undergo a progressive degeneration and at last disappear.
Tchistovitch[680], working in my laboratory, studied micro-organisms
pathogenic for the rabbit—the anthrax bacillus, the coccobacillus of
fowl cholera, and the bacillus of swine erysipelas—ingested by the
“dust-cells” of the alveoli. He has added the important observation
(already referred to in chapter IV) that these phagocytic elements are
not epithelial cells at all, but are really macrophages of lymphatic
origin. They are not found in the alveoli of new-born animals, but soon
appear there and instal themselves in such a manner that for long one
was led to regard them as true epithelial cells of the pulmonary tissue.
This tissue, invested with an extremely delicate covering, is incapable
of defending itself against the invasion of micro-organisms, but the
animal organism comes to its aid by sending a permanent army of
macrophages which evict from the alveoli, so far as is possible, both
micro-organisms and other foreign bodies. Under these conditions, we can
readily understand that similar cells which fulfil the same protective
function, are also found in the neighbouring bronchial glands. It has
long been recognised that the macrophages of these glands are often
crammed with various kinds of granules of foreign origin, which have
made their way into the lungs with the inspired air.
Toxic substances can be absorbed by the mucous membrane of the
respiratory channels. Roger and Bayeux[681] have shown that no lesion is
required in order that diphtheria poison may invade the mucous membrane
of the trachea, and so produce typical false membranes. The lung, we
know, is accessible to gaseous toxic substances; moreover, its surface
readily absorbs fluid poisons.
The protection of the digestive system is more complex than that of the
respiratory passages; this is not remarkable, when we consider the
greater complexity of the organs of digestion and the varied conditions
which they present with regard to microbial invasion.
[Sidenote: [435]]
The buccal cavity, so exposed to the entry of extraneous micro-organisms
along with the food and the external air, has a very rich microbial
flora, in which Miller[682], the author of our most complete work on
this subject, has recognised in man more than thirty species. Several
representatives of this flora, e.g. the _Leptothrix_ and the
_Spirochaeta_ are constantly present, and are very characteristic of the
buccal cavity of man. With them are frequently found pneumococci,
staphylococci, and streptococci, whose pathogenic power is undoubted.
Virulent diphtheria bacilli are also met with in a certain number of
quite healthy persons. It is astonishing that, in spite of this state of
things, wounds in the mouth heal very rapidly, and operations on the
buccal cavity done with insufficient or no aseptic precaution do not, in
the great majority of cases, set up infective complications of the
slightest importance. After certain buccal operations we are often
confronted with a complicated and open fissure; nevertheless the wound
thus left exposed is not ordinarily the seat of any infection either
local or generalised.
It is often asked, how under these conditions does the mouth defend
itself against the vast number of formidable micro-organisms. When the
theory of the bactericidal power of the body fluids was dominant, and
appeared to explain several important points in the general problem of
immunity, the saliva was studied from this “bactericidal” point of view.
Sanarelli[683], as the outcome of patient and laborious researches, came
to the conclusion that the human saliva acted as an antiseptic and
destroyed a large number of micro-organisms. It is true that he
recognised its efficacy only when few bacteria were subjected to its
action; but even when the saliva was incapable of killing a large number
of micro-organisms, it did not allow them to develop—it was a bad
culture medium; moreover, it had the power of attenuating the virulence
of certain pathogenic bacteria, such as the pneumococcus, so frequently
found in the mouth.
The conclusions of the Italian observer did not, however, meet with
general acceptance. Miller[684] did not believe that the saliva exerted
any bactericidal action, raising the objection that the absence of
nutritive value in the human saliva for bacteria is explained by the
fact that in his experiments Sanarelli employed filtered saliva, which
consequently had been deprived of much of its nutritive
substances,—epithelial débris, mucus, etc. Hugenschmidt[685], working in
my laboratory, carried out a special research on the influence of the
human saliva on micro-organisms, and arrived at conclusions quite at
variance with those reached by Sanarelli. In spite of the variety of
micro-organisms made use of, he could never satisfy himself that the
saliva had any bactericidal property.
[Sidenote: [436]]
He sometimes saw, no doubt, a certain slowness of growth or even the
destruction of certain of the micro-organisms sown at the commencement
of the experiment, but this was very slight and rather exceptional. In
most cases the micro-organisms, introduced into the saliva, grew
rapidly, so that their number, in a very short time, became very
considerable. Where the saliva brought about any diminution in the
number of micro-organisms, this semblance of bactericidal action could
be noted not only in the normal saliva, but; also, as in the lachrymal
secretion above described, in saliva heated to 60° C. Against certain
micro-organisms—the torulae and the staphylococci—the heated saliva
acted more vigorously than did the unaltered saliva. It is consequently
impossible to draw any parallel between the action of the saliva and
that of the cytases.
Since the saliva often contains (according to certain authors even
constantly) small quantities of potassium sulphocyanide, it seemed to be
worth while to ascertain whether this salt is capable of destroying
micro-organisms. The experiments carried out by Hugenschmidt, in order
to settle this point, demonstrated that when given in doses comparable
to those met with in the saliva, the potassium sulphocyanide exerts no
bactericidal action.
Powerless as an antiseptic, the saliva fulfils an important function in
ridding the mouth of micro-organisms in a mechanical way. The parotid
secretion and that of the other salivary glands dilutes the bacteria and
carries them from the pharyngeal cavity into the stomach. Hence, in
diseases where the salivary secretion is much diminished, the mouth
becomes the most important portal of entry for micro-organisms capable
of setting up secondary infections. The saliva is further useful in
diluting the alimentary detritus and preventing its stagnation and
decomposition in the buccal cavity.
[Sidenote: [437]]
In addition to the direct mechanical part played by the saliva, it
performs a very important indirect function. This fluid contains
microbial products and diastases, and is capable of exciting in the
leucocytes a positive chemiotactic activity. Hugenschmidt demonstrated
the fact by introducing into animals small capillary glass tubes
containing saliva. A certain time after being placed in position, these
tubes became filled with considerable masses of immigrated leucocytes.
The same result was obtained with guinea-pig’s saliva, enclosed in
capillary tubes and introduced into the peritoneal cavity of the same
species. Here, again, the leucocytes assembled in the tubes and ingested
the micro-organisms found in the saliva. The influence of the saliva on
the afflux of the leucocytes must be regarded as an act important for
the protection of the buccal cavity, and it is probably due to this
attraction of leucocytes that lesions of this region heal so quickly.
The leucocytes are very numerous in the glands of the mouth and the
tonsils always supply large quantities of them.
We must not lose sight of the fact that the epithelial covering of the
bucco-pharyngeal cavity also constitutes an important protective factor.
Just as on the surface of the skin, the corneal cells are in a permanent
state of desquamation, so the cells in the mouth are being constantly
renewed. This desquamation increases especially during mastication, when
enormous numbers of cells are thrown off; after every meal there is a
partial renewal of the surface of the lining of the buccal cavity. Being
covered on their surface, and in their interstices charged with
innumerable micro-organisms, the epithelial cells carry away with them
all this population from the mouth.
The numerous micro-organisms which persist in the mouth, in spite of all
these means for getting rid of them, must also play a certain part in
the defence against infections. It is very probable that many of these
saprophytes impede the multiplication of certain pathogenic bacteria;
but at present it is impossible to define more exactly these phenomena
of microbial competition. It is only because we have analogies in other
regions of the body that we are able to defend this position.
[Sidenote: [438]]
The saliva, incapable of destroying the micro-organisms themselves, is
able to act on their soluble products, as on certain other poisons. In
this relation the action of the saliva on snake venom is most familiar.
Wehrmann[686], who has made researches on this subject in Calmette’s
laboratory at Lille, has shown that the amylase (ptyalin) of human
saliva, mixed with very rapidly fatal doses of venom, quite prevents its
toxic action. Von Behring[687] reminds us on this point that the ancient
Psylli (a race of northern Africa), at the beginning of our era,
employed their saliva as an antidote against snake bites.
[Sidenote: [439]]
Powerless to kill the micro-organisms, the saliva carries them off
mechanically to the exterior or, more frequently, into the stomach. The
acid medium of this great reservoir exerts a very marked effect on these
microscopic organisms. It has long been recognised that the gastric
juice prevents putrefaction and can arrest it even when it has become
very advanced. From this observation an antiseptic action of this juice
was inferred. Bacteriological researches, undertaken to determine the
nature of this action, have demonstrated that several species of
micro-organisms die very shortly after being placed in contact with the
gastric juice _in vitro_. Straus and Wurz[688] found that even anthrax
spores and the tubercle bacillus could be destroyed by gastric juice,
after a prolonged sojourn in a sufficient quantity of this fluid.
Comparative researches, made with aqueous solutions of hydrochloric
acid, have demonstrated that the bactericidal action of the gastric
juice depends solely on the amount of this acid that it contains, that
is to say, the pepsin plays no part in the process. This juice exerts no
true digestive action on the micro-organisms, but it destroys a certain
number of them by its hydrochloric acid. This antiseptic action may also
be inferred from a series of demonstrations on the exaggerated microbial
multiplication in cases where the gastric juice has been poor in
hydrochloric acid. Several observers have confirmed this bactericidal
action of the gastric juice which is exerted specially against certain
species capable of causing grave infective diseases. On the other hand,
certain bacteria and other lower fungi are quite resistant to the
antiseptic action of this fluid; they adapt themselves very readily to
an existence in the stomach. Consequently there exists in this organ,
even in animals such as the dog, whose gastric juice contains most
hydrochloric acid, a special flora, whose most characteristic feature is
the relative insensibility to the acidity of this medium. The
Blastomycetes, along with the yeasts and the Torulae, constitute the
most frequent representatives of this flora; alongside these may be
grouped the Sarcinae and certain acidophile bacilli. Miller[689] has
isolated several of these micro-organisms from the contents of the
stomach, and has observed that, mixed with the food, they resist the
action of the gastric juice, even that of the dog, whose hydrochloric
acid content is greater than in man and many of the other mammals[690].
But these acidophile micro-organisms have no pathogenic power and
consequently are not much to be feared. It is very doubtful whether even
the infective bacteria which are easily killed by the gastric juice _in
vitro_, are often destroyed in the stomach. The typhoid coccobacillus,
which has shown itself to be so sensitive to the destructive action of
the gastric juice of man, of the dog, and of the sheep, is, from the
experiments of Straus and Wurz, quite capable of passing through the
stomach without being affected. Stern[691], as the result of his own
researches, as well as of those of his pupils, came to the conclusion
that this micro-organism is not in the least affected by the gastric
juice of a healthy man, containing the normal amount of hydrochloric
acid. It was only in cases of hypersecretion and of hyperacidity that
the micro-organisms of typhoid fever were destroyed before they reached
the small intestine.
The cholera vibrio also can pass through the stomach and its acid juice.
After Koch’s demonstration of the great susceptibility of this organism
to acids _in vitro_, it was generally concluded that it must perish in
the normal content of the stomach. Many cases have since been recorded
in which the cholera vibrio was found, in times of cholera epidemics, in
the faeces of healthy persons. In order to get into the large intestine
it had to pass through the normal stomach. In experimental cholera in
young suckling rabbits, a large number of vibrios were also found in the
distinctly acid contents of the stomach, and they were seen to pass into
the small intestine without any neutralisation of the acidity of the
stomach taking place. This example proves, once again, that the
phenomena that occur within the living body cannot be identified with
those that go on in the test-tube, _in vitro_.
[Sidenote: [440]]
Whilst the acidity of the gastric juice exerts a certain influence on
micro-organisms, the pepsin which it contains acts unfavourably on their
toxins. There are many poisons which are readily absorbed, without being
modified, by the mucous membrane of the stomach. Even the venom of
snakes can, under certain conditions, produce its toxic effect as it is
absorbed through the stomach. Thus, according to the experiments of
Wehrmann[692], pepsin exerts a very feeble action on this poison. On the
other hand, this diastase has a marked action on certain bacterial
toxins. Gamaleia[693] pointed out that pepsin destroys the diphtheria
toxin. Charrin and Lefèvre[694] have shown that it also weakens other
microbial toxins. According to Nencki and Mmes Sieber and
Schoumow-Simanowski[695], the gastric juice of the dog destroys
relatively small quantities of the diphtheria poison. A gramme of the
juice is capable of rendering innocuous 50 lethal doses of this toxin,
but, in order that this action may be produced, a prolonged contact of
the two substances is required. Since the neutralised gastric juice acts
in the same way, this effect must be attributed not to the acidity of
the gastric juice, but rather to the amount of pepsin it contains. This
diastase acts much more powerfully on the tetanus toxin, 1 gramme of
gastric juice neutralising 10,000 doses lethal for the guinea-pig. On
the other hand, abrin is not modified by the gastric juice according to
the researches of Répin[696], carried out in Roux’s laboratory.
Nevertheless, its action when administered by the stomach is feeble, and
Ehrlich[697] has been enabled to vaccinate small animals against this
vegetable poison by availing himself of his knowledge of this fact.
