THE JOURNAL

OF

IM M U N O L O G Y

V O L U M E V III

B A L T IM O R E , M D .
1923
ON THE CLASSIFICATION OF THE P H E N O M E N A OF
HYPER.SENSITIVENESS^

A IIT H U R F. CO CA ax d R O B E R T A. C O O K E
Prom the D ep ciiin cn l of BncterL.i‘>g]j and Ii.n n ” iiJii'>yu, D irisi- n of ' ¡I'liiiinnli'fj:;.
in Carnell University ilc d ic a l College and itte New Yur!: ifospit(d

Received for pubiieation >.Iay 1, 1922

U r A R T iiai? !•’. COCA

Robert Doerr was the first to recognize the need of ii elassi-
fication of the pherioiner.a of hj'persensitiveiiess. In attenipling
such a classification I3oerr (7), unfortiinatelj' chose as the ni;-in
heading the term Allergie (allerg}^ which had been introduced
by von Pirquet. This choice was particularly unhappy because
Doerr felt obliged in using it to observe with some strictness
the etymological significance of the term (altered reactivity).
The result of this observance was the inclusion in Doerr’s cate­
gory of allergies of phenomena of such different nature as to
make their association valueless if not positively confusing.
There seems, for example, to be no advantage in associating in
one category two so wideb/ different phenomena as the well
known morphine tolerance and morphine idiosyncrasy.
Doerr’s subdivision of “allergic” phenomena into those ex­
hibited to non-antigenic substances and those exhibited to anti­
genic substances is also inadvisable because such subdivision
necessitates a confusing separation of identical conditions of
hypersensitiveness in human beings, merely in accordance with
the presence or absence of antigenic propertj^ in the exciting
agent. Actually it seems that neither of Doerr’s published
^ Read at the annual meeting of the American Association of Immunologists,
Washington, D . C., r^Iay 1, 1922.
163

T H E J O U R N A L O F I M M U N O L O G Y , V O L . V I I I , N O . :i
 classification recognizes the existence of the i diosynerasies to
antigenic and non-antigenic 'proteins.
In a sumnaary of the literature of hypersensitiveness (3) the
writer expressed the above outlined criticism of Doerr’s classi­
fication and suggested as a main heading the word hypersensi­
tiveness. This word Vv'as alreadj^ in general use in the literature
of anaphylaxis; the writer merely proposed that it be recognized
in immunological parlance as a technical term (“terminus techni-
cus,” Doerr (S)) to signify any form of specific peculiar reactivity
in which the characteristic symptoms were different in the differ­
ent animal species and were different from the normal physio­
logical reaction to the respective agent.
Such technical use of a common word has many precedents
which show that no confusion need result from the practice.
The restricted use in mcdical literature of the common word
plague, for example, has resulted in no misunderstanding.
The writer’s definition of hypersensitiveness in the immuno­
logical sense was drawn from the cardinal facts of anaphylaxis
and of the human conditions of hay-fever, asthma, and other
idi()s3'ncrasies; it excluded, therefore, the sensitiveness of tuber­
culous individuals to tuberculiiu The separation of tuberculin
sensitiveness from the other two forms is amply warranted by
the clearly marked differences among the three phenomena;
hov\’ever, it would be a mistake, as Doerr (8) points out, not to
recognize tuberculin reactivity as a form of immunological
hypersensitiveness and this the writer now acknowledges.
As Doerr remarks, tuberculin hypersensitiveness is the best-
studied representative of a group of conditions of hypersensi­
tiveness to derivatives of microorganisms. The list of these
microorganisms is ever increasing and already includes Sporo-
triciium, Timothy Bacillus, TnchopJiyion, B. mallei, B. abortus
bovinus, B. melitensis, Spirochaeta pallida, and B. typhosus, in
addition to B. tuberculosis.
Since the known facts concerning this group of hypersensitive
conditions indicate an identity in the underlying mechanism of
all of them, an inclusive term seems to be needed to designate
the group. The designation “cutaneous hypersensitiveness,”
which was employed by Fleischner and Meyer, seems quite
inadequate because on the one hand the sensitiveness in infec­
tions is by no means confined to the skin and on the o th ^ hand
cutaneous sensitiveness is by no means confined to infections.
The designation "bacterial hypersensitiveness” seems objection­
able because infection with fungi causes the form of sensitiveness
that we are considering and because anaphylactic sensitiveness
can be produced with bacteria.
It is proposed, therefore, to use for the present the unwieldy
expression hypersensiiiveness of infection, which could still
be used even if it should be found that this form of hypersensi­
tiveness can be produced without actual infection with the
respective microorganisms.
Hypersensitiveness in its immunological sense can be defined
as a susceptibility in man and animal that is mediated by a
special mechanism, which may be specifically influenced (toward
increased or diminished sensitiveiiess) by the suitable adminis'
tration of the exciting agent - This definition permits the in­
clusion under one heading of all of the related forms of hy];crsen~
sitiveness. Tn most of these the sensitiveness is diminished by
the administration of the exciting agent (hay-fever, asthma, etc.,
dermatitis venenata, anaphylactic sensitiveness); in ordinary
serum disease and in drug idiosyncracy the reaction is often
increased at the second administration. The existence of the
special mechanism is indicated either by the absence of the sensi­
tiveness in most individuals of the same species or by its total
absence in other species. For example, only preA'iously treated
animals in whose tissues precipitating antibodies arc present
exhibit the usual form of anaphylactic sensitiveness. The
“reversed” form of anaphylactic sensitiveness presents an ex­
ception to the rule in that it appears that one of the esseiilial
{actors of the mechanism (the antigen), which is res]:onsible for
this form of sensitiveness, is present in the tissties of :ill individiials
of the species. In this case, however, tiie existence of tlie mech­
anism is betrayed by the specificity of the injected inmiune serum.
^ This definition was formulated in conforejice with D r, C’ooke.
 When the exciting agent possesses a normal physiologieal
action the meclianism of hypersensitiveness is ^e^x'aled in the
well known qualitative difference between the symptoms of
hypersensitiveness to the substancc and those of the normal
physiological effect.
The existence of the mechanism in dcrmaiitis ver.cnala can be
inferred from the exclusive susceptibility of human beings. In
the hypersensitiveness of infection the existence of the mechanism
is evidenced by the lacking sensitiveness of normal individuals
to the active agents; for example, tuberculin.
For reasons that are discussed in the second part of this com­
munication, Dr. Cooke suggests the subdivision of the forms of
hypersensitiven.ess into a “normal” group and an “abnormal”
group. The group of abnormal liy])ersensiti\'eness includes
anaphylaxis, the hy]3ersensitiveness of infection and those idio­
syncrasies that are controlled by the dominant gen demonstrated
by Cooke and Vander Veer. This latter sub-group evidently
needs a special term by which it may be conveniently desig­
nated and this need is satisfactorily met with the v/ord atopy,
which was kindly suggested by Professor Edward I). Perry of
Columbia University. The CSreek word aroirUY, from which" the
term was derived, was used in tlie sense of a strange disease.
However, it is not, on that account, necessary to include under
the term all strange diseases; the use of the term can be restricted
to the liay-fever and asthma group.
The classification here proposed is thus:
Hyper?ensitivencss

