Rapp. III, 7e Congr. int. Oto-Rhino-Laryng., Paris 1961. Adv. Oto-Rhino-Laryng.

,
vol. 10, pp. 86-114 (Karger, Basel/New York 1961).

From the Oto-rhino-laryngological Department of the University of Leyden

The Eosinophil Cell and its Role in Allergy and in
Infection

By R. VOORHORST

For an adequate discussion of the problems indicated by the

title of this paper, it is of first importance to define the terms allergy
and infection in the cadre of this symposium.
Allergy (v. PIRQUET) must be defined as an altered reactivity
of the organism in a qualitative sense. Differences in a quantitative
respect (hypersensitivity, hyperergy, hypergy, etc.) are not comprised
under the heading allergy. The term allergy however is an overall
concept which must be subdivided into different syndromes, viz. :
a) Atopy (Coca, reagin-type allergy, prototype: hayfever).
b) Anaphylaxis (Richet-Portiers, determined by the presence of
convential or blocking antibodies).
c) delayed type allergy (v. PIRQUET, prototype : tuberculin reaction).

Atopy and Anaphylaxis

Atopy and anaphylaxis can be joined together under the

heading immediate type allergy. Though both syndromes have this
in common that their symptoms are very similar, for they mainly
depend on histamine liberation, there are nevertheless many reasons
for distinguishing both. The most important reason is that atopic
reagins and anaphylactic antibodies are so very different. See table I.
In respect to the upper respiratory organs, atopy comes first
into consideration. The most typical example is hayfever, and all
other kinds of atopies before they can be accepted as such, must
resemble hayfever in some way.

Atopic Allergy of the Upper Respiratory Organs

Elsewhere (VOORHORST 1961) we have listed the characteristics

which must be met with for the demonstration of certain complaints
to be dependent on atopic allergy:
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Voorhorst 87
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Table I
Some Differences between Anaphylaxis and Atopy in Man.

1) Positive skin-reactions to an extract of the suspected allergen

must be found. These skin-reactions must be caused by the
presence of cell-bound reagins, which in principle can also be
demonstrated circulating freely in the blood.

2) The complaints must originate at first on the spot where the

allergen comes into contact with the organism. The localisation
of the complaints must be plausible (Kontaktregel Hansen).
3) The suspected allergen must be demonstrable in sufficiently
large quantities in the environment of the patient.

88 Voorhorst

4) The complaints must begin or increase after (experimental)

contact with the respective allergen and decrease if there is no
contact with the substance ("allergen-free rooms").
5) If one is considering a large group of patients, who are atopic
to the same allergen, there must be a quantitative relation
between the degree of atopic allergy and the quantity of the
allergen, which gives complaints.
6) The pathological manifestations on the spot where the allergen
comes into contact with the organism must resemble those
which are caused by histamine.
7) In more severe cases of atopic allergy there must be, for the
period during which the organism comes into contact with the
allergen, an increased production of eosinophil cells (this subject
will be dealt with more particularly in this paper).
8) This form of allergy is strongly constitutionally determined,
possesses a strongly heriditary character and is very closely
correlated with atopic constitutional dermatitis.
9) As a final proof a specific desensitization procedure must produce
good results.

Delayed Type Allergy and Infection

Quite apart from the dermatologie forms of delayed type

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allergy (contact dermatitis, etc.) in which mostly simple chemical

compounds are involved, which are only of minor importance in
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respect to the respiratory organs, (VOORHORST 1959) it is clear that
most delayed type allergic processes of nose and bronchi are related
to bacterial products and so delayed type allergy of these organs
cannot be discussed without discussing their inflammatory processes.
Inflammatory processes of nose and bronchi can be divided into :
Acute processes (caused by viruses, streptococci, pneumococci,
Haemophilus influenzae, etc.). These processes generally heal after
a short time, but sometimes change into chronic ones. The mechanisms
which underlie these processes are not too well understood.
The viruses are mostly harmful through their cytopathogenic
effect, some bacteria producing exotoxins or endotoxins, others
presumably other poisonous substances or enzymes.
The chronic processes can be divided into two kinds which may
change into each other, the purulent and the "allergic" and it is
very probable that delayed type allergic reactions to certain bacterial

The Eosinophil Cell and its Role in Allergy arid in Infection 89

products are responsible for many symptoms of these processes

both locally and generally (Koch phenomenon). These
symptoms however cannot easily be separated from other factors
which are certainly involved also.
In the discussion now of the role of the eosinophil cell in allergy
and infection we will deal first with its role in the atopic allergic
phenomena (atopic rhinitis and atopic asthma) and then in nonatopic
rhinitis vasomotoria and asthma. The latter diseases lack the
characteristics of atopic allergy altogether and are - as we think due
to chronic infectious processes (haemophilosis) either in the
purulent phase or even more frequently in the (delayed) allergic phase.
Of course it is evident that chronic infectious diseases can be
involved in cases of atopic allergy and vice versa, so that the separation
of the atopic and non-atopic diseases never can be sharp.