Répin explains this result as due to the very slight absorption of abrin
by the gastrointestinal mucous membrane. This same factor, Répin thinks,
may contribute also to the failure of various toxins when ingested. This
rule, however, is not an absolute one. Thus, the toxin of the botulinic
bacillus of van Ermengem[698] is not destroyed by the digestive
diastases, and it is certainly absorbed by the mucous membrane of the
alimentary canal. For this reason, when it is introduced by way of the
stomach, it exhibits a very violent toxic activity.
[Sidenote: [441]]
The stomach, though capable, through its acid, of preventing the
multiplication of certain micro-organisms, protects, very feebly, the
rest of the digestive apparatus. As soon as, in the duodenum, the
acidity is weakened or neutralised, the various micro-organisms commence
to multiply and soon develop very abundantly.
In the animal series the intestine proper presents a very great
variability, and even, in closely allied species, exhibits considerable
differences. From the particular point of view which interests us these
differences are very marked. Alongside insects, such as the silkworm,
the larvae of cockchafers and others, whose intestinal canal contains a
very rich bacterial vegetation, we have others which contain exceedingly
few micro-organisms or, indeed, none at all. This last condition is
represented by the caterpillars of small Lepidoptera, and notably by
those of several species of clothes-moths. These differences correspond
to the variety of the juices and digestive ferments met with in these
Invertebrata. As the physiology of digestion in these animals is as yet
little understood, it is at present impossible to define clearly the
conditions which regulate these phenomena. In any case, it is very
probable that the soluble digestive ferments destroy the micro-organisms
and prevent them from growing in the intestinal content. Otherwise it is
difficult to explain why the larvae of clothes-moths, which live in old
dusty textile fabrics, where the germs of bacteria are not wanting,
present a digestive canal from which micro-organisms are entirely
absent. The digestive juices, adapted to digest wool and even wax, are
evidently capable also of digesting the bodies of micro-organisms. In
other insects, which feed on vegetables and on substances less difficult
to digest, micro-organisms develop in the intestinal content, as in many
of the higher animals. Insects often have their intestine lined by a
very delicate chitinous membrane which offers no obstacle to the
absorption of the products of digestion, but prevents the
micro-organisms from reaching the epithelial layer. We have here a
defensive apparatus against microbial invasion, which must be the more
useful because this membrane is thrown off and renewed at each moult,
thus enabling the insect to rid itself at one swoop of a large number of
its microscopic inhabitants.
[Sidenote: [442]]
In the Vertebrata the canal of the pancreas and that of the small
intestine are always populated by a greater or smaller number of
micro-organisms, amongst which bacilli predominate. We know the great
difficulty experienced every time we wish to make experiments on the
pancreatic digestion outside the animal body. The digestive fluid,
alkaline and containing many bacteria, is soon transformed into a
microbial _purée_. We are then obliged to have recourse to antiseptics
to arrest this development and to bring into prominence the digestive
rôle played by the soluble ferments of the pancreas. This well-known
fact may be used as an argument against the existence of any kind of
bactericidal power in the small intestine of higher vertebrates. Even in
those animals which are distinguished by the remarkable poorness of
their intestinal flora, we fail to reveal the presence of bactericidal
substances. The Crustacea, e.g. the crayfish, and certain worms, such as
the _Ascaris_, contain few micro-organisms in their intestine. The
former feed on putrescent substances, the latter inhabit the small
intestine of man and animals, populated by myriads of bacteria. It might
be supposed that, under these conditions, the intestinal content must
contain a mass of micro-organisms or, if that be not the case, that it
must contain some substance which is powerfully bactericidal. In
reality, neither one nor the other of these suppositions receives any
confirmation. The intestines of the two Invertebrata I have named are
very poor in micro-organisms and their contents do not exhibit the
slightest bactericidal power. When a little of their contents is placed
in tubes and kept at a suitable temperature it is not long before it
becomes filled by a great number of bacteria of various kinds.
To explain this poverty of the microbian flora of the intestines in
these examples we must postulate some kind of mechanical purification,
facilitated by the peristaltic movements of the digestive canal.
[Sidenote: [443]]
Even in animals which have an abundance of micro-organisms in the small
intestine, there must be produced some phenomenon which brings about the
disappearance of a certain number of them. In mammals the small
intestine always contains far fewer micro-organisms than does the large
intestine; in birds, the coecum is much richer in bacteria than is the
rest of the digestive canal. Schütz[699] has attempted to demonstrate
the disinfecting power of the small intestine in the dog by feeding it
on substances to which he had added a large number of Gamaleia’s vibrio
(_Vibrio metchnikovi_). After convincing himself that micro-organisms
perish in the digestive canal and are never found in the excrementa,
Schütz introduced into his dogs a cannula, one branch of which passed
into the pylorus, the other into the duodenum. By means of a small
apparatus he could readily interrupt the communication between the
stomach and the intestine. The vibrios, mixed with biscuit, and softened
with water, introduced directly into the duodenum (whilst the stomach
was kept completely isolated), penetrated into the large intestine in
small numbers only. The lower part of the colon, the rectum and the
excrements gave no cultures of vibrios and did not give rise to any
growth except that of the _Bacillus coli_. In this case the disinfection
of the intestine took place without any help from the gastric juice.
Further, when Schütz killed dogs, after giving them food in which
vibrios were mixed, these organisms were found in the intestine only.
The gastric acidity, therefore, is not capable of killing these
organisms, or of preventing them from passing into the small intestine,
in which alone they were killed. It was only with the aid of purgatives,
such as castor-oil or calomel, that Schütz succeeded in preserving the
vibrios in the intestines and in finding them in the dejecta. This
observer did not carry his investigations further and did not make out
the mechanism by which the small intestine destroyed such large numbers
of vibrios. He supposes that alongside a mechanical factor, such as the
very active peristaltic movement, there exist others, perhaps chemical
processes, capable of killing these micro-organisms.
[Sidenote: [444]]
This question of the defensive action in the small intestine is,
consequently, far from being settled. The data collected indicate merely
that the problem is a very complex one. It has been shown, however, that
very virulent bacteria may pass through the digestive canal not only
without injuring the animal but even meeting their own death in this
organ. The anthrax bacillus, so fatal to mice and guinea-pigs, may be
swallowed by these animals without the slightest danger to them. It may
then be found in the small intestine, but not in the large intestine,
this proving that the gastric acidity is incapable of destroying them
outright. To produce generalised anthrax by way of the intestine, it was
necessary that the animals should swallow the spores of anthrax along
with spiny plants, as in the experiments of Pasteur and his
collaborators[700], or along with sand or powdered glass. In these cases
the intestinal lesions served as the port of entry for the bacillus, the
intact mucous membrane of the intestine preventing their penetration.
Mitchell, in an unpublished work, undertaken in my laboratory, succeeded
in giving fatal anthrax to guinea-pigs, even when he fed them with
spores mixed with the “crumb” of bread soaked in milk. During the whole
period of the experiment the animals took no food capable of producing
lesions of the wall of the intestine. But examples of infection under
these conditions are altogether exceptional. In the great majority of
instances the animals were not attacked. The same rule applies also to
many other micro-organisms, which can be ingested with impunity although
their inoculation into the blood and tissues sets up infections which
are inevitably fatal. Many animals may, without running the least risk,
swallow large numbers of bacteria which in man produce grave intestinal
disease. Thus, it has never been possible to produce typhoid fever
regularly and with certainty in any of the species of animals to which
masses of typhoid coccobacilli were given by ingestion. We may recall
the difficulties which so many investigators have met with in inducing
intestinal cholera in laboratory animals, which are so refractory to
Koch’s vibrio. Only very young animals, especially unweaned rabbits, are
capable of contracting fatal intestinal cholera, but these animals may
contract it not only from the true cholera vibrio but also from
Gamaleia’s vibrio. As soon as rabbits begin to feed on vegetables they
acquire an immunity which is insuperable.
It is most assuredly not the digestive ferments of the intestine that
protect the animal against infection through the intestine. The contents
of every part of the small intestine of the Vertebrata permit an
abundant development of all sorts of bacteria, and in solutions of
trypsin not only do pathogenic and resistant micro-organisms grow
luxuriantly, but also saprophytes and the most inoffensive bacteria.
Weigert[701] influenced by this fact even saw in it an objection to the
theory that the destruction of micro-organisms in the animal, notably
that which is effected by the phagocytes, is to be regarded as an act of
digestion. It is a remarkable fact that whilst trypsin is so powerless
against micro-organisms the intracellular ferments, and especially
microcytase, whose kinship with the group of trypsins is undeniable, are
able to bring about their digestion so completely.
[Sidenote: [445]]
It was thought that among the digestive fluids the bile more especially
exerts a definite antiseptic power. It is undeniable that this fluid is
not indifferent for certain bacteria. Talma affirms that it is
bactericidal for several micro-organisms, especially the diphtheria
bacillus. In many of his experiments, however, the bile proved to be
incapable of killing micro-organisms introduced directly into the
gall-bladder. According to the researches of Gilbert and Dominici[702]
the bile does not prevent the abundant development of micro-organisms
capable of setting up diseases of the biliary passages, such as the
_Bacillus coli_. I have tried to prevent the multiplication of the
cholera vibrio by the addition of bile, but my results were entirely
negative. If the bile in an undiluted state has such a slight action
upon so many kinds of bacteria, it is evident that we cannot count upon
its antiseptic action when it passes into the small intestine, where it
is mixed with all sorts of other substances.
[Sidenote: [446]]
The digestive fluids of the small intestine, either those that are
non-bactericidal, the pancreatic juice, or those that are not very
active, the bile, are, nevertheless, capable of producing a marked
influence on certain poisons, and amongst others on certain microbial
toxins. According to the experiments of Nencki and of Mmes Sieber and
Schoumow-Simanowski (_l.c._), trypsin is much more antitoxic against the
diphtheria poison than is pepsin. Thus, the pancreatic juice of both the
rabbit and the guinea-pig destroys this toxin much more actively than
does the gastric juice. The pancreatic juice of the dog exerts a very
powerful action on the same toxin. A gramme of this fluid neutralises
ten thousand lethal doses of the toxin. Wehrmann, also, found that
trypsin inhibits the poisonous action of snake venom. Bile also exerts
an action upon certain poisons. Mixed with diphtheria and tetanus toxins
it prevents their pathogenic effect. It also neutralises the venom of
snakes, as has been observed by Fraser[703], Phisalix[704] and
Calmette[705]. All the venoms, when placed in contact with fresh bile
for 24 hours, induce no injurious effect when the mixture is injected
into normal animals. Bile, heated to 100° C., and even to 120° C., is
still, though more feebly, active. To obtain these results, however, it
is indispensable to prepare, beforehand, a mixture of the two fluids.
When injected separately, whether at the same time as, before, or after,
the venom, the bile does not prevent poisoning. The venom when injected
directly into the gall-bladder of the rabbit sets up fatal intoxication
to the same degree as does the same dose of venom introduced
subcutaneously. Calmette, who made this experiment, explains this
negative result as due to the too rapid absorption of the venom, which
has not had time to be affected by the destructive action of the bile.
A protective action of the bile has been determined with regard to two
viruses, the micro-organisms producing which are not, as yet, known.
Koch[706] succeeded in vaccinating Bovidae with the bile of animals that
had died from rinderpest, and Frantzius[707] prevented animals from
contracting rabies when he inoculated into them rabic virus mixed with
the bile of rabbits that had succumbed to that disease. Vallée[708]
points out, however, that the bile of the normal rabbit produces exactly
the same effect. Here, then, we have to do with a preventive action of
the bile, as such, against the rabic virus. In the present state of our
knowledge it is impossible to say whether this influence of the bile is
directed against the toxin or against the unknown micro-organism.
Analogy would lead us to accept the former of these two suppositions.
The bile, active against certain poisons, does not, however, prevent
poisoning by cholera toxin nor by that of botulism, two most typical
intestinal intoxications.
[Sidenote: [447]]
Since diastases and the digestive juices are incapable of affecting
micro-organisms and since certain of these latter perish in the
intestines we must seek some other cause for their destruction. It is
probable that the vital competition among the micro-organisms, whose
rôle could be foreseen in the buccal cavity, is of still greater
importance in relation to the phenomena of pathogenic action or of the
innocuousness of infective bacteria in the intestinal canal[709]. This
complex and difficult chapter, up to the present, has been studied in a
very imperfect fashion. In our observations on cholera we have remarked
that under certain conditions the cholera vibrios do not develop on
gelatine plates, except in the neighbourhood of certain adjuvant
micro-organisms such as the Torulae and the Sarcinae. Guided by this
fact we have succeeded in producing intestinal cholera in suckling
rabbits, with races of vibrios which, when ingested alone by these
animals, remain innocuous or set up the disease only occasionally. We
have convinced ourselves of the helpful action of certain
representatives of the gastro-intestinal flora upon true cholera[710].