Normal^ (Cooke) Abnormal

1. Dermatitis venenata 1. Anaphylaxis

2. Seram dii-oate (ordinaiy) 2. Hyr.crsensitiveness of infection
3. Atopy

The three abnormal forms are distinguished by the following

features:
 Anaphylactic sensitiveness

1. Is exhibited only against precipitinogenic proteins (Doerr).

2. Is passively transferable to normal animals with the sonuu of
sensitized animals.
3. Is completely removable by the procedure of desensitization.
4. Is not inherited.
5. Is expressed, in the acute reaction, in symptoms and pathological
changes Vvdiich difi’er characteristically in the guinea-pig, tlie rabbit and
the dog.
The hypcrsensitivcness of infection

1. Is exhibited against non-precipitinogcnic substances; for example,

tubercuhn, which seems to be, as Doerr suggests, secretory products
of bacterial growth.
2. Is not passively transferable to nonnal animals with the senun
of sensitive animals.
3. Seems to be greatly lessened if not completely removiible by the
suitable injection of the active substance.
4. Is not inherited.
5. Is expressed, in the acute general reaction as well as in the culane-
ous reaction, in symptoms and pathological changes which do not differ
characteristically in the different animal species l)ut which do differ
from the characteristic sjinptoms and pathology of acute anaphylactic
shock in the respective animal.
6. Is not developed after injections of the active sul)stanco, l)ut
regularly develops in the course of an infection vritli the microiirganisms.
The injection of the killed cultures results in anaphylactic sensitiza­
tion to the injected material.
7. Seems in tuberculosis to be passively transferable to normal
guinea-pigs by the injection of the crushed tubercles from infected
guinea-pigs (Bail, 1, 2).

A topic hypersensitivencss

1. Is exhibited against non-precipitinogcnic substances as well as

against precipitinogenic siibstances.
2. Has not been shown to be passively transferable to normal in­
dividuals with the blood of sensitive individuals. The one observa­
tion of Ramirez needs confirmation, being susceptible of a (_tLifcrent
explanation.
 3. Can be greatly lessened but not completely removed by the suit­
able injection of the active substance (Cooke, 5).
4. Is inherited, subject to a dominant gen (Cooke and Vander Veer, 6).
5. Is expressed in pathological changes the more important of which
are different from those of the anaphylactic reaction in the guinea-
pig, the rabbit or the dog.