The Eosinophil Leucocyte

According to many investigators the eosinophil leucocyte plays

an important though not a very clear role in different allergic
situations. Some investigators even think that they can deduce from
the presence of eosinophil cells in certain processes, that allergic
factors are involved in these processes.
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The eosinophil cell was discovered by WHARTON JONES in 1846

and received its name form EHRLICH (1879) who demonstrated
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that the granules could be stained by acid dyes and as eosin in
particular was used for this purpose, he called these cells eosinophil
leucocytes. Since that time numerous papers on the eosinophil cell
have been published (SAMTER estimated in 1955 this number to
be about 10000) but nevertheless we know very little about the
proper function of this cell.
The typical eosinophil granules are rather resistent, and consist
of phospholipoids and phospholipoproteins with a fairly large
quantity of oxyribonucleinic acids. In a free state the granules are
sticky. They contain moreover a considerable amount of iron and
phosphorus.
The Charcot-Leyden crystals, which are frequently seen in
sputa, etc. which are rich in eosinophil cells, can be experimentally
produced very easily by mechanical lesions of the eosinophils and
are presumably an intermediary product of the autolysis.

90 Voorhorst

At the moment it is generally accepted that the eosinophil cell

originates in the bone-marrow and that only in cases of extra medullary
hematopoiesis are eosinophil cells formed outside this organ.
Some investigators (DÉROBERT, GODLOWSKI) think that there is
also an extramedullary origin of the eosinophil cells (metaplasia).
Against their hypothesis are the following observations: (BIGGART
1932; VOORHORST 1958) that there is a good correlation between
the degree of eosinophilia of the bone-marrow and the blood eosinophilia,
and also that mitosis of eosinophil cells in tissues heavily
infiltrated with eosinophil cells, is never seen.
The eosinophil cell has mostly the typical nuclear form of a
pair of glasses. In cases of extreme eosinophilia, the younger phases
of medullary eosinophilopoieses can be observed outside the bonemarrow.
The eosinophil granules are relatively resistent and it may
happen, that, when the granules are phagocytized by mononuclear
elements (histiocytes) one may get the impression that these are
mononuclear eosinophil cells. We think that all these facts are the
cause of some confusion about the place of origin of these mononuclear
eosinophil cells. LENDRUMS selective staining with hematoxylin-chromotrope
contributed much to a better understanding of
these facts.
The number of eosinophil cells in the blood is not constant.
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It is dependent on the productivity of the bone-marrow on the one

hand and on the other on the disappearance of the cells from the
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blood into the tissues. In man there is a diurnal rhythm with a
minimum during the hours before noon. Mice also show such a
diurnal rhythm, though their minimum is during the night, the
period in which they are most active. In women there is a monthly
rhythm caused by the menstrual cycle with a decrease of the
number of eosinophil cells in the proliferative phase. The number of
circulating eosinophil cells can be diminished by numerous factors,
such as injections of epinephrin, insulin, histamine, etc. We also
find an eosinopenia in all kinds of stress-situations. How far all
these cases of decrease of the number of eosinophil cells are due to
a stimulation of the hypophysis-adrenal system is still questionable.
ESSELIER (1952) demonstrated that the eosinopenia caused by
ACTH is compensated within two days by an extra suppletion of
eosinophil cells from the bone-marrow. Six days afterwards another
(small) eosinopenia can be observed which, according to ESSELIER,
can be explained if it is assumed that the large number of eosinophils