Following on these observations, it was quite natural to suppose that
this flora might also contain micro-organisms capable of hindering the
development and toxic action of the cholera vibrio. We have even
advanced the hypothesis that these “hindering” micro-organisms in the
flora of the digestive canal may explain the immunity of animals, of
many human individuals, and even of the population of unattacked towns,
to intestinal cholera. We should have, then, in the intestinal contents,
inhabited by a number of micro-organisms and deprived of bactericidal
juices, an important factor which in many cases guarantees a refractory
condition. It must be stated, however, that prolonged studies, carried
out with the object of demonstrating in suckling rabbits the precise
part played by these micro-organisms which prevent cholera, have not
given any satisfactory results. This we attribute to our very imperfect
knowledge of the microbial population of the digestive organs.
[Sidenote: [448]]
If the destruction by representatives of the normal intestinal flora of
the micro-organisms which penetrate into the intestines has not as yet
been satisfactorily demonstrated, the power of these latter to destroy
microbial toxins cannot be doubted. We[711] have shown that a great
number of micro-organisms develop well in broth cultures of the tetanus
bacillus which contain a quantity of specific toxin. This toxin is
destroyed under the influence of this microbial vegetation, but the
production of antitoxin never results. Charrin and Mangin[712] have
observed similar facts.
As the destruction of bacterial toxins by micro-organisms takes place
with great constancy and rapidity, it is quite natural to suppose that
the same phenomenon occurs also in the intestinal canal of living
animals in which pathogenic micro-organisms have succeeded in secreting
their toxic products.
The liver having long been recognised as the purifying organ of the
products resulting from digestion, it has been asked if it might not
also play a part in the destruction of microbial poisons. Certain facts
point to its inhibiting influence on the action of nicotine, atropin,
and of certain other alkaloids, and we have other facts which
demonstrate the power of the liver to transform into urea the ammoniacal
substances arising from the activity of the digestive glands. When
Nencki, Pawloff, and their collaborators[713] succeeded in making the
portal vein communicate with the vena cava, and thus were able to
suppress the purifying function of the liver, they found that their dogs
became poisoned in consequence of the accumulation of ammonia in the
animal organism.
Guided by these data as to the protective rôle played by the liver an
attempt was made to apply them to the action of this organ on bacterial
toxins such as the diphtheria poison. The numerous attempts undertaken
in this direction have given negative results: the liver was not found
to be capable of destroying this toxin. Bouchard, Charrin and Ruffer
have studied the action of the liver on the pyocyanic toxin. They
thought that they could make out a certain antitoxic action of this
organ, but, later, Charrin[714] convinced himself that the bacterial
secretions are only “moderately modified” under these conditions, and
that it is more especially the parts soluble in alcohol which undergo
modification in the liver. Now, the true bacterial toxins, as is well
known, are distinguished by their insolubility in alcohol. Moreover in
the numerous experiments made by Roux and Vaillard and so many other
observers on the tetanus and diphtheria toxins there has never been any
evidence of any kind of antitoxic action of the liver.
[Sidenote: [449]]
The digestive organs are furnished throughout with a defensive apparatus
against micro-organisms; this consists in an accumulation of lymphoid
tissue in the form of patches or groups of solitary glands:—the tonsils,
Peyer’s patches, and the solitary glands of the intestine. These organs
produce a large number of phagocytes which are able to come into close
contact with the micro-organisms. Ribbert[715] and Bizzozero[716] have,
independently or almost simultaneously, described glandular masses in
the coecum of the rabbit in which they recognise the presence of many
micro-organisms derived from the intestinal content. They noted that the
greater number of these bacteria were within cells, and regarded this as
an example of phagocytic reaction. Manfredi[717] was able to confirm
this interpretation by the demonstration that the ingested
micro-organisms were dead. Later, Ruffer[718] studied this question in
my laboratory. He observed intestinal phagocytosis in Peyer’s patches in
several species of animals, and showed that the lymphoid tissue
contained large macrophages filled with bacteria and microphages in
process of intracellular digestion. Amongst these latter he recognised
leucocytes, which in turn contained micro-organisms. The accumulation of
phagocytes in the lymphoid organs of the digestive canal constitutes, so
to speak, the last act of a struggle which is spread over a very wide
field.
Some years ago Stöhr demonstrated[719] that the wall of the intestine,
and especially the tonsils and other lymphoid organs, are traversed by
an enormous number of leucocytes which execute a kind of migration
towards the cavities containing micro-organisms. This continual and
normal condition is often termed Stöhr’s phenomenon. It is evident that
we have here a process of phagocytic defence in which the leucocytes,
disseminated through the digestive canal, give chase to the
micro-organisms that are nearest to the living portions of this organ.
When we remove a particle of mucus from the surface of the tonsils of a
person in good health we always find that it contains leucocytes,
especially microphages, filled with micro-organisms of all kinds.
[Sidenote: [450]]
The protection of the digestive mucous membrane is a more complicated
process than that of other mucous membranes, and many of the points
concerned therein are still obscure and need to be elucidated by further
research. It might be thought that the phenomena, associated with the
defence of the mucous membrane of the genital organs, being much more
simple and yet of similar nature, should be much more easily made out,
and that these would throw light on several aspects of the problem of
the general defence of the animal. Obstetricians and gynaecologists have
certainly given much attention to this question as regards the female
genital organs, but we are still far from possessing a satisfactory
knowledge of this subject. There already exists quite a literature on
the question, dominated by the work in two volumes published by Menge
and Krönig[720], but a satisfactory solution has still to be obtained.
At birth the vulva and the vagina are free from micro-organisms, but
they soon become inhabited and a fairly abundant flora, in which may be
recognised certain predominant species, such as the bacillus of
Doederlein, is developed. Micro-organisms, therefore, can exist in the
vulva and the vagina, and yet, when we introduce into these organs
cultures of various bacteria, saprophytic or pathogenic, they soon
disappear. We have the phenomenon to which Menge has given the name of
“autopurification” of the female genital organs. He himself, as well as
his predecessors, Doederlein and Stroganoff, tried to make out the
mechanism of this purification. In the new-born female child the
phenomenon is less complicated than in the adult. According to Menge the
acidity of the vaginal secretion in these infants at first prevents the
development of a large number of bacteria. Associated with this factor
is a marked emigration of leucocytes, which destroy the bacteria by an
act of phagocytosis, or perhaps by their products that have escaped into
the vaginal mucus. As a third element to which much importance is
attributed, we must accept the intervention of acidophile bacteria which
grow well in acid secretions but which hinder the development of other
micro-organisms. Doederlein concludes that it is more especially to the
bacillus which bears his name that the vagina owes its protection
against infective germs. Menge, however, attributes this action to a
whole series of bacteria.
[Sidenote: [451]]
After introducing a quantity of the _Staphylococcus pyogenes_ into the
vagina of new-born females, Menge found that they grew for a certain
length of time. Their presence excited a great accumulation of
leucocytes in the vaginal mucus, this being followed by a very marked
ingestion of the micro-organisms, but it was only from the moment when
the vagina became peopled with the bacteria which constitute its normal
flora that the staphylococci began to disappear. This process of
autopurification only ceased three days after the introduction of these
bacteria. Menge asked himself whether some purely mechanical element did
not contribute to rid the vagina of the micro-organisms which had
entered it. To settle this point he introduced into this cavity grains
of vermilion, and as these latter remained there for a longer period
than did the micro-organisms, he concluded that the vagina was incapable
of purifying itself by mechanical means. We must, however, in these
experiments take into account the fact that the micro-organisms which
Menge introduced into the vagina excited considerable reaction,
accompanied by a marked leucocytosis. Under these conditions there
should be produced a greater quantity of the mucous secretions which
could much more readily carry off with them the micro-organisms that had
come into the vagina than the smaller quantity could deal with the
vermilion. It is very probable, therefore, that, just as in the case of
the other mucous membranes, that of the female genital organs is capable
of mechanically expelling fine particles, and especially
micro-organisms.
[Sidenote: [452]]
With the object of throwing further light on the problem of the
autopurification of the vagina, Cahanescu[721], working in my
laboratory, undertook experiments on the females of several species of
mammals. The mare, as producing the greatest amount of vaginal mucus,
was selected by this observer as suitable for the settling of this
question of the bactericidal power of this secretion. The result was
absolutely negative, even when such an inoffensive saprophyte as the
_Coccobacillus prodigiosus_ was used. The autopurification of the vagina
of the female dog, rabbit and guinea-pig, was found to be neither very
marked nor very active. The micro-organisms introduced into the vagina
usually remained there for some time. Of all the factors in the
microbial destruction which Cahanescu was able to make out that of the
accumulation of leucocytes was the most active. Sometimes he observed an
extraordinary amount of phagocytosis, whilst in other experiments this
was slight or even absent. Many of the leucocytes being killed in the
vaginal mucus, it is possible that in some cases a certain bactericidal
action of the cytases which have escaped from these dead leucocytes is
set up. It is true that the vaginal secretion of the mare did not
exhibit this antimicrobial property _in vitro_, but in the other animals
experimented upon it was found impossible to make similar experiments,
the quantity of mucus being too small. In woman the acidity of the
surface of the mucous membrane of the vulva and of the vagina, so
frequently present, may play a certain part in the protective action
against those bacteria which cannot tolerate the acid medium, but the
animals studied by Cahanescu, even female dogs, do not possess this
advantage, their mucous membranes usually having an alkaline reaction.
In the urinary channels this acid reaction also plays a part, as one of
the defensive agencies against the penetration of bacteria. This may
also be effective in man and other animals that have an acid urine. In
many other animals, however, where the urine is alkaline micro-organisms
do not pass into the deeper parts of the urinary organ under normal
conditions. Here it is to the outflow of the urine that the bladder owes
its immunity against pathogenic micro-organisms and saprophytes. When we
connect two flasks containing sterilised broth in such a way that the
fluid flows slowly from one of them into the other, the former never
becomes contaminated by the micro-organisms which are present in the
latter, in which latter the broth is soon transformed into a _purée_ of
bacteria, whilst in the former the broth remains unaffected and aseptic.
This purely mechanical factor has been well brought out by
Preobrajensky[722] as the result of work carried out in Duclaux’s
laboratory. The sterility of the normal urinary bladder must be
attributed to a similar cause. When the urine begins to stagnate in the
bladder it very readily becomes contaminated.
[Sidenote: [453]]
Since the acceptance of the view that the suprarenal capsules serve to
neutralise the effect of certain toxic substances elaborated in the
body, there has been an inclination to assume that these organs might
also fulfil an antitoxic rôle against microbial poisons. The hypothesis
was advanced that this function might be shared by the suprarenal
capsules with the thyroid gland and with certain other problematical
organs. We have already stated (Chapter V) that the suprarenal capsules,
in some experiments where spermotoxin was injected into rabbits,
exhibited a certain antispermotoxic power. But, up to the present, no
exact fact has been observed that would favour the idea of an antitoxic
action of the above-mentioned organs against bacterial toxins. Roux and
Vaillard[723], in their great work on tetanus, have made experiments in
this direction, but their results did not justify them in giving a
positive answer to the question.
Nature does not make use of antiseptics to protect the skin and the
mucous membrane. The fluids which moisten the surface of the mouth and
of other mucous membranes are not microbicidal, or are so to a very
slight degree, and then rather of an exceptional nature. Nature rids the
mucous membranes and the skin of a large number of micro-organisms,
eliminating them by epithelial desquamation, and expelling them along
with fluid secretions and excretions. Nature, like the doctors of the
present day who replace antisepsis of the mouth, intestine, and other
organs by washing with pure physiological saline solution, has chosen
this mechanical method. She avails herself of the help of inoffensive
micro-organisms to prevent pathogenic micro-organisms from taking up
their abode in these positions, and she is constantly sending to all the
mucous membranes and the skin an army of mobile phagocytes which explore
the ground and rid it of micro-organisms. When these begin to get more
numerous the phagocytic reaction becomes more intense. A struggle takes
place between the two living elements—phagocytes and micro-organisms. In
those cases where the animal remains unaffected the former gain the
upper hand.
CHAPTER XIV
IMMUNITY ACQUIRED BY NATURAL MEANS
Immunity acquired after recovery from infective diseases.—Immunity
acquired in malaria.—Humoral properties of convalescents from
typhoid fever.—Preventive power of the blood of persons who have
recovered from Asiatic cholera.—Antitoxic power of the blood of
persons who have recovered from diphtheria.
Immunity acquired by heredity.—Absence of hereditary immunity properly
so-called.—Immunity conferred by the maternal blood and by the
yolk.
Immunity conferred by the milk of the mother.
[Sidenote: [454]]
It has long been known that an attack of one of many of the infective
diseases brings about a refractory condition of the organism against
that disease, a condition which persists for many years, and may even
endure for life. Even before the microbiological era of medical science
had arrived it had been fully established that a person who had
recovered from small-pox might come in contact with and nurse small-pox
patients without risk of contracting a second attack of the disease. The
same thing has been observed purely empirically in several other
infective diseases, such as whooping-cough, typhoid fever, scarlatina,
mumps, etc. On the other hand it has been shown that certain infective
diseases, such as fibrinous pneumonia, erysipelas, recurrent fever, and
influenza, do not leave behind them the slightest trace of an immunity.
It has often been observed, indeed, that after a first attack of any of
these diseases there is a marked susceptibility to a second attack.
Between these two extremes come the infections which are followed merely
by a refractory condition of shorter duration than that which follows
the diseases of the first group. The first of this intermediate group is
measles, which gives rise to a relatively long immunity, then come in
order bubonic plague, anthrax, cholera, etc.