The writer’s review of the subject of hypersensitiveness was

written from the point of view of a proposed new classification
and the description of the symptoms and pathology of the differ­
ent forms of hypersensitiveness was devoted ahnost exclusively
to the characteristic phenomena in each instance. Thus, the
bronchiospasm in the guinea-pig, the arteriospasm in the rabbit,
the hepatic congestion in the dog and the symptomatic effects
of these changes were placed in the foreground with the purpose
of emx‘)hasizing the wide difference among them as one of the
cardinal criteria of anaphylactic hyperseiisitiveness. This cri­
terion was added to the several others on which the separation
of tuberculin sensitiveness from anaphylaxis was based.
Doerr objects to the prominence given to this difference on the
ground that it is m.ereh'- the necessary consequence of the special
organization of each animal species and lie points to the different
physiological reaction of the dog, the cat, and the rabbit to mor­
phine as an analogous situation. Doerr’s objection here is,
however, beside the point, as an examination of his cited analogy
will show. If the typical action of an unknown alkaloid does
not differ in the three animals that Doerr mentions in the char­
acteristic manner of morphine, then the unknown alkaloid cannot
be morphine. Similarly, if any phenomenon of hypersensitive­
ness fails in its typical expression to exhibit in the guinea-pig, the
rabbit and the dog the differences which characterize the phenom­
enon of acute anaphylactic shock in these three species, then
the phenomenon of hypersensitiveness in question cannot be
that of anaphylaxis.
In continuation of his objection to this point of differentiation
Doerr attempts to establish an identity of the characteristic
symptoms of atopic hypersensitiveness and some of the symptoms
of anaphylaxis.
 Doerr likens the flow of tears, which sometimes oceiirs in
anaphylactic shock to the condition of haj^-fever in which aiso
there is a flow of tears. However, lachrymatioxi aloïie does not
constitute hay-iever and there is no other ground for identifying
this occasional minor symptom of anaphylaxis with the condition
of atopic coryza. In other words, there is no evidence that the
occasional flow of tears in anaphylactic shock is caused bj'- a
primar}^ irritation of the conjunctiva.
To Doerr gastro-intestinal symptoms are of identical signifi­
cance whether, as in the anaphylactic shock of the dog, thej' are
due to passive congestion of the portal tributaries, or to a direct
irritation of the gastro-intestinal mucous membrane as in the
hypersensiti\'G human being.
The asthmatic dyspnoea, which Doerr likens to the bronchio-
spasmic asphyxia of anaphylaxis in the guinea-pig is more than
probably not due to contraction of the bronchial mus(‘!es, but to
an edematous swelling of the bronchial mucous membrane.
Finally, Doerr thinks that the cutaneous manifestations of
human hj'persensitiveness (eruptions) may be represented among
the anaphylactic symptoms of the guinea-pig by an itching of
the skin which he assumes to exist on account of the fact that
this animal often scratches its nose, ears and pavrs in ¡)roiracted
anaphylactic shock. However, there is no >vay of iiiulirsg out
whether the cause of the scratching is really situated in the
skin or elsewhere, perhaps in the lungs. Those who use ether
anesthesia in guinea pigs will recall the etiorts to scratcli the
upper parts of the body v/hich these animals regularly make
after the ether has been administered for a time. One is not
obliged to look upon these efforts as indicating an effect of the
ether upon the skin; they may be due to an irritation of the lungs.
The grounds for separating the three forms of abnoimal
hypersensitiveness are sufficiently plain in the outlines of their
prominent features gi\'en above. The grounds for their asso­
ciation must also be borne in mind; they have been set forth in
the definition of hypersensitiveness. Dr. W . J. Elser® has sug-
^ Persona] communication.
 gested that the special mechanism may be actually nothing
positive, but only the absence of some normal element. This
suggestion, however, is confronted with the difficulty, under
such a hypothesis, of explaining the specificity that has been
SO constantly exhibited on the hyposensitization of atopic
conditions (Cooke and Vander Veer). The hypothesis would
need the supporting assumption that a different normal element
is lacking in the hypersensitix'eness to each exciting agent.
Admitting, then, the greater lilcelihood that tlie mechanism
of the different forms of hypersensitiveness is something positive,
one is naturally influenced by the example of anaphylaxis to
imtigine that the mechanism of the other two forms is essentially
of antibody-antigen nature.
Doerr actually assumes the existence of anti-tuberculin anti­
bodies in explanation of the tuberculin reaction and one is,
indeed, tempted to follovv him here; because one may well ask
^^'hy a specific, positive mechanism that is developed during
infection and that reacts specifically with a product of the re­
spective microorganism may not be called an antibody.
The remarkable differences bet^veen the conditions under which
this “antibody” is developed and I'cacts and those controlling
the development and reaction of the known antibodies demand
explanation.
One of the outstanding difficulties confronting the antibody-
antigen conception of the tuberculin hypersensitiveness is the
passive transferrence of the sensitiveness to the normal animal
by the injection of crushed tubercle tissue. This procedure
makes it necessary to assume that the anti-tuberculin “anti­
bodies” are j>resent in the tubercle tissue. Since tuberculin
sensitiveness does not develop without the formation of tuber­
culous tissue (Krause-Doerr) one must further conclude that
the hypothetical antibodies are produced only by tuberculous
tissue. Doerr goes so far as to say that only tuberculous tissue
