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any of these agents useful in the infectious diseases,

THE VACCINES

Before taking up the question of the use of vaccines in produc-
ing a nonspecific response it may be well to quote briefly from a re-
cent paper of Wright. Inasmuch as Wright has done more than any
other immunologist to emphasize the factor of strict specificity in
vaccine therapy, introduced the method of estimating such specific re-
sponse on the part of the patient by means of the opsonic index,
recommended the use of autogenous vaccines, etc., it is but fitting
to record his present attitude.

"Let me start quite at the beginning. Long after the principle of pro-
phylactic inoculation had established itself in medicine, it was accepted
that to inoculate microbes into the already infected system would be
as illogical as to instill further poison into an already poisoned system.
Pasteur was the first to teach, us here a distinction. He pointed out, in
connection with immunization against rabies, that a vaccine might legiti-
mately come into application in the incubation period. That was the be-
ginning of therapeutic immunization; and from that time forth it was
recognized that you may legitimately inoculate in the incubation stage,
and try to get in advance of the infection. But it was in everybody's
mind that immunization took 10 days to establish itself. When I showed
in connection with antityphoid inoculation that bactericidal substances
were very rapidly elaborated, it became plain that this involved shifting
the old landmarks and taking in further territory for therapeutic immuni-
zation, and one had to ask oneself all sorts of penetrating questions. One
had to ask oneself in connection with 'generalized infections' at what par-
ticular stage of the infection one was to regard the body as overmastered
by the bacterial poison, and incapable of further immunizing response.
Again, in connection with 'localized infections' one had to inquire whether
they should not be envisaged as general infections indefinitely arrested
in their incubation stage, and whether they might not, in consonance
with that, be brought within the sphere of inoculation.

"Further consideration suggested that the problem of therapeutic in-
oculation can be approached also from a point of view different from that
taken up by Pasteur. With respect to immunizing response, the body had
been visualized as a single and undivided unit. That is clearly erroneous.
One region of the body may be making immunizing response while the
other is inactive. For instance, in the stage of incubation it is presumably



THE NONSPECIFIC AGENTS 31

only the region which is actually harboring the microbe, and in the stage
of generalized infection it is presumably the entire body which is incited
to respond. And again, in localized infection we may making here some
reserves assume that we have only localized response.

"Placing ourselves at this point of outlook, therapeutic immunization
will, it is clear, be theoretically admissible so long as there remains in the
body any part which is not already making its maximum immunizing
response. And the program of therapeutic inoculation would accord-
ingly consist in exploiting in the interest of the infected regions of the
body the immunizing responses of the regions which are uninfected.

"Results of Vaccine Therapy

"Keeping that now in view, let me try, very briefly, to tell you what are,
in my view, the results which have been achieved by applying this thera-
peutic method. I can do that in a very few words.

"In every form of infection a certain quota of unequivocal successes
may be credited to the method, and especially successful results have been
obtained in furunculosis and acute inflammatory sycosis; in 'poisoned
wounds' meaning by that localized cellulitis set up by a streptococcus in-
fection; in streptococcal infections taking the form of lymphangitis, in
erysipelas; in tubercular adenitis, tubercular joint infections, tubercular
dactylitis, tubercular orchitis, and tuberculous infections of the eye, es-
pecially in phlyctenules of the conjunctiva; again in bronchitis, in chole-
cystitis, and gonorrheal rheumatism. The most dramatic and convincing
convincing because here no other therapeutic measures are employed as
adjuncts are the successes obtained in streptococcal lymphangitis, in
streptococcal cellulitis I am thinking of those cases which have already
been incised without striking benefit and in conjunctival phlyctenules.

"When we analyze the successes and failures* of vaccine therapy the
following points come out quite clearly:

"(1) Vaccine therapy is generally unsuccessful where the infection
as in phthisis is producing constitutional disturbance and recurring
pyrexia.

"(2) Vaccine therapy is also generally unsuccessful where we have to
deal with unopened abscesses, or sloughing wounds with corrupt discharges.

"(3) In long-standing infections vaccine therapy is much less success-
ful than in recent infections.

"To see what auxiliary measures should be applied in these cases, I
must take you back for a moment to the region of general principles. . . .