[Sidenote: [455]]
It should be stated that the first attack of any of the infective
diseases causes modifications more or less permanent in the organism,
and is always followed by immunity. Even in erysipelas, a disease where
the relapses are so frequent that certain individuals are, so to speak,
predestined to re-acquire it at short intervals, an immunity is
produced, but a very transient one. Since the discovery of the
streptococcus of erysipelas by Fehleisen[724], this observer, and
several other investigators, have inoculated it into persons affected
with malignant tumours. In the course of a series of experimental cases
of treatment it was noted on several occasions that after a first
inoculation, followed by typical erysipelas, a period of immunity was
developed, during which the introduction of the streptococcus produced
no result. It has also been observed that recurrent fever, when
inoculated into monkeys, sets up a very transient but real refractory
condition. In fibrinous pneumonia, also, the relapses are generally
separated by periods of immunity, of longer or shorter duration.
[Sidenote: [456]]
It was generally supposed that an attack of malarial fever was not only
not followed by any immunity, but that a first attack predisposed the
organism to a second. Facts of this kind have often been observed and
cannot now be questioned. Nevertheless, an acquired immunity against
malaria is developed under certain conditions. During his travels in New
Guinea, Koch[725] found that in certain regions whilst most children
below ten years of age are attacked by malaria, and Laveran’s parasite
can be demonstrated in their blood, older children and adults are
completely immune from this infection. Koch is convinced that in this
instance we have an example of immunity acquired by natural means as the
result of an attack of malaria at the younger age. This great observer
bases his conclusion on the fact that unattacked adults, coming from
districts where the children contain the parasite, do not contract
malaria when they migrate to other malarial regions, whilst natives
coming into these same regions from districts where malaria does not
exist are soon attacked. Max Glogner[726] has attempted to explain these
facts established by Koch, on the assumption that the unaffected adults
simply benefit by their natural immunity and that we have here a kind of
selection: the adults who are susceptible to malaria die as the result
of this disease, whilst others, naturally refractory, resist and show
themselves incapable of contracting the disease even in other malarial
regions. Glogner in support of his view cites the case of the children
of the orphanage at Samarang (Java), who for many years are subject to
relapses and to malarial re-infections and are incapable of acquiring
the slightest immunity. According to Koch, Glogner’s example cannot be
compared with that of the children of New Guinea. In the former case,
the natural course of the disease is interrupted by treatment with
quinine, which must prevent immunity being set up; whilst, in the
latter, the children are abandoned to their fate, and, receiving no
treatment, slowly acquire a true immunity. It is evident that this
acquired immunity in malaria is a complex phenomenon on which fresh
researches must be made; but it cannot be questioned that, under certain
conditions, it comes under the general rule and can be naturally
acquired.
This general rule is that, in infective diseases, immunity is usually
developed after a first attack. The acquired refractory condition is of
very long duration in certain cases, but very transitory in others. To
the discovery of the vaccination by attenuated micro-organisms, made by
Pasteur and his collaborators, the objection was often made that many
diseases, such as anthrax, might relapse. This is undoubtedly the case;
the anthrax bacillus may attack the same individual several times;
nevertheless the acquired immunity against this disease is very real,
though the refractory condition lasts for one or a few years only,
instead of persisting for a very much longer period, as in the case of
typhoid fever, mumps, and small-pox. Bearing in mind the possibility of
a relapse in the case of these infective maladies, attempts at
artificial vaccination should never be relinquished.
[Sidenote: [457]]
Among the examples of immunity acquired by natural means must be cited
that of syphilis, a very special case. It has long been known and
demonstrated by numerous experiments on man, that individuals who have
presented the primary symptoms of syphilis contract a marked immunity
against a new infection. The syphilitic chancre does not relapse, and
yet this very manifest and persistent immunity does not prevent the
individual, immune against re-infection, from continuing to be ill and
of being the field for the later syphilitic phenomena. This special
refractory condition has done great service in establishing the etiology
of certain diseases which we were justified in suspecting to be of
syphilitic origin. Many clinical observers have accepted this origin for
general progressive paralysis. Others deny any causal relation between
the two diseases. Krafft-Ebing[727] has resolved this question by the
application of the law of acquired syphilitic immunity. The inoculation
of the syphilitic virus into ten persons attacked by general paralysis
was followed by no chancre at the seat of inoculation and by no other
primary or secondary symptom of syphilis. The patients with general
paralysis present a real immunity against these symptoms; consequently
general paralysis is a tardy manifestation of syphilis.
The acquired immunity against re-inoculation by the syphilitic virus is
established immediately after the end of the period of incubation of the
first infection, and is of lifelong duration[728]. Besides this very
special and, so to speak, partial immunity, there exists in syphilis a
second form of acquired immunity which is of a more general nature.
According to the law known as the law of Baumès-Colles, the mother who
suckles her infant, hereditarily infected with syphilis through the
father only, enjoys a real anti-syphilitic immunity.
[Sidenote: [458]]
In tuberculosis the few facts of acquired immunity that have been
observed present a certain analogy with those bearing on immunity in
syphilis. A large number of well-observed facts demonstrate that a
person who has suffered from scrofula or has manifest symptoms of
tuberculosis properly so called, cannot count upon an immunity against
pulmonary phthisis. It might, then, be supposed that no acquired
refractory condition exists in connection with this disease. Koch[729]
has clearly demonstrated, however, that tuberculous guinea-pigs, into
which the bacilli of tuberculosis have been introduced subcutaneously,
react against these bacilli in a very special manner. The presence of
these micro-organisms immediately sets up an active inflammatory process
at the point of inoculation; this brings about the expulsion of the
bacilli with the exudation; a voluminous slough is developed, which,
when shed, carries with it a large number of bacilli, a process followed
neither by the formation of a permanent ulcer nor by hypertrophy of the
neighbouring glands. As in syphilis, the animal has acquired immunity
against re-infection by the tuberculous virus, which, however, in no way
prevents the first inoculation from becoming generalised and setting up
a fatal tuberculosis of almost all the organs. Koch’s observations,
which have served as the basis of his researches on tuberculin, have
been confirmed by other investigators. The reaction of the tuberculous
organism against re-infection has received the name of “Koch’s
phenomenon.”
Clinical medicine has afforded many data of the highest importance
bearing on the establishment of an acquired immunity in many infective
diseases; but a scientific study of the mechanism of this immunity could
only be founded on the result of microbiological researches obtained
during the recent period of scientific activity. The general conclusion
to be drawn from these researches is that the immunity, acquired by
natural means, is very analogous to that which is obtained artificially
by vaccination by the various methods already mentioned. The phenomena
observed in animals inoculated with the various known vaccines present a
great resemblance to those that obtain during recovery from a disease
contracted under natural conditions. To support this thesis it would be
necessary for us to survey the mechanism of healing, which would carry
us too far afield, the subject being far too vast to be summarised here.
We must, then, content ourselves with a few remarks inserted for the
instruction of the reader on this subject.
Those diseases against which no remedy exists are most suitable for
furnishing us with important information on immunity acquired by natural
means. We have already seen in the case of malaria to what point
therapeutic treatment can modify the natural course of the phenomena.
For this reason it will be useful to consider first the immunity
acquired as the result of a first attack of typhoid fever. The immunity
which develops in this example is both marked and persistent; the
therapeutic intervention which might disturb the natural phenomena is
_nil_.
[Sidenote: [459]]
As yet we do not know the mechanism of healing in typhoid fever. This
disease affecting the human species exclusively (the experimental
peritonitis of animals, set up by the typhoid coccobacillus, is
distinguished by very marked differences), it is very difficult to find
a means of studying it at all satisfactorily during the phase of
recovery. Even in default of this knowledge, however, it is possible to
gather some idea as to the changes which the blood plasma undergoes, not
only during the course of an attack of typhoid fever, but also during
and after convalescence.
Some time ago Chantemesse and Widal[730] observed that the blood serum
of persons attacked by typhoid fever acquires the property of inhibiting
the experimental peritonitis set up by the typhoid coccobacillus in
laboratory animals. The blood of the patient becomes “preventive.”
Against this conclusion the objection has been raised that in the large
doses of serum employed by the above observers a protective effect can
be obtained, even when using the blood of normal men, i.e. neither
suffering from typhoid fever, nor having recovered from this disease.
Later researches, however, have confirmed the observation made by
Chantemesse and Widal. It is no doubt true that the injection of half a
cubic centimetre of normal human serum into the peritoneal cavity of an
untreated guinea-pig is often sufficient to render it refractory to a
dose of typhoid coccobacilli fatal to the control animal. We have an
ordinary protective action, such as described in Chapter X. The blood of
typhoid patients is, however, capable of protecting normal animals, in
doses which exhibit not the slightest protective action if normal blood
be used.
[Sidenote: [460]]
The protective power of the blood serum of convalescents has been
studied very carefully by Pfeiffer and Kolle[731]. In certain
individuals very small quantities (0·001 c.c.) of this fluid were quite
sufficient to confer on guinea-pigs an immunity against fatal typhoid
peritonitis. This power was at its maximum only during the first weeks
of convalescence. In one case, in which these observers were able to
study the properties of the blood on two separate occasions, they found
that two months after the first examination there had been a marked
falling off in the acquired protective power. In a second case, where
the blood was examined a year after the patient had recovered from a
grave attack of typhoid fever, they found only feeble indications of
this specific protective property. “Everything seems to indicate,”
conclude Pfeiffer and Kolle, “that the protective typhoid substances
were rapidly eliminated by the blood stream. If further researches
should confirm these results, as yet few in number, we might conclude
therefrom that the immunity which, after an attack of typhoid fever,
persists for years, frequently even for the rest of life, would be
independent of the amount of ready-prepared protective substances in the
blood” (_l.c._ p. 218). The facts upon which this conclusion is based
confirm the general thesis that even acquired immunity is in no way the
function of any humoral property.
We know that in the protective serums there is constantly found the
specific fixative (the sensibilising substance of Bordet, the
intermediary body or amboceptor of Ehrlich). It was, therefore, quite
natural that this substance should be sought in the blood of patients
who were suffering, or had recovered, from typhoid fever. Bordet and
Gengou[732] easily demonstrated, by the method described in Chapter ix,
the existence of typhofixative in the blood serum of two individuals
convalescing from this disease.
Widal and Le Sourd[733] extended this discovery to the blood taken
during the course of the disease from typhoid fever patients. The ten
cases studied by them all gave a positive result, whilst all the samples
of blood from persons suffering from various other diseases possessed no
typhofixative. As yet we do not know whether this substance persists for
any length of time after recovery or not. In this respect we have much
more information concerning another humoral property of typhoid
patients,—specific agglutination. Guided by the fact that, even during
the course of the disease, the blood of persons suffering from typhoid
fever acquires protective properties, Widal sought to find out whether
the agglutinative power of the fluids of the body appears equally early.
We know that his studies gave a positive answer, and that the blood of
typhoid patients may have agglutinative properties from the first day of
the disease. This fact was made use of by Widal to establish the serum
diagnosis of typhoid fever, a method now generally used in clinical
medicine. The question which most interests us at this moment is whether
this acquired agglutinative property persists for any length of time
after the recovery of the patient, and whether it can be employed as the
measure of immunity obtained.
[Sidenote: [461]]
In certain cases the serum was found to be fairly strongly agglutinative
for a considerable period after recovery had taken place. But these
cases are rare, and the agglutinative power, like the protective power
of the blood, usually begins to decrease very soon after recovery.
Bensaude[734] observed that the former disappeared between the 10th and
95th day of apyrexia. Widal and Sicard[735] have noted in certain of
their cases the complete disappearance of the agglutinative power of the
blood, which took place in one case on the 18th, in another on the 24th
day of defervescence. In many convalescents, fifteen to thirty days
after the commencement of apyrexia, the agglutinative power begins to be
attenuated.
Previous to these researches on the protective and agglutinative
properties, Stern[736] had already put the question: May we not draw
some general conclusion as to the bactericidal power of the blood serum
of convalescents from typhoid fever? He found that the typhoid
coccobacilli did not thrive so well in the blood serum of persons in
good health as in that of convalescents, in which they give abundant
cultures. Widal and Sicard (_l.c._) subjected this question to a fresh
examination, and showed that in this respect there exists no constant or
marked difference. Thus, in ten samples of serums from individuals who
had never been under the influence of the typhoid infection, four were
found to be bactericidal for the typhoid coccobacillus. In twelve other
samples, drawn from convalescents from typhoid fever, five exhibited a
bactericidal power against the same micro-organism.
All the researches made on acquired immunity after recovery from typhoid
fever demonstrate clearly that, in this case, it is impossible to
attribute it to humoral modifications, which are usually more transitory
than the immunity.