reacts with tuberculin and he offers this as the explanation of
the characteristic difference between the tuberculin reaction,
and that of anaphylaxis.
But Doerr seems to have overlooked here the reactivity of the
 skin, conjunctiva and uterine muscle (all non-tuberculous tissues)
in tuberculosis. The mystery of the anti-tuberculin antibodies
is deepened by the experiments of Fellner, which confirm, in a
way, those of Bail in the passive transferrence of tuberculin
sensitiveness. Fellner obtained the reaction tissue resulting
from a von Pirquet cutaneous test and inoculated it, mixed with
tuberculin, into the skin of a normal; that is, tuberculin-nega­
tive individual. This inoculation resulted in a distinct reaction
which w'as absent or very weak in the control inoculation Avith
the tissue alone. It T\-ouId seem from this experiment that newly
formed tubercle tissue even '»vhen it is far removed from the focus
of infection; that is, from the tubercle bacilli, quickly begins to
produce anti-tuberculin antibodies.
The anti-tuberculin antibody is not produced in normal
animals by the injection of tuberculin, with vfhich it reacts.
It is produced only in tubercle tissue, but it is diffused out of this
parent tissue into the other tissues of the body w'here, also, it is
capable of reacting with tuberculin. Notwithstanding this
demonstrated diffusibility, the antibody has not been demon­
strated in the blood. W ith one exception, the uterine muscle,
the tissues thus, so to speak, passively autosensitized are not
those that are involved in anaphjdactic sensitization. The skin
is not sensitive in anaphylaxis and the bronchial muscles are not
sensitive in the tuberculous guinea pigs.
Finally, passive sensitization in anaphylaxis has not been ac­
complished by the transfer of any tissue of a sensitive animal
excepting the blood. The exact reverse of this is true in tubercu­
lin sensitiveness.
The foregoing parallel summary of the facts concerning the
anti-tuberculin antibody and the anaphylactic antibody reveals
an antithesis that would seem to discourage the attempt to as­
cribe an antibody-antigen nature to the tuberculin reaction.
Nevertheless, this hypothesis appears to be the most promising
at present, although further, convincing confirmation of the
experimental basis of the hypothesis is demanded.
For an assumption of an antibody-antigen nature of the
mechanism of atopic hypersensitiveness there seems to be no
reasonable evidence whatever.
 In the writer’s previously published discussions of this question
this conclusion was drawn from the first four features of atopic
hypersensitiveness mentioned above. These, more bi’ielly stated,
are:
1. The non-antigenic property of some atopens.
2. The absence of proof that atopic hj'persensitiveness can
be passively transferred.
3. The absence of desensitization in atopy.
4. The determining influence of the atopic dominant.
One of the results of Doerr’s definition of the word “allergie”
was the iiiclusion under that heading of both “ toxin hypersensi­
tivencss” and antitoxic inununity.
In the author’s review in Tice’s Practice of ]\Iedicnie, it was
ponitcd out that whenever the exciting agent of hypersensitive­
ness possessed a normal physiological action that action v>'as
nearly ah^'ays different from its effect in the hypersensiti\'e indi­
vidual. This difference was proposed as a criterion by which
the existence of the inechanism of hypersensitiveness can be
determined and in accordance with tliat criterion the so-called
toxin hypersensitivencss was excluded from the category of what
v.'as then referred to as true hypersensitiveness; because the
symptoms of “hypersensiti^'eness” to the toxin were alway s those
of the normal action of the toxin.
The later study of Park^ has further justified the exclusion
because Park finds that there is no hypersensitivencss to toxin;
the phenomenon that vras formerly considered toxin hypersensi­
tiveness is merely a lessening of the primary lethal dose by means
of fractional administration. According to Park, this phenome­
non is observed only within the period previous to the production
of antitoxin; that is, before the specific reaction mechanism has
appeared.
Doerr rests his grouping of antitoxic immunity with the
phenomena of anaphylaxis on the ground that “ the toxins are
antigens, which are neutralized by their antibodies exactly as
are the anaphylactogens.” But specific neutralization is not
' Read at t!ie annual mooting of tbo American Association of Immunologists,
W asiiington, D . C., M ay 1, 1922, unpublished.
the criterion by which the anaphylactic state is judged as is
evident in the fact that such neutralization of precipitin with
precipitinogen takes place in the blood of guinea-pigs without
the development of anaphylactic shock; it is not the neutraliza­
tion of the antibody in the animal body that counts, but the
resulting irritation of the cells. Anaphylactic shock is not, as
Doerr would define it, “ an antibody-antigen reaction,” but the
secondary effect of such a reaction. Since neither toxin nor
antitoxin enter into any phenomenon of hypersensitiveness it
would be only confusing to consider their mutual relationship
under that heading.
The question as to the possibilitj" of the occurrence of anaphy­
lactic sensitization in human beings remains undetermined.
Doerr has misunderstood the writer’s attitude upon this ques­
tion, remarking in one place that (according to Coca) ‘ ‘the human
being cannot be sensitized, cannot be made anaphylactic.”
Actually the writer w'rote in two places as follows:
. . . . it seems necessarj' to conclude: first, that if anaphylaxis
does occur in man, it does so only very rarely and secondly, that
there is no positive evidence that anaphylaxis occurs at all in human
beings (4).
In conclusion it may be said that, while it is not possible to assert
that anaphylaxis does not occur in human beings, it is a fact that the
existence of the condition of anaphylaxis in human individuals has not
been demonstrated....................