*I here, as clear thinking exacts, exclude from the failures of vaccine
therapy the failures of that preventive inoculation against individual infections
to which vaccine therapy is the usual precursor. The efficacy of such prophy-
lactic procedure is a question apart. But I may usefully point out to you
that the superior credit which attaches to antityphoid inoculation, and preventive
inoculation against infective diseases generally, as compared with preventive
inoculation against what I may call individual infections, is probably attributable
to the fact that, in the case where we are dealing with an infective disease, the
external circumstances are as favorable to success as they are in the case of
inoculation against "individual infections" unfavorable.



32 PROTEIN THERAPY

"Nonspecific Immunization

"In the foreground stands the question of nonspecific immunization.
That immunization is always strictly specific counts as an article of faith;
and it passes as axiomatic that microbic infections can be warded off only
by working with homologous vaccines; and that we must in every case
before employing a vaccine therapeutically, make sure that the patient is
harboring the corresponding microbes. I confess to having shared the con-
viction that immunization is always strictly specific. Twenty years ago,
when it was alleged, before the Indian Plague Commission, that anti-
plague inoculation had cured eczema, gonorrhea, and other miscellaneous
infections, I thought the matter undeserving of examination. I took
the same view when it was reported in connection with antityphoid inocu-
lation that it rendered the patients much less susceptible to malaria. Again,
seven years ago, when applying pneumococcus inoculations as a preventive
against pneumonia in the Transvaal mines, I nourished exactly the same
prejudices. But here the statistical results which were obtained in the
Premier Mine demonstrated that the pneumococcus inoculations had, in
addition to bringing down the mortality from pneumonia by 85 per cent,
reduced also the mortality from 'other diseases' by 50 per cent. From that
on we had to take up into our categories the fact that inoculation produces
in addition to 'direct' also 'collateral' immunization. This once recognized,
presumptive evidence of collateral immunization began gradually to filter
into our minds. Among, I suppose, many thousands of patients treated
by vaccine therapy in private and in hospital, it happened every now and
then that a patient was treated with a vaccine which did not correspond
with his infection, and that that patient indubitably benefited. Again,
it was not an uncommon experience for the subjects of a very chronic in-
fection (such as pyorrhea) who were treated first by a stock vaccine, and
afterwards with an auto-vaccine, to assert that they derived more benefit
from, and to ask to be put back upon treatment by the stock vaccine.

"From such cases hints are conveyed to us that there may exist a use-
ful sphere of application for collateral immunization; and that such sphere
may, perhaps, be found in those cases where the infection is of very long
standing, and where the patient has become very sensitive to, and has
probably come very near the end of his tether in the matter of immunizing
response to, the particular species or strain of microbe with which he is
infected. It will, with regard to such patients, be remembered that they
constitute the third of those three classes of cases to which I referred to
at the ouset of this lecture as very intractable to vaccine therapy.

"We are, however, here considering primarily the question of principle;
and in connection with this what is of fundamental importance is : that
we should discard the confident dogmatic belief that immunization must
be strictly specific, and that we should in every case of failure endeavor to
make our immunization more and more strictly specific. We should instead
proceed upon the principle that the best vaccine to employ will always be
the vaccine which gives on trial the best immunizing response against
the microbe we propose to combat.

"I would point out that this would almost certainly not involve any
revolutionary change in the accepted practice in either serum therapy or



THE NONSPECIFIC AGENTS 33

in prophylactic or ordinary therapeutic inoculation. But it would mean
taking into account in cases which proved intractable to treatment with
the homologous vaccine the possibility of seeking for collateral immuniza-
tion by inoculating a microbe or mixture of microbes other than that with
which the patient is infected. The trial of this procedure might perhaps
recommend itself where from the outset there is very little immunizing
response to the homologous vaccine, and also where, as in long-standing
cases of tubercule or streptococcus infection, the power of direct immuniz-
ing response to the corresponding vaccines is becoming exhausted."