[Sidenote: [462]]
The immunity which follows an attack of cholera is far from being either
as powerful or as prolonged as that which follows typhoid fever. Certain
individuals have contracted cholera twice during the same epidemic, but
such cases are exceptional, whilst acquired immunity, temporary at
least, may be looked upon as the general rule. Many points in the
pathogenesis of intestinal cholera are still obscure; nevertheless we
are justified in affirming that this disease is a real intoxication by
the cholera poison manufactured, in the small intestine of man, by
Koch’s vibrios. The action of the vibrionic toxin is sufficient to set
up a grave and often fatal attack of cholera; but in the majority of
cases a secondary infection by the vibrio which penetrates into the
intestinal wall, denuded of its epithelial layer, is associated with the
action of the poison. Sometimes this micro-organism becomes generalised
in the animal, and is found in the blood and in many of the organs.
The facts I have here briefly summarised may be utilised to explain
certain characters which are found in the fluids of individuals who have
recovered from an attack of cholera. Soon after the discovery of the
tetanus and diphtheria antitoxins, and almost immediately after the
demonstration of the protective power of the blood, taking advantage of
the epidemic of Asiatic cholera, which developed in Europe from 1892,
the new data began to be applied to that disease. We have already
referred in a preceding chapter to the fact that the blood serum or the
blood of those in good health and who have never had Asiatic cholera, is
capable of preventing cholera peritonitis in the guinea-pig inoculated
with Koch’s vibrios. In order to obtain this protective action, the
injection of a pretty large dose, about half a c.c., is necessary. This
property is in no sense specific, for the same blood, injected in the
same doses into guinea-pigs, will protect them not only against this
vibrio, but also, and indifferently, against many other bacteria, such
as the typhoid coccobacillus, the _Bacillus coli_, etc.
The blood or blood serum, coming from those who have recovered from
Asiatic cholera, may, on the other hand, acquire a specific protective
power. It will, indeed, prevent infections by other micro-organisms;
but, to obtain this effect, it is necessary to inject the same
quantities of it as of the blood coming from normal individuals. On the
other hand, when we wish to prevent cholera peritonitis in the
guinea-pig, we need introduce minute doses only of the serum of persons
who have recovered from an attack of cholera. Lazarus[737] was the first
to make this interesting observation. In three cases of cholera studied
by him, the serum withdrawn some time after recovery exhibited an
extraordinary protective power: a decimilligramme of the blood serum of
these patients was quite sufficient to prevent the death of a guinea-pig
inoculated intraperitoneally with the cholera vibrio. Soon after, G.
Klemperer[738] made a similar observation in two other cases that had
recovered, but the blood, in his convalescents, was much less active
than was that in the cases cited by Lazarus.
[Sidenote: [463]]
Issaeff[739], working in Koch’s Institute in Berlin, examined the blood
of several persons who had recovered from cholera, and found that the
serum had always acquired a specific protective property; this property
never developed before the third week from the commencement of the
disease, and had completely disappeared as early as three months after
this period. Several examples studied by A. Wassermann[740] and
Sobernheim[741] fully corroborate this conclusion. Our own
researches[742] on twenty-four cases indicate a very great variability
in the protective power of the blood of persons who had recovered from
cholera. We were able to demonstrate its presence in rather more than 58
per cent. of these cases. Sometimes this power was almost as marked as
in the example given by Lazarus, whilst in others it was very feeble,
often even _nil_. We were unable to demonstrate any relation between the
gravity of the disease and the strength of the protective power of the
blood. Thus, in a moderately severe case of cholera, a very small
quantity of serum (0·001 c.c.) was sufficient to protect the guinea-pig
from fatal cholera peritonitis, whilst in another, an extraordinarily
grave case, even a quantity of 2 c.c. was incapable of producing the
same effect. In these two cases the blood had been withdrawn at the
corresponding period after the commencement of the disease
(seventy-third and seventy-fifth days). Sobernheim (_l.c._) found the
protective power of the serum most marked in a person who had cholera
vibrios in his normal dejecta, but who was always in good health and was
only examined because he was living with cholera patients.
[Sidenote: [464]]
All these observations point to the fact that neither recovery from, nor
immunity against, cholera can be regarded as a consequence of the
protective power of the blood. This power does not manifest itself until
some time after complete recovery has taken place, and then disappears
too soon, that is to say at a moment when acquired immunity ought still
to be maintained. On the other hand, the irregularity in the protective
power of the blood indicates that this humoral property is something
secondary. Since Asiatic cholera is an intoxication by the cholera
toxin, we can readily understand that the protective power, resulting
from the invasion of the living parts of the organism by the vibrios,
should here play a part of little importance. We know already that this
power is due to the presence of substances manufactured by phagocytic
elements, placed in contact with vibrios. In the experimental infection
of rabbits by the cholera vibrio, as demonstrated by Pfeiffer and Marx,
the cells of the spleen, of the lymphatic glands, and of the
bone-marrow, produce the protective substances. We have no idea of the
source of these substances in Asiatic cholera in man.
Asiatic cholera, being an example of intoxication of intestinal origin,
it might be supposed that the antitoxic power of the body fluids should
be specially manifested after recovery has taken place. On this point
our knowledge is as yet very imperfect, because it was not until after
the end of the last epidemic of cholera that we learnt how to prepare
the toxin. In a case of cholera (M.S.), contracted in our laboratory,
the blood serum was examined to ascertain its protective power and its
antitoxic activity. This fluid, withdrawn more than three weeks after
the commencement of the disease, was found to be protective only in a
large dose (0·5 c.c.), in which dose even the serum of normal persons is
capable of producing the same effect. It was found in an experiment with
suckling rabbits that the antitoxic property of the blood serum of M.S.
was _nil_. It did not prevent these rabbits from dying of intestinal
cholera after the absorption of the vibrios, in spite of a dose of three
c.c. of serum injected some time previously.
This experiment, unique up to the present, is, of course, insufficient
to enable us to affirm that recovery from Asiatic cholera may take place
without the development of antitoxic power in the body fluids. That this
is so is, nevertheless, probable. In other intoxications of microbial
origin, certain data have been collected which point to the same
conclusion. Thus, Knorr[743] observed that the blood of guinea-pigs
which had recovered from tetanus did not exhibit any antitetanic power.
Vincenzi[744] made a similar observation in a man who had recovered from
tetanus.
[Sidenote: [465]]
[Sidenote: [466]]
We are much better informed as to the antitoxic property of the blood of
persons who have recovered from diphtheria. Klemensiewicz and
Escherich[745] have studied two cases of diphtheria in which the
defibrinated blood withdrawn some time after recovery was found to be
protective for the guinea-pig against a lethal dose of diphtheria
bacilli. This fact has been confirmed by several other observers,
especially by Abel[746] and Orlowski[747], the latter of whom made his
researches under the direction of Escherich. In these experiments the
antitoxic power of the blood was demonstrated against diphtheria toxin
employed without bacilli. According to the data collected by the above
authors the antitoxic property of the body fluids was not exhibited
during the early days of convalescence, but was well marked in the
second week after recovery. This power was maintained for a short time
only, disappearing in a few months. Amongst the observations collected
on this subject the most interesting is that made by Escherich. In an
infant examined for the first time whilst it was still in good health,
the blood was incapable of protecting the guinea-pig. Some time after
this negative result had been obtained the child was attacked by a mild
diphtheria, which gave rise to the development of antitoxin, for its
blood when again examined exhibited a very high antitoxic power. This
proves most clearly that even a slight attack of diphtheria is capable
of producing antitoxic power in the body fluids. This observation may be
utilised to explain the frequency of the presence of this property in
the blood of persons in good health who, according to their own
statements, have never had diphtheria. This fact has been established by
the researches of A. Wassermann[748], Abel (_l.c._), and Orlowski.
According to the last observer, the blood in one-half the children in
the hospital at Gratz who had not been attacked with diphtheria was
antitoxic against the diphtheria toxin, sometimes even to a higher
degree than was that of the children who had recovered from this
disease. Wassermann has demonstrated that in adults this
antidiphtheritic power of the blood is even more frequent than in
children, and that it increases with age. Nevertheless, these persons
affirm that they have never had an attack of the disease. To explain
this very paradoxical fact, Wassermann asked himself whether the
individuals whose blood was antidiphtheritic did not owe this property
to the action of pseudo-diphtheria bacilli. Although incapable of
causing the disease, these bacilli might, perhaps, exert a certain
immunising influence and give rise to the production of an antitoxin
active against true diphtheria toxin. Researches, directed to the
clearing up of this point, have not led Wassermann to reaffirm his
suggestion. It must be observed that the varieties of these
pseudo-diphtheria bacilli are numerous, and that some of them, perhaps,
may be capable of fulfilling the function suggested by Wassermann. On
the other hand, it is proved that the specific and virulent diphtheria
bacillus may be found in the throat of persons in good health either
without inducing diphtheria, or only giving rise to a very slight form
of disease of very short duration. We must bear in mind that in persons
who have not had typhoid fever, but who live among patients suffering
from this disease, the blood may be very agglutinative (Foerster); that
in others, unattacked by cholera but containing Koch’s vibrios in the
intestine, the blood may acquire a high specific protective power
(Sobernheim). It is probable that the same rule applies also to the case
of diphtheria, and that, consequently, the blood of persons in good
health, but containing the diphtheria bacillus in their bodies, may
acquire antitoxic power.
This humoral power, once developed, may even be transmitted from the
mother to the foetus and so become hereditary. Abel (_l.c._) examined
the blood serum of four adult women, taking it from the placenta after
parturition. Each time it was found to be distinctly antitoxic against
the diphtheria toxin. Later, Fischl and Wunschheim[749], working in
Chiari’s laboratory in Prague, studied the blood of new-born children
from the same point of view. They showed that in the majority of cases
this fluid prevents the production of a fatal disease in the guinea-pig,
in spite of the injection of several lethal doses of very virulent
diphtheria cultures. The blood of new-born children is equally capable
of neutralising the diphtheria toxin, that is to say, of protecting
animals against poisoning by this toxin. The above observers do not
doubt that this antitoxic power comes directly from the maternal blood
through the placental circulation. This fact appears to throw some light
on the phenomena of immunity acquired by heredity.
[Sidenote: [467]]
Until quite recently we have had very vague notions as to the
possibility of transmitting to descendants the immunity contracted as
the result of recovery from an infective disease or after vaccination.
It has long been known that natural immunity may be transmitted
hereditarily. Certain families or certain races are characterised by a
special insusceptibility to certain infective diseases. It must even be
admitted that this innate immunity has been transmitted from generation
to generation. It is quite otherwise with acquired immunity. We know
that as a rule the characters acquired during life are not transmitted
to descendants; it is only in special cases, in the very lowest
organisms, such as the bacteria and their allies, that we may observe
the conservation of certain acquired characters through an infinity of
generations. The attenuation of bacteria or the absence of the formation
of spores, once acquired under special conditions, may thus be
transmitted to their descendants who develop and live under normal
conditions.
[Sidenote: [468]]
[Sidenote: [469]]
After the discovery of anthrax vaccine by Pasteur, Chamberland and Roux,
and an attempt had been made to vaccinate large flocks of sheep, it was
an easy matter to investigate whether immunity acquired by the parents
was transmissible to their offspring. Several observers, amongst whom I
may specially cite Chauveau[750], Rossignol and Cienkowski, got together
a certain number of data bearing on this question. These data showed
distinctly that, in certain cases, the lambs born from vaccinated sheep
presented, from birth, an undoubted resistance to the anthrax bacillus.
This fact, however, was neither constant enough nor sufficiently marked
to enable us to count upon the young animals being in a refractory
condition, and thus avoid having to submit them to vaccination by the
two Pasteur vaccines. This necessity threw into the background the
researches on the hereditary transmission of acquired immunity. It was
only much later that this question was again taken up on a purely
theoretical basis. Ehrlich[751], to whom science is indebted for so many
works of the highest importance upon immunity, again took the initiative
in exact and minute researches upon the heredity of immunity, acquired
as the result of vaccination against toxins. In this relation he studied
the immunity of the descendants of animals immunised against
phanerogamic toxins, such as ricin, abrin and robin, and later, in
collaboration with Hübener[752], that of the offspring of animals
vaccinated against tetanus toxin. Ehrlich proved very clearly that the
antitoxic immunity acquired by the father is never transmitted to his
progeny. This fact alone is quite sufficient to show that it is not a
true immunity that is met with in young animals born of mothers who have
acquired a refractory condition; true immunity is transmitted by the
sexual elements, the spermatozoon and the ovum. Certain observers,
Tizzoni[753] and his collaborators Cattani and Centanni, thought they
could overthrow the rule established by Ehrlich. They believed that the
male rabbit, vaccinated against rabies, was capable of transmitting its
immunity to its progeny. Charrin and Gley[754] expressed the same
opinion as regards animals of the male sex vaccinated against
experimental pyocyanic disease. But the very precise experiments of
Wernicke[755], Vaillard[756] and Remlinger[757] upon a whole series of
infective diseases and intoxications, such as diphtheria, cholera
peritonitis, anthrax, experimental typhoid septicaemia, etc., showed
conclusively the correctness of Ehrlich’s results. Well-vaccinated
males, even when hypervaccinated, never transmit their immunity to their
descendants. This acquired property, like so many others, is not
hereditary in the strict sense of the word. The females, on the other
hand, with rare exceptions, transmit their acquired immunity to their
young, but this transmission can in no way be attributed to the ovum; it
is here, then, no longer a question of hereditary immunity properly so
called. According to Ehrlich the female furnishes in her blood plasma
the antitoxin which passes into the circulation of the foetus. In all
respects this is allied to the so-called passive immunity (or antitoxic
immunity of von Behring). It is due entirely to the direct introduction
of antitoxin, manufactured by the cells of the maternal organism, into
the body of the progeny. The living elements of the foetus play no part
in it, and it is for this reason that the antitoxins and immunity in the
new-born animal disappear so very rapidly,—within a few weeks after
birth. Wernicke accepts the views of Ehrlich in their entirety. He found
that the immunity of female guinea-pigs was transmitted to the new-born
animal; but this hereditary transmission was exhausted in a single
generation; it was not found in the second generation. Wernicke was able
to demonstrate that the refractory condition in guinea-pigs, born of
mothers vaccinated against diphtheria, persisted for three months.