We find ourselves, thus, in agreement wdth Doerr when he

writes:
It is not, for example, impossible, that the sharp distinction drawn by
Coca between idiosyncrasy (atopy) and anaphylaxis can be upheld,
but that both forms of hypersensitiveness appear in human beings^ (8).

In fact, the alteration of the writer’s definition of hypersensi­

tiveness to permit the inclusion of the hypersensitiveness of in­
fection has removed Doerr’s chief objection to the classification
previously proposed and there is left no important disagree­
ment with Doerr as to the essential nature of the associated
phenomena.

The italics are introduced by the writer.

 n J ’ a i i .: f. I i i i u n n i i f a e f s f . , 1009, 4 , 70,
(2? IS '.n .: Z iM ls p ’i r , f. Im m u i'- ita o tfii'., 1912, 1 2 , 451,
!.i) Ciii-x, A. 1'.: Tice’s Praciiee of Aledicine published by \V. F, Prior Co.,
liafiorito’.vii, ¡920, 1, 107.
(4) C o c a , A, F ,: Jour, Im iiiunol,, 1920, 5, 3G.3,
(.5) CooivE, ]i. A,: Jour, Immuiu)!., 1922, 7 , 219,
i'G) C ooke , R . A,, an d Va.vdeh V ker , A.; Jour. Imtium ol,. 1916. 1 , 201.
(7) ])oi:i:r, T{ .: Kolle-Vrn.-'iii'rinann-naiulbuch dcr pal hogcncn .Mikroorganismen
2*^*'' Auflagc,
(5) D oeuu , R ,: Vveiciiardt’s Ergel'.nit:sc der Hygiene, etc,, 1922, 5, 73.