This use of bacterial vaccines for "collateral immunization" as
Wright uses the term, or for nonspecific stimulation, is a modern con-
ception that dates practically from the work of Renaud and of Kraus.
The former used typhoid vaccine in the treatment of a number of non-
typhoidal diseases ; the latter treated typhoid patients with colon vac-
cine, and then proceeded to treat puerperal infection and other acute
infections with typhoid and colon vaccines with remarkable results.
Until this time the fear of overdosage had kept back investigation in
this particular field. The disastrous effects that had at times followed
the injection of tuberculin in tuberculosis had made a profound impres-
sion on medical men, and the emphasis placed on the negative phase of
the opsonic curve after vaccine injection had a similar effect. With
the introduction of the sensitized vaccines of the French school larger
doses came to be used, but here again a generalized reaction was
avoided. Occasionally one finds records of more heroic dosage and
cures following on general reactions; thus Szily cured a severe
ophthalmoblennorrhea with several large doses of gonococcus vaccine.

Following the publication of Kraus's results a large number of
observers have used heterovaccinotherapy in the treatment of dis-
eases of various kinds. The reaction of these various bacterial vac-
cines varies of course; in general, however, the following bacteria
have given results.

Typhoid Vaccine. The toxicity varies greatly with the age and
the strain. For convenience the vaccine is usually made up with 100
million organisms to the cubic centimeter, of this approximately 25
to 50 million may be given at the first dose if the particular vaccine
is not too toxic; great care must be observed. Typhoid vaccine is
followed by a prompt chill and temperature reaction, usually by a
leukocytosis. Headache is a common accompaniment.

Colon Vaccine. Colon vaccine is usually followed by a severe
reaction, which may, however, be delayed for several hours after the
injection. Headache is usually severe after several hours. It has
been used more frequently by English observers. The dosage should
not exceed 25 million for the first intravenous injection; for later re-
actions this may be increased.

Dysentery. Dysentery strains of all types when injected, both



34 PROTEIN THERAPY

subcutaneously or intravenously, are relatively toxic and resemble
typhoid and colon vaccines in their general effects.

Cholera, prodigiosus, proteus, and a number of other organisms
have been injected intravenously by various observers.

Meningococci. The dose used is usually about 100 million. The
injection is followed by a prompt chill that has its onset in from 15
minutes to one hour and lasts usually a half hour. Headache is com-
mon, nausea and vomiting quite exceptional. The temperature rise is
marked and reaches its maximum in from 6 to 8 hours. Herpes has
been commonly observed after the injections.

Gonococci. Dosage and reaction similar to the meningococcus.
Leukocytosis is well marked with both types of organisms and reaches
a maximum in from 5 to 7 hours. With the gonococcus vaccine herpes
is less frequent.

Streptococci. The streptococcus is evidently not as toxic as the
typhoid and colon bacilli, and the reaction is frequently delayed from
8 to 10 hours. A dosage of 100 million is usually followed by only
a mild temperature reaction. A chill is not so common and the leu-
kocytosis is lacking. The vaccine does not seem to be a good agent
for nonspecific stimulation.

Staphylococci. Similar in dosage and in reactivity to the strep-
tococcus vaccine. Followed by a leukocytosis of considerable extent
and has been found more useful than the streptococcus vaccine.

Pyocyaneus. Pyocyaneus Vaccine was one of the first used for
heterovaccinotherapy (by Rumpf in the treatment of typhoid in
1893). Its use has not been extensive enough to justify any con-
clusions as to its value. Dollken has used it in the treatment of
gummata.

Pneumococcus. In dosage and reaction similar to the strepto-
coccus, with a certain degree of latitude with different strains. The
leukocytic response is not marked ; indeed may at times be absent.

Influenza Bacilli. Influenza bacilli injected intravenously have
been given in doses of from 50 to 100 million organisms with relatively
little reaction on the part of the patient. There is as a rule no chill,
but the temperature response may be from 2 to 3 F. several hours
after the injection.

Diphtheroids. Both diphtheroids and diphtheria bacilli seem to
produce little reaction when injected intravenously. A dosage of
from 25 to 200 has been injected intravenously, followed after a long
latent period (10 hours) by some general reaction, slight chill, tem-
perature rise of from 1 to 2 F. and headache. Usually there is no
leukocytosis.