Vaillard found that it was retained in certain cases for an even longer
period,—up to the fifth month. On one occasion he even observed the
transmission of the immunity to a second generation. A female
guinea-pig, born of a mother immunised against tetanus, gave birth to a
young one which, when tested a month after birth with a ten times lethal
dose of the toxin, contracted merely a slight tetanus.
From this fact, as well as from the fact that the immunity of the young
ones born of vaccinated mothers persists longer than does that conferred
by the injection of antitoxic serum, Vaillard concludes that there
exists a kind of hereditary immunity which is “fixed” by the cells. He
thinks that not only the antitoxins and other antibodies but also
certain living elements, especially the leucocytes, are able to pass
from the maternal blood into that of the foetus and to transmit to it
the properties acquired by the mother. At this point we may recall the
facts demonstrated by von Behring and Ransom that antitoxin persists
much longer in the blood of an animal when it is introduced with the
serum of the same species. (We have described these observations in
Chapter XII.) Now, since in hereditary transmission the antitoxin passes
over with the blood plasma of the same species, whilst in the
experiments on antitoxic immunity it is generally injected with the
serum of a different species, it is easy to understand that the former
should persist for a longer period than the latter. It is, therefore,
very probable that this immunity of the offspring from vaccinated
mothers is not in any way a case of true hereditary immunity, but is due
simply, as maintained by Ehrlich, to the passage of ready prepared
antibodies from the mother to the foetus. In the immunities against
diphtheria and tetanus we have the direct passage of antitoxins; in
transmitted immunity against infection by the vibrios of Koch and
Gamaleia, so carefully studied by Vaillard, we have, very probably, the
passage of corresponding fixatives from the mother to the foetus.
[Sidenote: [470]]
Dzierzgowsky[758] in a recent study on hereditary immunity denies the
passage of antibodies and toxins through the placenta. He thinks that
the foetus does not acquire its immunity through the blood of the
mother, but at a very much earlier period. The ovum contained in the
Graafian follicle would, according to this observer, come in contact
with a fluid very rich in antitoxin, whence it might imbibe the
necessary amount of this antibody to ensure the immunity of the new-born
animal. Dzierzgowsky bases this opinion on experiments in which
antidiphtheria serum injected into pregnant goats and dogs did not
produce any antitoxic power in the blood of the foetus. But in the
experiments on these animals the injections consisted of the serum of
the horse—a different species. This must modify, profoundly, the
conditions of the passage of the antitoxin through the placenta.
Dzierzgowsky made a single experiment upon a mare, immunised with
diphtheria toxin, and its foal. Whilst the serum of the former was
markedly antitoxic, that of the foal did not possess this property in
the slightest degree. Hence the conclusion that the antitoxin of the
mother had not passed into the blood of the foetus. But the blood of the
foal was not withdrawn until some ten months after birth. Now, as the
so-called hereditary immunity only lasts for a very short time
Dzierzgowsky’s experiment supplies no evidence against the passage of
antitoxin through the placenta.
In order to prove that the immunity against toxins may really be
acquired by the ovum, Dzierzgowsky[759] carried out a series of
experiments with the eggs of fowls immunised against diphtheria toxin.
The yolk of the egg, in accordance with the discovery made by F.
Klemperer, contained antitoxin; and this antitoxin passed into the blood
of the hatched chickens. These facts, though in themselves very
interesting, cannot be used to refute the view that antitoxins pass
through the mammalian placenta. It is true that this view is perhaps not
yet completely proved, but it accords well with all the known facts.
Thus, the frequent presence of diphtheria antitoxin in the blood of
new-born infants is explained much better on the assumption that it
passes through the placenta than that it is due to an immunisation of
the ovum surrounded, in the Graafian follicle, by antitoxic fluid. It is
difficult to conceive how this immunity could be so fully retained
during the nine months of pregnancy.
[Sidenote: [471]]
In support of his interpretation of the phenomenon of immunity
transmitted by the mother to her progeny Ehrlich invokes his beautiful
discovery of the immunity conferred by the maternal milk. A vaccinated
female is capable of communicating to her young a portion of the
antibodies manufactured in her organism, not only by the blood channels,
but also, in certain cases, by the milk with which she feeds her young.
[Sidenote: [472]]
The transmission of antitoxins by milk has been demonstrated by Ehrlich,
and this has since been confirmed by many observers (see Chapter XII).
When Ehrlich found that the immunity of the progeny is retained for a
longer time than is that which is conferred by injections of antitoxic
serum, he conceived the idea of investigating whether the cause of more
prolonged retention did not reside in the transmission of the maternal
antitoxin by the milk. With the object of verifying this he took, at the
moment when they had given birth to young, unvaccinated mice and mice
that had been vaccinated against various toxins (ricin, abrin,
tetanotoxin). He so changed the progeny that the vaccinated mothers
nourished the young born of the normal mice, whilst the normal mothers
suckled the offspring of the vaccinated mice. The result of these
ingenious and delicate experiments fully confirmed his anticipations.
The vaccinated mice transmitted their immunity not only to the young
ones to which they had given birth but also to those they had merely
nourished with their milk. This observation proved, to demonstration,
that the antitoxins are absorbed by the alimentary canal, a very
important fact from several points of view. Later researches have shown
that only very young mice are capable of assimilating antitoxin through
the intestinal wall. Adult mice, fed by Ehrlich with quantities of
antitoxic milk, acquired neither immunity nor any antitoxic property of
the blood. Later, Vaillard (_l.c._) was able to show that even the young
of other species of animals such as the guinea-pig and the rabbit are
incapable of appropriating the antitoxins from milk by the alimentary
canal. He repeated Ehrlich’s experiments with new-born guinea-pigs and
rabbits which he caused to be suckled by mothers vaccinated against
tetanus. These young rodents, so treated, were found to possess no
immunity whatever; they were not able, therefore, to absorb the
antitoxin found in the milk of their nurses. Remlinger (_l.c._) made
similar experiments with young guinea-pigs and rabbits suckled by foster
mothers which had been vaccinated against the coccobacillus of typhoid
fever. As in Vaillard’s experiments, the result was negative, the milk
of the foster mother did not communicate any refractory condition to the
nurselings. Remlinger drew the same conclusion from his researches on
the transmission of the agglutinative property of the body fluids. When
female rabbits and guinea-pigs are vaccinated during gestation the young
ones acquire, along with the immunity against the typhoid coccobacillus,
a certain agglutinative power of the blood serum. When, however, these
vaccinated females suckle the progeny of non-vaccinated mothers the
agglutinative power of the milk of the foster mother never passes into
the blood of the nurselings. Some years before this, Widal and
Sicard[760] had demonstrated the same fact that young rabbits and
new-born kittens, when fed with agglutinative milk, acquired no power of
agglutinating the typhoid coccobacillus. They agreed with Ehrlich,
however, that the blood serum of young mice fed with agglutinative milk
acquired the power of agglutinating the typhoid micro-organism.
[Sidenote: [473]]
As it was important to determine whether the human subject was capable
of acquiring a certain immunity by absorbing antibodies contained in the
milk, the study of this question was taken up, especially from the point
of view of agglutinative power. Although the relations of this
agglutinative power with immunity are very problematical it would be
interesting, bearing in mind the analogy between the agglutinative,
antitoxic, and protective properties, to ascertain whether the ingestion
of agglutinative milk can confer any agglutinative property on the blood
serum. Numerous researches in this direction were carried out in
connection with typhoid fever. Widal and Sicard (_l.c._) caused a person
to drink daily (for a period of three weeks) half a litre of milk coming
from an immunised goat, a milk which powerfully agglutinated the typhoid
coccobacillus. The blood, examined on several occasions, never showed
the slightest agglutinative power. This experiment goes to prove that,
in the adult human subject, the agglutinin does not pass from the
alimentary canal into the circulation. May it not perhaps be otherwise
in infants which are fed on milk only? An observation by Landouzy and
Griffon[761] seemed to confirm this supposition. They first demonstrated
the agglutinative power of the blood serum in a woman who had contracted
typhoid fever three months after her lying-in. Being a mild attack the
woman continued to suckle her child during the whole course of the
fever. On examination of the blood of the infant it was found that the
serum agglutinated the micro-organism of typhoid fever. These observers
did not measure the agglutinative power of the blood, either in the
infant or in the mother. This omission deprives their observation of
value since it is now recognised that normal human blood fairly
frequently exhibits some power of agglutinating the typhoid
coccobacillus. For diagnostic purposes it is necessary, therefore,
always to measure this power in order to be sure that it is higher than
that of the normal blood.
It is all the more difficult to draw any positive conclusion from the
observations of Landouzy and Griffon because in several similar cases
the result has been entirely different. Thus Achard and Bensaude[762]
have shown that the blood of an infant, suckled by a nurse attacked by
typhoid fever and whose serum became distinctly agglutinative, was
incapable of bringing about clumping of the typhoid coccobacilli.
Schumacher[763], working in Fraenkel’s laboratory in Halle, studied a
case with very great care. A woman gave birth at full term to an infant
whose blood serum exhibited a certain agglutinative power. The mother
suckled the infant from its birth. Although her milk manifested a very
considerable agglutinative property, the blood of the child exhibited
not only no increase in agglutinative power but a marked diminution. The
agglutinin of the maternal blood had not passed into the fluids of the
child.
[Sidenote: [474]]
From the point of view of the impossibility of acquiring immunity by
suckling, therefore, the human subject may be grouped with the
guinea-pig, rabbit and cat. Up to the present the mouse is the only
exception. It would be very important, with the object of finding a
means of communicating immunity by way of the intestine, to study the
precise conditions which govern this phenomenon. In hereditary immunity,
or rather in what appears to be such, those cases where the new-born
animal exhibits a resisting power induced by the vaccination to which it
has been subjected in the womb of the mother must be borne in mind. We
have already cited the example given by Remlinger of rabbits and
guinea-pigs born refractory against the typhoid coccobacillus, which had
been injected into the mother animals. In those cases where the
vaccination of the mothers has been carried out during the period of
gestation the immunity of the young ones is more permanent than when it
was completed before that period. Into this same group come those cases
where women, vaccinated during the course of pregnancy, give birth to
infants refractory to vaccine. Similar facts have been reported by
veterinary surgeons with regard to sheep-pox; Arloing, Cornevin, and
Thomas[764] have offered similar demonstrations with regard to
symptomatic anthrax.
These results may be more or less closely associated with those where
the child attacked by an infective disease immunises the mother. Such
facts are rare. We know that a healthy mother may give birth to a
syphilitic child; the affected father introducing the virus with the
sperm, the contaminated foetus contracts the disease and the new-born
infant is syphilitic. According to Ehrlich and Hubener (_l.c._ p. 54),
the foetus instead of infecting the mother sets up in her a refractory
condition. It must be confessed that as yet we do not understand the
mechanism of this immunity; but in any case we have here to do with an
example of immunity naturally acquired under very special conditions.
Here again must be recognised another form of immunisation:—where the
child born of a syphilitic mother remains healthy and contracts syphilis
neither by the breast nor through the kisses of the mother. Here,
undoubtedly, we have an immunity against syphilis acquired in the womb
of the mother, who may, however, readily communicate her disease to
other persons by means which are without effect on her own infant. This
example comes under the law of Profetta. Here again the mechanism of the
acquired immunity is absolutely unknown.
[Sidenote: [475]]
It must be admitted that, generally, we are still very imperfectly
informed concerning immunity as acquired by natural paths. In cases
where this immunity is developed as the result of an attack of an
infective disease the phenomena observed closely resemble those that
have been observed after vaccination by living, fully active, or
attenuated viruses, by micro-organisms which have been killed, or by the
products of these micro-organisms. These vaccinations which bring about
isopathic (von Behring) or active (Ehrlich) immunity give rise to
transient and mild diseases and are confined almost completely to the
diseases contracted by natural means which terminate in recovery and
give rise to a refractory condition. The immunisation of the foetus
comes into the same series.