II

B Y ROBERT A. COOKE

,v chispiiiciition of any branch of scicnce usually carries vrith

it a:i air of finality. The present classification is not suggested
ill tliat v;ay for we recognize fully the many loopholes in our
knovrledgo of tlie subject. On the other hand a classification
ur.duubtedly aids in a pro])er alignment and grouping of the
facts and serves, not as an end, but as a means of advancement
in tlie study of a subject. The classification itself is not so im-
]«ortant but the facts upon which it is based must be genuine,
then, with further study and the correlation of new facts, a new
grouping and classification may be needed. But it has seemed
wise to attempt a classification of certain biological reactions,
namely hypersensitiveness, in the light of present facts as we
now see them.
Dr. Coca has just given a defence of the use of the word hy­
persensitiveness in a restricted immunological sense and it is a
useful and satisfactory word to designate a certain group of
biological reactions occurring in man or animal. In his article
on Hypersensitiveness he says ‘ Tf an individual reacts specifically
or particularly with characteristic symptoms to the administra­
tion of or to contact with a quantity of any substance, which,
to the majority of the members of the same species of animal is
innocuous, that individual is said to be ‘hypersensitive’ to that
substance.” The term ‘hypersensitiveness’ must be reheved
of some of the restrictions originally imposed by Coca and to­
gether we have formulated the definition which he has already
given and which I repeat.
 Hypersenbitivciieps is a state of susceptibility in man and
animal in ^^’hich the reaction is mediated by a special mechanism
that occurs naturally or is developed artificially and \ \hich may
be specifically influenced (increased or diminished) by tl;e suit­
able administration of the excithig agent. In other words there
are t\^■o criteria by which v,’e distinguish hypersensitivcness from
other biological reactions. First, it requires a special mechanism
and secondly, it is susceptible to specific alteration.
The term “special mcchanism,” employed in the definition,
unless explained, would connote a positive factor in the reaction
such as antibodies in the mechanism of anaphylaxis. It must be
understood however that we do not know the mechanism of the
reaction in atopy. It is concei's^able that it is due to the absence
of some normal bodily constituent of an, at present, unknown
nature. Certain it is that the reaction is not mediated by any
demonstrable, positive factor, such as the anaphylaxis antibody.
The term special mechanism then is used to denote a procedure
which may depend upon either a positive or a negative factor.
Since the nature of the reaction is unkno’.vn in certain forms
of hj^persensitiveness two criteria have been formulated by which
to determine the presence of a special mechanism when the
estabhshment of the mechanism is not controllable and artificially
induced as it is in anaphylaxis and infection. First, the absence
of the reaction in a considerable percentage of the sanre species
as, for example, atopy occurring in only ten per cent of the wliite
race. Second, the absence of the reaction in other mammalian
species though present in one, as serum disease occurring in
ninety per cent of the Caucasian race but absent in other mam­
malia.
W ith these points clearly in mind we can exclude reactions to
chemical, thermal and mechanical irritants and also the ordinary
pharmacological reactions of drugs, but not some of the so-called
drug idiosyncrasies, which are genuine forms of atopy, some in­
herited, some probably induced.
The normal or pharmacological action of drugs depends for
the most part upon a direct action of the drug upon certain tis­
sues or cells and this is essentially identical for all mammalia
and even lower animals. In other words, in pharmacology the
action of drugs is qualitatively similar throughout the mammalian
group, although effects may be apparently widely different, but
the reasons for the differences appear on critical analysis. For
example atropin has the same action, paralyzing the vagus,
in man and in rabbits, but the effects are widely different in
that vagus paralysis in man commonly causes marked cardiac
acceleration but, in the rabbit, in the absence of tonic vagus
impulses, this does not occur. Again, niorphine in the frog
induces strychnine-like con-v’uisions whereas these are not apparent
in m.an. But the pharmacologists know and have very good
proof of the fact that inor]:»hine does markedly increase tiie reflex
irritability of the anterior horn cells in man and convulsions are
only prevented because death results early fromi the depressant
effect of the drug on the respiratory centre. Paralysis of the
respiratory centre docs not immediately cause death in the
frog.
Another type of differeirces in drug effects is seen in the appar­
ent tolerance of the frog to colchicin. This drug is highly toxic
in all warm blooded animals. The tolerance of the frog entirely
disappears w'hen its temperature is elevated to that of the warm
blooded animals. Colchicin is not decomposed or oxidized to
its toxic constituents except at a temperature higher than that
which is normal for the frog.
Many other examples might be cited but these suffice to show
that the normal action of drugs is not mediated by any special
mechanism, that the action is qualitatively similar throughout
the mammalian group. To be sure, there are certain variations
in the effect of drugs within the same species. Enormous indi­
vidual variations occur to most every drug such as caffein, strych­
nin, digitalis and histamine, but these are purely quantitative.
To certain drugs, notably morphine, alcohol and nicotine, there
is an acquired tolerance. Let us examine the facts in regard to
the drug tolerance to see whether or not it bears any relation to
the specifically altered reactions of hypersensitiveness. In other
words is drug tolerance a form of immunity, desensitization, or
hyposensitiveness?
 The tolerance to alcohol induced by habitual use is non-speci­
fic. An increased tolerance to ether and chloroform is created
at the same time and^ further, the increase of this tolerance is
very limited and very gradually developed. "V^Tiat about mor­
phine tolerance! In the first place the tolerance to morphine
is very limited, it is never increased to more than twenty times
the fatal dose and usually only four to five times and this only
after long continued use. If a man is tolerant to four times the
fatal dose, five times the fatal dose will kill with the same symp­
toms and in the same time that the drug acts upon a normal
man. Again the tolerance acquired to morphine is limited to
the cells of the cortex and respiratory centre. The other mor­
phine effects in the body, cardiac, intestinal, etc., proceed without
alteration.
The pharmacologists do not conceive drug tolerance as in
any way comparable to immiuiity, deseiisitization, or hyposensiti­
zation. Without further discussion then it v;ould seem that the
word hypersensitiveness in its immunological sense and as de­
fined is free of the danger of being confounded with any biologi­
cal reactions occurring in the reahn of pha^nlacoîog^^
Under the general heading Kypersensiti^eness we at once
recognize the three distinct types of reactions which were origi­
nally distinguished by Coca, namely anaphylaxis, atoi^y, and tiie
sensitiveness of infection. They arc forms of hypersensitiveness
because they depend each upon its own special mechanism for
the production of symptoms. What this mechanism may be in
atopy we do not know today, but, whatever it is, it develo-'s
naturally in man as a result of certain inherited factors. There
is one feature that is common to these three states and that is
a qualitative cellular alteration within the species. The anaphy­
lactic or sensitized guinea-pig is qualitatively different from tlie
normal pig. The atopic man is qualitatively unlike the ncjrnial
man. To be sure there are variations in degree of sensiti\'eness
within each group. Guinea-pigs may be relatively more or less
anaphylactic and individuals may be relatively more or less
atopic. But these are purely quantitative variations and in­
dependent of the underlying fundamental qualitative change.
 For this reason we have grouped these three states under a sub­
heading, abnormal— abnormal hypersensitiveness dependent upon
qualitative differences within the species. But this connotes
the necessity for a subheading of normal— normal hypersensi­
tiveness dependent only upon quantitative variation within the
species and such forms I believe we have in two clinical conditions
of man; namely, serum disease and dermatitis venenata.