While all these organisms may produce some reaction, either
mild or severe, they are by no means quite comparable in their effect
on the leukocytic response. Schittenhelm, Weichardt and Greissham-
mer have called attention to some of the differences that exist follow-



THE NONSPECIFIC AGENTS 35

ing the intravenous injection of different kinds of bacteria, certain
organisms being followed by a prolonged leukopenia instead of a
leukocytosis, others producing myelitic stimulation, others a lym-
phatic stimulation, etc. Dollken in his recent discussion and study of
heterobacteriotherapy brings out the fact that the stimulation by
different bacteria may not be omnicellular, but rather selective; that
the clinical result, too, is by no means independent of the kind of
organism injected. Thus he found that while pyocyaneus vaccine
was effective in gummata, a pseudodiphtheria vaccine was quite
without effect. In neuralgia a prodigiosus vaccine gave an excellent
clinical result, while cholera and dysentary vaccine was not followed
by equal clinical improvement. In a like measure in the treatment
of acne neither prodigiosus nor pyocyaneus vaccine proved useful,
while the autogenous vaccine was promptly followed by improve-
ment.

The injection of vaccines is not, like milk, followed by any
styptic effect; on the other hand, they are not as a rule hemolytic,
as nucleohistone and albumoses may be. The resistance to rein-
jection also differs with the different organisms. Thus there is a
rapid tolerance, or increased resistance established to typhoid,
pyocyaneus, pseudodiphtheria and several other vaccines, while milk,
representing a native protein, may at times become more marked in
its effect with subsequent injections.

Mixtures of vaccines have also been employed. Thus the "Arthi-
gon" of Bruck contained a number of strains of gonococci and 10%
of protargol and was used extensively in Germany in the treatment
of gonorrheal complicationi. "V accinurin" is a recent mixture rec-
ommended by Dollken for use in neuralgia and neuritis and consists
of prodigiosus organisms and staphylococci which have been permitted
to autolyze.

Danysz' method of treating disease has been discussed in full in a recent
number of the Bulletin medicate. He describes anew the technic and his
experience in 352 cases since 1913. In seeking for an efficient antiana-
phylactic, he started from the theory that the focus of production of the
substances generating the anaphylaxis in the majority, if not in all, of the
chronic, noncontagious diseases, is in the bowel: The albuminoid matters
or microbian contents of the intestinal canal passing into the blood through
the congested intestinal mucosa act as antigens and induce the anaphylactic
state of the organism. Consequently, he reasoned, the microbes isolated
from the intestinal contents ought to act as antigens when inoculated or
ingested. The microbes are isolated from a scrap of stool by sowing on
ordinary culture bouillon and then making pure cultures on gelose, and
then mixing the cultures in the same proportions as found originally.
This is diluted with physiologic serum, sterilized with heat and the dose
determined by weight. For ingestion, the dose is 1/10 to 5/10 mg. of the
microbian bodies; for injection 1/1,000 or 1/1,200 mg. At first he made
an autogenous antigen for each patient, but finding that the species and



36 PROTEIN THERAPY

proportions of bacteria were so uniform, he used a polyvalent heterogeneous
preparation in some cases.

Muck's Antigen. Much has recently described a vaccine which
he terms "Immunvollvaccine' for intramuscular injection, which he
has used in the treatment of influenza. It is prepared from a num-
ber of nonspecific antigens: (a) Reactive proteins, the metabolic
products of several nonpathogenic bacteria, (b) a lipoid mixture from
bile, and (c) a fat mixture of animal derivation. The theory under-
lying such a mixture is that of partial antigens which he has developed
in tuberculosis.



BACTERIAL EXTRACTS AND RELATED SUBSTANCES

The use of bacterial extracts and of bacterial growth products
to produce a nonspecific temperature increase is not a recent inno-
vation.

Tuberculins have been used for this purpose for some time, es-
pecially in the treatment of paresis, as introduced by v. Jauregg. For
this purpose a relatively large dose is used, beginning with 0.01 mg.
and increasing rapidly until as much as 0.5 mg. is injected. The
temperature reaction is a prolonged one; usually a leukocytosis is
produced. It offers no particular advantages over milk injections
which produce practically the same results.

Kaiser has used Tebelon, the isobutyl ester of oleic acid (intro-
duced by Stoeltzner) , in a number of surgical conditions. Like other
nonspecific substances it acts as a pyrogenic agent even in nontuber-
culous diseases.