On the other hand, the immunity which was believed to be hereditary and
which results merely from the direct passage of the antibodies of the
blood or of the milk of the mother to the foetus and to the child come
into a group of cases characterised by what Ehrlich has termed a
condition of passive immunity. We have already discussed (Chapter X) the
thesis that this term “passive” is applicable only in rare cases. Most
frequently it is necessary that the living cells of the organism which
receives the antibodies—antitoxin, fixatives or others—should contribute
their quota in order to ensure the refractory condition. This rule is
undoubtedly applicable to the examples of immunity acquired by the
new-born progeny of unaffected mothers.
CHAPTER XV
PROTECTIVE VACCINATIONS
Vaccinations against I. Small-pox.—II. Sheep-pox.—III. Rabies.—IV.
Rinderpest.—V. Anthrax.—VI. Symptomatic Anthrax.—VII. Swine
Erysipelas.—VIII. Pleuropneumonia in the Bovidae.—IX. Typhoid
Fever.—X. Plague.—XI. Tetanus.—XII. Diphtheria.
[Sidenote: [476]]
In the preceding chapters I have attempted to present to the reader a
general view of the phenomena of immunity against infective
micro-organisms and against their toxic products. I shall now attempt to
give a review of the facts acquired in connection with the prevention of
the infective diseases of man and of the chief domestic animals by means
of vaccination. Vaccinations as we know can be carried out either with
viruses the constituents of which have not as yet been recognised, with
micro-organisms grown on various nutrient media, with virulent or
attenuated micro-organisms, or with microbial products deprived of the
micro-organisms by which they have been built up. In addition to these
methods we may vaccinate with protective or antitoxic serum and other
body fluids, with normal serum, or with a whole series of fluids not
excepting water.
[Sidenote: [477]]
I. _Vaccination against small-pox._—We naturally commence the series
with vaccination against small-pox, which is one of the oldest and one
of the best known, having been practised in every country in Europe for
more than 100 years. Small-pox, a very contagious and fatal malady, was
very rife in the 18th century. Large cities like London and Paris were
severely affected. One-tenth of the total mortality was due to this
disease. According to statistical information, very exact for that
epoch, the deaths from small-pox in London during the course of the
second half of the century (1751–1800) numbered more than 100,000
(102,112) persons. During the first half of the same century this
disease caused great ravages in France, especially in Paris, where,
according to certain statistics (Haeser), about 14,000 persons died in
1716.
[Sidenote: [478]]
Variolisation or “inoculation” coming to Europe from the East, had come
into extensive use when, at the end of the 18th century, the discovery
was made that cow-pox, the varioliform disease of the Bovidae, produced
in persons who milked cows suffering from this eruption an immunity
against small-pox. This idea, popular in origin, was known to breeders
in England, France, Germany, and Holland; we have thus an indication
that this knowledge must date from a fairly distant period. Jenner gave
the question a scientific and experimental basis, and it was only after
his intervention that vaccination by the contents of the pustules of
cow-pox began to spread more generally. During the 19th century an
immense amount of material bearing on this question was collected; we
have thus been enabled to attain absolutely exact results, and that in
spite of the very imperfect state of our knowledge on the etiology of
small-pox and of cow-pox. Long ago Chauveau[765] demonstrated that the
virus of these diseases must be organised, because that of the vaccine
would not pass through a filter. This organism has been carefully
sought, but sought in vain in spite of all improvements in
microbiological methods. It was thought that the cocci so often found in
the contents of the vaccinal pustule was the specific micro-organism of
cow-pox. Such was the opinion of the illustrious botanist Cohn[766]. It
was soon shown, however, that this was not the case. The cocci,
principally staphylococci, are “secondary” micro-organisms which may be
absent from the vaccine without its losing anything of its action. A
search was then made for the micro-organism of the vaccine among the
protozoan organisms. L. Pfeiffer[767] announced the discovery of a
species of vaccinal _Amoeba_. Guarnieri[768] has even described various
stages in the reproduction of this hypothetical parasite; but
Salmon[769] demonstrated, in a work carried out in the Pasteur
Institute, that we had here to deal merely with leucocytes which had
entered epithelial cells and had there undergone marked degeneration.
Funck[770] thought that he was able to confirm the discovery of the
sporozoon of vaccinia, but his error was easily demonstrated
(Podwyssozki and Mankowski)[771]. Up to the present, then, we have no
knowledge of either the micro-organism of small-pox or of that of
vaccinia. We still employ, as formerly, the virus taken from the
vaccinal pustule. Even the relations which exist between the two viruses
and the two diseases which they have set up have not yet been settled.
Several authors believe that the bovine disease is only a modified and
attenuated form of human small-pox; whilst others maintain that we have
two very different exanthemata, one of which—cow-pox—is capable of
setting up immunity not only against itself but also against small-pox.
[Sidenote: [479]]
For a long time, in order to vaccinate against small-pox, the contents
of the vaccinal pustules which formed on the human subject after an
original inoculation of the virus of cow-pox were employed. But a number
of cases of infection by syphilitic virus and certain other accidents
caused this method to be abandoned. A number of years ago, however,
there spread throughout Europe and into several countries of other
continents another method, which consists in vaccination by “animal
lymph,” that is to say, by the contents of pustules developed on the
skin of the calf. This method was first carried out at Brussels in 1868,
under the direction of Warlomont, at the Institute founded by the
Belgian Government for the preparation of vaccine. The original virus
came from a genuine case of cow-pox and has since been kept up by
uninterrupted passage from calf to calf. The virus is introduced into
the shaved skin of the region between the groin and the udder as far
forward as the umbilicus. It is inoculated superficially into the
epidermis by cuts one centimetre long. At the points of inoculation
characteristic pustules develop; from these the vaccinal content is
withdrawn, on the fifth day in summer or the sixth in winter. The
contents are removed by pressure and by scraping the pustules. The
scrapings are mixed with water and glycerine. The vaccine thus prepared
is put into small glass tubes which are sealed at both ends. This
method, with slight modifications, has extended to many other countries,
and is carried out either in private establishments or in State
institutions as in Germany. For the purpose of purifying the vaccine it
is diluted and then allowed to sediment or it may be subjected to
centrifugalisation. The object of these measures is to rid the “lymph”
of the micro-organisms which accompany it. This object is, however, only
imperfectly attained and is moreover accompanied by an attenuation of
the vaccinal action. On the other hand, precautions are taken to ensure
all possible cleanliness during the operation of inoculation and whilst
the calves are under treatment. Thus, great care is taken to disinfect
the area of inoculation with alcohol or some other antiseptic and to
dress the pustules during the course of their development. Similarly the
arms of the patient to be vaccinated are well washed; following in this
the rules of asepsis rather than of antisepsis for fear that the
vaccinal virus might be destroyed by antiseptic substances. Various
instruments are made use of for vaccination and care is taken to
sterilise these before they are used. Sometimes the lancet is used,
sometimes “plumes à vaccin” or vaccinostyles, or a bistoury of
iridio-platinum (Lindenborn) etc.
When the vaccine is of good quality and the operation of vaccination is
well done, there is no doubt as to the protective result obtained
against small-pox. The observations that have been collected for a great
number of years past, in many countries, place this beyond doubt. There
are, indeed, statistics from which it is impossible to draw any precise
conclusions because they are founded upon too scanty figures or deal
with conditions that are too complex. This is the case with the Swiss
vaccinations. Certain cantons (such as Zug and Uri) have made
vaccination obligatory, whilst others (Bern, Zurich, Lucerne, etc.) some
years ago abolished the law which compels the vaccination of all
children in infancy. It happened that for some years small-pox had more
victims in the cantons of the first group than in those of the second.
The opponents of antivariolic vaccination attempted to use this as an
argument against the utility of this method. But a more detailed study
of the facts clearly shows that it is impossible to draw from it any
conclusion whatever. Even in those cantons where vaccination is supposed
to be compulsory this law is not carried out rigorously, and the number
of persons vaccinated often does not exceed that in the cantons where it
is not obligatory.
[Sidenote: [480]]
In order to gain some idea of the utility of vaccinations we must
collect statistics on a much larger scale than are those obtainable from
the Swiss cantons. Germany furnishes such statistics. Compulsory
vaccination was introduced there more than a quarter of a century ago
(1874), and statistical information has been collected with great care.
With the exception of a slight increase during the period from 1879 to
1885 small-pox has diminished progressively since the proclamation of
the new law, and has become so rare that in 1897 there were only 5 fatal
cases in the whole German Empire. In the space of 13 years (1886–1898),
in a population which embraces two-fifths of the total inhabitants of
the German Empire, there were altogether five fatal cases of small-pox
occurring in persons who had been successfully revaccinated. Moreover,
the majority of the cases of small-pox occurred in the maritime towns or
in the vicinity of the frontier of the Russian Empire.
Specially favourable results have been obtained in the German army, in
which, even before the law of 1874, vaccination was compulsory. In 25
years there occurred in the Prussian army only two cases of death from
small-pox. In summing up the statistical data on vaccination
Kübler[772], from whom we have borrowed the above statements, expresses
himself as follows: “The history of small-pox must in all cases register
the fact that this dreaded disease has, as the result of general
vaccination, not only become rare in the German Empire but that it has
almost completely disappeared” (p. 365). The example of Germany
encouraged several other countries to introduce compulsory vaccination,
and Roumania, Hungary, and Italy have in turn promulgated similar laws.
Here also it was not long before satisfactory results were obtained. In
Italy especially the mortality from small-pox has largely decreased in
recent years.
[Sidenote: [481]]
In England, where compulsory vaccination was introduced some time ago,
it was abolished in 1898. As the opposition of the people became more
manifest, the law, although it continued to exist formally, was carried
out very imperfectly. The number of unvaccinated children had gradually
increased in such a fashion that in London itself in 1897–1898 it
attained the proportion of 24·9%, whilst in certain provincial districts
it has oscillated between 78·4 and 86·4%. Under these conditions, the
abolition of the law of compulsory vaccination was only the legal
sanction of an accomplished fact. According to the details which have
been supplied to me by the Jenner Institute in London (which has taken
in hand the distribution of vaccine), vaccinations since they are no
longer compulsory have become more frequent in England, and the quantity
of vaccine distributed has increased considerably. This quantity,
however, is not adequate because small-pox has again made its appearance
in London in the form of a pretty serious epidemic[773].
In France a law is being framed which will render infant vaccination
compulsory. Up to the present this has not been the case, and small-pox
from time to time causes considerable ravages, as we may see at this
moment in Paris. During recent years the mortality from small-pox in
France has been from 90 to 100 times greater than in Germany. It is
greater amongst the female population than amongst males; this
constitutes a fresh argument in favour of vaccination. Although not
compulsory for the whole of the French population, it is so for soldiers
and for children who carry on their studies in schools, and it is for
this reason that small-pox is rarer amongst males. The most complete
demonstration of this is found in the incidence of small-pox in the
French army. In spite of a less numerous contingent of troops
(451,941–457,677) the mortality from small-pox was greater during the
period when vaccination was not yet carried out generally (1885–1887)
than during the period (1889–1896) when it was rigorously enforced on a
much larger number of soldiers (524,733–564,643). From 13·6 fatal cases
per year in the first period the annual figure fell to 6.
[Sidenote: [482]]
It follows, when we take into consideration the whole of the very
numerous data at our disposal, that the usefulness of vaccination
followed by revaccination after some (5–7) years cannot be seriously
called in question. As to the inconveniences that may be caused, they
are observed in very rare cases, and then most frequently when impure
vaccines are used, or when the vaccinated skin becomes contaminated.
According to the German statistics there were registered in the space of
13 years (1885–1897), in 32 millions of vaccinations, 113 fatal cases as
the result of infection of the wounds. In forty-six of these it was
proved that the small wound had been contaminated by impurities
introduced by those attending on them. The remaining 67 fatal cases
could be ascribed to the vaccines themselves. We must, however, still
regard these cases as too numerous and as being readily avoidable by the
adoption of rigorous asepsis. To sum up, the anti-variolous vaccination
by the virus of cow-pox constitutes a method of very great value in the
prevention of one of the most dreaded of infective diseases, but it is
evident that improvement can still be made in this branch of practice.
If science should succeed some day, as we may be permitted to hope it
will, in finding the micro-organism of vaccinia and of small-pox, and it
should succeed in growing it in pure media, it might react very
beneficially on the practical application of vaccination. The more
simple the methods, the less chance will there be of the occurrence of
those unsuccessful cases which, even now, are rare exceptions.
II. _Vaccinations against sheep-pox_ (_la clavelée_).—Sheep-pox, being a
disease very similar to human small-pox and very serious from an
economic point of view, the idea was conceived of fighting it by methods
similar to those used against small-pox. Since the 18th century there
has been practised on a large scale the artificial immunisation of sheep
by the inoculation of the virus of the sheep-pox (clavelisation) just as
the variolisation of man was practised before the discovery of cow-pox.
For this purpose it was necessary to have a considerable quantity of
virus; this was obtained by inoculating sheep-pox into the skin of
sheep. This inoculation was effected either with a lancet or, according
to Soulié’s method[774], by means of a Pravaz syringe. The pustules,
developed under these conditions, were generally of large size and
capable of furnishing a considerable quantity of the virulent lymph
(_claveau_) used for immunisation. This fluid, when gathered pure, and
kept in a closed vessel protected from light and heat, retains its
virulence for a long time: unlike what is observed in the case of
vaccine, the addition of glycerine destroys the virulence of the lymph
pretty quickly. For use, the lymph is diluted with ten times its volume
of 2% borated water; the fluid thus obtained is inoculated into the
extremity of the tail or of the ear; usually a pustule, which remains
single, is formed at the point of inoculation. Clavelisation rarely sets
up a generalised eruption which is always serious and sometimes fatal.