SERU M DISEASE

In the first place we must not confound serum disease with

the inmiediate reaction occurring in Inmian iitopy. They differ,
first, in their pathogenesis, the one inherited and the other not;
secondly, in their incubation period, the one instantaneous, the
other after an interval of about five to fifteen days; thirdly, in
their symptomatology, dyspnea from broncliial edema being
the outstanding feature in atopy and urticaria the principal
symptom in serum disease.
Kor must serum disease be confounded with the possible serum
anaphylaxis occurring in man. I say possible, because in the
nature of things it is not feasible to experiment on man, but a
sufficient number of chnical cases is reported to make it seem
probable that anaphylaxis dees occur in man. But these clinical
experiences are not yet supported by any absolute proof. By
serum disease is meant those nianifestations of urticaria, pruri­
tus, joint pains, and febrile movement, occurring after an incuba­
tion period of usually five to fifteen days.
From 1905 vÆen von Pirquet and Schick amiounced their
theory, the antigen-antibody nature of the reaction known as
serum disease was accepted until 1920 when Coca’s critical
analysis of the facts threw graA'e doubts upon tiie correctness
of this assumption. Hamburger and Moro, von Pirquet and
Schick, C, W. Wells, Francioni, Longcope and Rackemann and
Longcope and Mackenzie, have all studied serum disease from
the point of view of von Pirquet’s theory and the results of their
studies fail to show any constant reiationship between the symp­
toms of the disease and the specific precipitins in the blood and
between the symptoms of the disease and the presence or absence
 of antigen in the blood. If for no other reason, this lack of
relationship alone is sufficient to overthrow von Pirquet’s theory.
'If this contention is valid, as it appears, then serum disease is
not anaphylaxis.
Heredity plays no part in serum disease. A few years ago,
when serum was given as diphtheria antitoxin in relatively small
amounts, the general incidence of serum disease w'as given as
ten per cent. In 1916 the writer, with Vander Veer, had con­
cluded from a statistical study that the general incidence of
what w^e now call atopy was about ten per cent. The close
approximation of the incidence percentage for serum disease
and the natural human form of hypersensitiveness was the de­
termining factor by which Coca then grouped these conditicns
as similar, under the heading of allergy.
With the introduction of an antipneuxnococcus seruni, iis(d
in large amounts intravenousl}", the general incideiiee of seruiu
disease has risen to ninety percent, according to the ol)scr\’aiioiis
of Cole, Longcope and jNIackenzie, as well as tlie st;itislics ccii-
lected by Coca from the Boston City Hospital.
Another point recently brought forward by Coca is tliat the
percentage incidence for serum disease is practical]}' ilse s;;me,
ten to thirteeJi per cent after subcutaneous injection, in all age
groups, thus differing entirely from the pcrcentiigc ijicid-;iice oí
the inherited forms as shown by the figures obt-.uned in lijiii l)y
the writer with Vander Veer and later taipportcd hy Adkiiisori
and again today by Spain. Kor, as meniioned abfsve, is ílícre
any identity in the incubation ])eriod or tlie clinical syn.jptnms.
As a matter of fact the two reactions serum disease and serum
atopy have nothing in common other than a connr.on inciting
agent. The immediate reaction of atopy iiiui íl¡e dcunx-d reac­
tion of serum disease may and may liOt a]>}:car in the sanie in­
dividual as a result of the same dose of serum. Clinically 'we
see violent immediate reactions with, later, nrarked serimi dis­
ease, mild serum serum disease or no serum disease at all and,
on the contrary, we see marked serum disease witli no inmiediate
reaction or a mild immediate reaction may ha\'e occurred. That
they do co-exist is due solely to the fact that seruiu disease occurs
in 90 per cent of all humans. This quantitative symptomatic
independence of the two reactions in individuals susceptible to
both certainly connotes an independent mechanism for each
reaction. It would then seem logical to conclude that serum
disease is not a manifestation of atopic hypersensitiveness.
The question may then well be asked, is serum disease a form
of hypersensitiveness; that is, is it dependent upon a special
mechanism and is the reaction specifically influenced as the re­
sult of tlie administration of the exciting agent?
Serum disease as seen in man cannot be reproduced in animals®
and further, as recently shown by Coca in his study of serum
disease in the American Indian, this race is much less susceptible
to the disease, only 46 per cent, than is the white man in which
over 90 per cent are susceptible.
Yfith regard to the second point— alteration of the reaction
by administration of the exciting agent— the observations of
von Pirquet and Schick supported by Goodall and by Currie,
have established the fact that there is a definite short­
ening of the incubation period following reinjection and, though
not the rule, von Pirquet and Schick and Goodall have reported
cases with an entire absence of symptoms of serum disease on
reinjection when the first injection had given typical manifesta­
tions. But it must be borne in mind that these alterations of
reaction do not conform to the principles of desensitization or
anti-anaphylaxis nor to the phenomenon of hj'posensitization
of atopy.