Typhin. Biedl in 1915 noted that the nonspecific reaction could
be elicited with histamin, the toxicity of which had been previously
studied, v. Groer made use of this knowledge in preparing a mix-
ture of nucleoprotein and histamin from typhoid bacilli which he
called "typhin" to be used in place of whole bacilli for intravenous
injections. The chief advantage of the preparation lay in the fact
that with such a substance the dosage might be standardized and
the reaction gauged. With this "typhin" v. Groer treated 23 cases
of typhoid, of whom 18 made a prompt recovery and 5 died. In
the case of a typhoid patient that recovered by crisis after the in-
jection and died a few days later from an intercurrent condition, v.
Groer observed at the autopsy that the ulceration of the bowel had
practically healed and that the spleen was small (v. Wiesner has
recorded similar observations).

It is interesting to note that v. Groer found no increase of anti-
bodies in the serum of patients after the injection despite the fact
that such patients made an excellent and prompt recovery after the
injections.



THE NONSPECIFIC AGENTS 37

Intramuscular injections are recommended for common use. He
also gave small doses of digitalis a few days preceding the injection
in severely toxic cases.

Coley's Fluid. This consists of fluid culture products of the strep-
tococcus and pyocyaneus. It is used particularly in sarcomata in
which it was usually followed by a severe systemic reaction and some
evidence of digestion and autolysis of the tumor, but never to the ex-
tent of complete eradication of the neoplasm.

Pneumococcus Autolysate. Among bacterial autoly sates which
were prepared on a specific basis but which in all probability were
effective, when therapeutically active, as nonspecific agents were the
pneumococcus autolysates of Rosenow, recommended for use in lobar
pneumonia.

Phylacogens (Schafer's Vaccine.) These represented bacterial
growth products of a number of bacteria first prepared by Schafer
and used with some success in arthritis. They were later prepared on
a commercial scale and marketed under the trade name of
Phylacogens. Inasmuch as the method of preparation and exact com-
position is not known, the reaction merely a nonspecific one, other
and less expensive agents will be found more satisfactory and more
easily controlled.

COLLOIDAL METALS

Colloidal metals were perhaps first used as therapeutic agents by
Crede in 1895. Crede used silver preparations on the assumption
that they were actively streptococcocidal, and they were introduced
by him in the treatment of streptococcus infections. The range of
application was, however, soon extended to septic conditions in gen-
eral (it was no longer considered a specific streptococcicide but to pos-
sess heterobactericidal properties) and latterly it has been surmised
that its usefulness depended not on its particular chemical structure
but on properties of colloidal metals in general which produced
the nonspecific reaction and were therefore typical ergotropic agents.
Earlier workers had followed Crede in the interpretation of the method
of action (Marquis dos Santos and Alphonse Pinto) ; Albrecht sur-
mised that the catalytic property of the finely dispersed metals
might have a definite relation to the therapeutic effect; while later
the reactive leukocytosis that followed the injections was studied
and held responsible for the therapeutic result. (Dunger, Sahli, Bruntz
and Spillmann.)

Bonnaire and Kausch both noted and emphasized the important
fact that following the intravenous injection a chill, fever and leu-
kocytosis were commonly observed. This febrile reaction, just as
in other nonspecific reactions, varies considerably with the disease
process. In sepsis Kausch noted that the high temperature dropped
promptly by lysis, whereas afebrile cases, such as carcinoma, responded



38 PROTEIN THERAPY

with a sharp febrile rise. Eberstadt in treating erysipelas did not
observe any initial rise in temperature following the injection; a
lysis occurred in his four cases.

The fact that colloidal metals are active catalytic agents has
led to the theory that in the organism they act therapeutically by
virtue of this property as inorganic ferments. Vergely in a recent
review calls attention to this effect in connection with the enormous
surface developed by colloidal preparations of this type. A liter
of a 0.5 per thousand solution of colloidal gold, for example, presents
a surface of 150,000 square centimeters, while the same weight of
gold in a compact form presents a surface of only 50 square milli-
meters. In therapeutics, they whip up the organism but if it is unable
to respond, they can do no good. If the patient is unable to produce
more leukocytes, there is no chance of success. In selecting the



Online LibraryWilliam Ferdinand PetersenProtein therapy and nonspecific resistance → online text (page 5 of 36)