[Sidenote: [483]]
In France the law ordains the clavelisation of flocks in which sheep-pox
appears; but it interdicts its practice in unattacked flocks;—it is easy
to understand the reason for this; in infected flocks all, or almost
all, the sheep, gradually become ill and the illness lasts for some
time; clavelisation diminishes both the duration and the gravity of the
disease; the mortality that it causes, although sometimes very great,
the French sheep being very susceptible to sheep-pox, is always much
less than that due to a natural contagion;—on the other hand, the
clavelisation of a healthy flock, beyond the fact that it may cause
considerable losses, is attended by the special danger that it creates
centres from which the contagion may invade all the flocks of the
district.
But there are countries in which protective and general clavelisation
does not present these inconveniences—the countries where the disease is
endemic and where the sheep are very resistant to the action of its
virus. This is the case in Algeria; sheep-pox exists there permanently
without doing much damage; but the Algerian sheep, which take sheep-pox
without suffering any apparent illness, communicate to French sheep
amongst which they are introduced a very malignant sheep-pox which
sometimes kills as many as 50 per cent. of the flock. This explains and
justifies the measures recently taken by the Minister of Agriculture,
forbidding the importation of Algerian sheep into France unless they
have been vaccinated at least a month previously.[775]
In many other countries clavelisation is likewise enacted, being
authorised in cases where it may be very useful and interdicted in other
cases. In certain countries, _e.g._ Germany, Holland, and Denmark,
clavelisation can be put into force by the Government, which alone has
the right to authorise it under certain circumstances.
[Sidenote: [484]]
III. _Antirabic vaccinations._ Vaccination against rabies has this point
in common with those against small-pox and sheep-pox, that it is
effected with a virus whose micro-organism is as yet unknown. On the
other hand, it is distinguished by its efficacy during the incubation
period. When persons are vaccinated during the incubation period of
small-pox, or sheep during the same period of sheep-pox, the
vaccinations by vaccine and _claveau_ are incapable of arresting the
disease and the infections continue to follow their normal course. When,
on the other hand, we vaccinate men or animals that have been bitten by
mad animals or inoculated with the rabic virus by other means, the
antirabic vaccination, with rare exceptions, prevents the development of
rabies. This vaccination, taking advantage of the length of the
incubation period of rabies, constitutes, therefore, a special type,
intermediate between protective vaccination, properly so called, and a
therapeutic method of treatment.
It is to Pasteur that science and humanity owe the invention of this
method. Aided by his collaborators, especially by Roux, he established
in the first place a whole series of important facts on the subject of
the rabic virus and of experimental rabies. He then set himself to
elaborate a practical method capable of preventing the manifestation of
the disease in dogs inoculated with rabic virus and in men bitten by mad
animals. He succeeded in solving this problem in 1885.
Pasteur’s antirabic vaccines are prepared from the spinal cords of
rabbits that have died of experimental rabies as the result of the
inoculation of the virus bearing the name of “fixed virus.” Prepared in
the laboratory, this virus presents the characteristic feature that when
inoculated under the dura mater of rabbits it sets up in them the first
rabic manifestations after an incubation period of six or seven days.
The disease soon assumes the typical paralytic form which lasts several
days. Whilst the period of incubation presents only very limited
variation, the time of death is subject to much greater variation,
especially according to the season of the year. Sometimes the rabbits
will die on the eighth day after the inoculation of the virus: but death
may be delayed one or two days, rarely more.
It is necessary to wait for the natural death of the mad rabbits before
the spinal cord is extracted, and not to kill them before this term, for
it is only during the final moments of life that the rabic virus is
abundant and is distributed uniformly through the whole substance of the
organ. After removal from the vertebral canal the cord is suspended in
glass vessels containing solid potassium hydrate at the bottom. A whole
series of cords so prepared are then kept in a dark chamber heated to
23° C. or thereabouts. The progressive desiccation which the cords
undergo under these conditions diminishes their virulence. At the end of
several days of this treatment the desiccated cord, instead of producing
rabies in 6–7 days in rabbits inoculated under the dura mater by
trepanning, induces it after longer periods of incubation. Finally, the
cords do not produce even the slightest symptoms of the disease.
[Sidenote: [485]]
The fundamental basis of the Pasteurian method consists in the fact that
the desiccated cord, inoculated as an emulsion below the skin of
animals, produces in them a complete and permanent immunity against
inoculation of the most powerful rabic virus beneath the dura mater.
This experiment, frequently repeated on rabbits and dogs, justified
Pasteur in 1885 in attempting the first vaccinations of persons bitten
by rabid animals, especially dogs. The encouraging results of these
early attempts led to the foundation of the Pasteur Institute in Paris,
devoted, in part, to antirabic vaccinations. Shortly afterwards,
antirabic Institutes were founded in many other European towns, and
later in North and South America, in Indo-China, the East Indies, and in
Africa. At present there are in France six such Institutes (Paris,
Lille, Marseilles, Montpellier, Lyons, Bordeaux), in Russia 9, in Italy
6, etc. The last of these institutions founded in Europe is that of
Berlin, where it forms a branch of the Institute for Infective Diseases
carried on under the direction of Robert Koch. The foundation of an
antirabic institute in Berlin had a very important significance from
several points of view. In the first place, it indicates the definite
acceptance of the Pasteurian method, a method which has been discussed
so long and so keenly. Secondly, it proves that even in a State where
there is a highly organised sanitary police, antirabic vaccinations may
still be of great service.
Seeing that it was in the Pasteur Institute of Paris that the method of
antirabic vaccinations was first elaborated and that it has undergone a
very prolonged ordeal, the method there used serves as a model for the
practice of almost all other institutes. Although in some of them
methods which differ more or less from the original may have been
introduced, the fundamental principle upon which they are based remains
the same.
[Sidenote: [486]]
According to the Pasteurian method properly so called the vaccinal
inoculations are commenced with cords that have been dried for 14 days
and have thus lost their virulence. A piece five millimetres long is
pounded up with very weak veal broth. Up to 3 c.c. of the emulsion thus
prepared is injected below the skin of the flank. The same day a second
injection of the same quantity of an emulsion of a cord which has been
drying for 13 days is made at the corresponding position on the opposite
side. Each day an advance is made by injecting emulsions of cord which
are increasingly fresh and the treatment is concluded by the
introduction of virulent cords, which have been kept at 23° C. for 3
days only. The ordinary medium treatment lasts for 15 days. On the first
5 days two vaccine injections a day are made. On the last 10 days, when
gradually fresher and more virulent cords are employed, only a single
injection is made each day. The injections are made with syringes of the
Pravaz type and are carried out under conditions of rigorous
cleanliness.
If the bites are numerous, or if they are situated on exposed parts, the
treatment is prolonged for 18 days and is further distinguished in that
the cords of 4 and of 3 days are injected much more frequently.
In especially grave cases, when the bites are on the face and head, the
treatment extends over 3 weeks. A more rapid progress is made by making
four injections instead of two during the two first days; in this way a
greater quantity of the virulent cords is injected than in the first two
types of treatment.
The effect of the antirabic vaccinations is usually very good. During
the early years of their application the results were fully discussed
from all points of view, and no efforts were neglected of seeking out
objections of every kind. For the purpose of obtaining rigorously
accurate statistics a separate division was made, at the Pasteur
Institute, for the cases of persons treated after bites inflicted by
dogs whose rabic condition had been demonstrated experimentally (by the
injection of an emulsion of the bulb below the dura mater or into the
anterior chamber of the eye of the rabbit or guinea-pig). A second and
special set of statistics was drawn up of cases where the bites had been
inflicted by animals whose rabic condition had been recognised by
veterinary examination. Individuals bitten by animals that were simply
suspected to suffer from rabies were kept separate.
[Sidenote: [487]]
Thanks to this systematic classification we were able, at the Pasteur
Institute of Paris, to establish the fact that the antirabic
vaccinations performed on persons bitten by animals that were
undoubtedly mad resulted in an extremely low mortality from rabies.
Finding it impossible to attack these results, demonstrated with the
precision of a laboratory experiment, the adversaries of the Pasteurian
method alleged that, quite apart from any vaccination, the percentage of
cases of rabies in persons bitten by mad animals is not greater than
amongst the vaccinated. A hitch in the application of the new vaccinal
method soon demonstrated how entirely unfounded was this objection. At
the Bacteriological Institute of Odessa, founded in 1886, that is to say
almost immediately after the Paris Institute, the first attempts at
vaccination were followed by a mortality from rabies of 5·88 per cent.,
a figure incomparably higher than that of the Paris Institute. Analysing
the probable causes of this want of success it was found that the
Russian rabbits, being much smaller than the French ones, furnished far
too small an amount of vaccinal matter. This being the case, the
introduction of a more intensive treatment was sufficient to cause the
mortality to drop suddenly to 0·8 per cent. This fact, added to so many
other proofs, finally convinced the most sceptical and brought about a
general acceptance of the Pasteurian method.
In course of time the number of cases observed has become very
considerable and the experience gained in the manipulation of this
method very wide. The improvements made in the details of the vaccinal
practice have brought about a progressive diminution in the mortality
amongst the persons treated. From 0·94 per cent. in 1886 the mortality
(counted from the 16th day after the completion of the vaccinations)
fell in 1897 to 0·39 per cent., in 1900 to 0·28 per cent. In the space
of 15 years (1886–1900) there have been treated in Paris 24,665 persons,
of whom 107 died from rabies, giving an average of 0·43 per cent.[776].
The greatest mortality was registered during the early years of the
application of the method, and the rate of the later year’s (1896–1900)
oscillated between 0·39 per cent. and 0·20 per cent.
The results obtained in the majority of the other antirabic institutes
corroborate those of the Pasteur Institute of Paris. Thus, according to
the latest statistics of the St Petersburg Institute[777], the
mortality, in 1899, among persons who had completed their vaccinations,
was about 0·5 per cent. At Berlin[778] there were treated during the
same period 384 persons, of whom 2 died from rabies during treatment,
whilst a third succumbed on the 14th day after the close of the
vaccinations. Only this latter case ought, according to the principles
generally accepted, to be counted as an unsuccessful case, this would
give a mortality of 0·26 per cent.
Quite recently, the antirabic treatment has been so reinforced that the
treatment terminates with the injection of cords desiccated for two days
or even one day only. The results of this intensive treatment have not
yet been reported upon.
[Sidenote: [488]]
According to the statistics of the Berlin Institute rabies is far from
being so rare in Germany as was, at one time, generally supposed. During
the year 1899 its presence was demonstrated, by the experimental method,
in 206 dogs coming from various districts. It is in Silesia, Western
Prussia, and Posen that rabies in dogs has been observed most
frequently.
Antirabic vaccinations have also been performed on herbivorous animals
(sheep, goats, cattle, and horses) which are immunised by means of
injections of the rabic virus into the veins, according to the method
suggested by Nocard and Roux[779], as the result of experiments made by
Galtier[780].
[Sidenote: [489]]
IV. _Vaccinations against rinderpest._ For some time attempts were made
to find a means of immunising the Bovidae and other ruminants,
susceptible to rinderpest, against this terrible disease, which causes
great ravages in regions where it is endemic and greater still in those
regions where it only appears in epidemic form. The good results
obtained from “clavelisation” suggested the idea of immunising against
rinderpest by the inoculation of the rinderpest virus, but all such
attempts gave unsatisfactory results, the inoculation setting up a
rinderpest as grave, and often as fatal as the natural disease. Only in
recent years have we succeeded in elaborating methods of vaccination
really capable of coping effectively with rinderpest. Koch[781] went to
Cape Colony, where this disease had recently appeared and had caused
enormous losses, with the intention of finding a practical method of
arresting the scourge. In spite of his technique and incomparable skill
he was as unsuccessful in finding the parasite of rinderpest as had been
other investigators. The micro-organism of this disease remains unknown.
It was necessary, however, to seek a remedy against it. Koch, studying
the properties of the bile of animals that had died from rinderpest,
recognised that the injection of this bile into normal animals conferred
upon them a fairly certain immunity, and this fact served as the basis
on which to work out a practical method of combating rinderpest on a
large scale. At first this method was received with much enthusiasm, but
experience soon demonstrated the inconveniences it often presented.
Kolle and Turner[782], who continued the researches on rinderpest in
Cape Colony, extolled Koch’s method at the commencement of the epidemic
with the object of establishing around the original disease centre an
unaffected zone which would interfere with the propagation of the
disease. They recognised, however, that this method could not be
employed generally, for the reason that it does not set up immunity
until the end of eight days, during which period the animals may
contract the disease. Further, it demands the sacrifice of a large
number of animals in order to provide the vaccinal bile required for the
vaccinations; finally, it confers an immunity of short duration only
(four to six months).
[Sidenote: [490]]