DERM ATITIS VENENATA

For some years we have undertaken, more or less casually, a

study of the irritants in poison ivy and sumac. These are readily
extracted in 95 per cent alcohol and in chloroform, as shown by
the fact that a small amount of the extract applied to the intact
skin produces the typical vesicular lesion. Dr. Spain recently
undertook a more intensive study, and in a recently published
work from our clinic, he has shown that the eruption occurs only
I’ This is true with the single exception reported by Zinsser of what appeared
to be serum disease in one monkev.
after an incubation period of from two to fourteen days, in one
case twenty-four days. He further showed that the typical
vascular lesion could be produced by test in 64 per cent of 104
cases, including children and adults. More recent and still
unpublished work indicates that this percentage may be consid­
erably increased for in no case tested with the stronger sumac
extract has the reaction failed, except that no reaction has yet
been obtained with the strongest extracts in infants before the
age of three.
Other facts elicited are that this extract is non-toxic for animals
when injected intravensouly and the skin of anim.als, dogs, rab­
bits and guinea pigs, is not in any w^ay affected by the applica­
tion of the exti-act to the skin. Tn other words the active principle
is not a simple escharotic.
It is not necessary to argue that this reaction is not an anaphy­
lactic reaction for it is non-antigenic. The reaction in man is
not a form of atopy on account of the high general incidence and
the fact that incidence by age groups does not show the in­
fluence of bilateral, unilateral and negative inheritance. That
it is a form of hypersensitiveness however is evidenced by the
fact that the reaction is mediated by a special mechanism that
is absent in animals and is not developed in the human until the
age of three. That the reaction can be specifically influenced
by administration of the extract is evidenced in some still un­
published work but will not be further discussed here.
These two reactions observed in man, serum disease and der­
matitis venenata, for the reasons given above would seem prop­
erly to be included as forms of hypersensitiveness and because of
their incidence in such a large percentage of the white race are
satisfactorily grouped under the subdivision of “normal” forms,
showing only quantitative variation within the species.

CONCLUSIONS

The term hypersensitiveness has been defined.

Biological or cellular activities in response to mechanical and
thermal and chemical irritants, as well as the ordinary pharma­
 cological reactions of drugs, are excluded as requiring no special
niechanisrii and not subject to specific alteration by the use of
the specific agent.
Hypersensitiveness is subdivided into;
1. Normal forms dependent only upon quantitative variations
within the species, serum disease and dermatitis venenata have
been discussed as examples.
2. Abnormal forms dependent entirely upon qualitative
differences \^'ithin the species. In this group belong: (a)
anaphylaxis, an antigen antibody reaction; (6) atopji", the in­
herited human hypersensitiveness; (c) the sensitiveness of
infection.