The Eosinophil Cell and its Role in Allergy arid in Infection 91

which had suddenly left the bone-marrow died almost at the

same moment. It would then be concluded that the life-span of the
blood-eosinophil cell is about six days. In our own experiments with
ascaris eosinophilia in mice (VOORHORST, 1958) we had analogous
results. The peak in the number of bone-marrow eosinophils preceded
that of blood-eosinophils by two days. The increased number of
bone-marrow eosinophils had disappeared 2 days before that of the
blood-eosinophils, so that in mice the life-span must be estimated
at about two days. The disintegration of eosinophil cells presumably
occurs in the reticuloendothelial system. Many times eosinophil
granules are seen in cells belonging to this apparatus. Frequently
after spleen extirpation an eosinophilia is seen, and also after
blocking of the RES by means of trypan blue. A hyperactivity
of the spleen causes an eosinopenia.
According to JEANNERET and ESSELIER (1954) an eosinophilia
can be due either to an increased production of eosinophil cells by
the bone-marrow or to an inhibition of the disintegration by the
RES. The latter authors think that the eosinopenia from cortisone
is caused both by inhibiting the eosinophils swarming off the bonemarrow
and by the increased phagocytosis of these cells by the
RES. Corticoids have no strong influence on the eosinophil cells in
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the bone-marrow itself.

Estrogenic and androgenic hormones have an inverse influence :
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They cause a blood-eosinophilia. Furthermore, increase of circulating
blood-eosinophils can be seen after repeated injections of crude
liver-extracts, a phenomenon already discovered by MINOT and
recently confirmed in rabbits. What mechanism is involved in this
eosinophilia is altogether unknown.
The function of the eosinophil cells is also very uncertain.
They do have phagocytizing functions, though in a lesser degree
than the neutrophils. Proteins are also phagocytized and it has been
thought that the eosinophil cells play a role in the disintegration of
certain proteins. The eosinophil leucocyte contains according to
Code a certain quantity of histamine, but at the moment we do
not think that these cells are the source of a hyperhistaminemia.
It is much more probable that they have the task of removing the
histamine from the blood. This view is supported by the enzymatic
equipment of these cells (Vercauteren 1951), which points to a
function in the further metabolizing of histamine.

92 Voorhorst

Periferal Eosinophilia

In manifest atopic processes, eosinophil cells can always be

found in the organ in which reagin and allergen meet each other,
e. g. in the mucous membranes of nose and bronchi. Eosinophilia
of nasal mucus and sputum can be considered as a direct consequence
of the tissue-eosinophilia. This eosinophil tissue infiltration can be
called a periferal eosinophilia. It appears, that by the reaction between
reagins and allergens eosinophil cells are attracted (probably
chemotactically) from the circulation. This is least to be doubted
in hay-fever. During the hay-fever season practically in every
sample of nasal mucus a smaller or large number of eosinophil cells
can be found. Out of this season this is seldom the case in the same
group of patients (see fig. 11).
It should be conceivable that this normal reaction with a periferal
eosinophilia, should be related to the atopic constitution. This
is however not the case. BERGER AND LANG (1930) demonstrated
that a local infiltration of the reaction area with eosinophils (attracted
chematoactically from the circulation) also occurs in the
Prausnitz-Küstner technique, though the normal recipients themselves
had a normal number of circulating eosinophil cells during
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the experiment.
WERNER (1956) saw something analogous in the skin area
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which had been treated by an injection of a histamine solution,
though it must be realised that the localization of histamine in both
cases is not the same. ARCHER (1959), working with ponies, demonstrated
also that histamine causes a chemotactical attraction of
eosinophil cells. They persist in the skin for about 4 days. Antihistamines
applied locally depressed this effect, almost completely
though their action is effective for only a relatively short time. Pretreatment
of the skin with corticoids did not prevent the local
eosinophilia caused by histamine injections, nor did a general pretreatment
with ACTH either. 5-Hydroxytryptamine had no influence
on the eosinophil cells at all.
In experimental animals we see the same infiltration of
eosinophil cells as a consequence of a number of reactions. The
guinea-pig shows these eosinophil infiltrations very readily, especially
in anaphylactic reactions. Soon after a subletal anaphylactic shock
the lungs are full of eosinophil cells. If a part of the lungs of a
guinea-pig immediately after beginning of the shock and before the

The Eosinophil Cell and its Role in Allergy arid in Infection 93

eosinophil infiltration is transplanted into the peritoneal cavity of

another (untreated) guinea-pig, then within about two hours there
is an eosinophil infiltration of the dead lungpart. Presumable substances,
liberated in the lungs during the anaphylaxis, have attracted
these eosinophil cells (SAMTER 1953).
The guinea-pig however is no ideal experimental animal for
studying reactions of the eosinophil system, because a number of
factors such as protein disintegration products, histamine and
acetylcholine cause reactions of the eosinophil cells in this animal.
The author however also saw an attraction of eosinophil cells
in mice which had had an ascaris suis infection before, after intraperitoneal
administration of ascaris products. As has been explained
elsewhere, infections by worms give rise to reactions which are very
similar to atopic reactions (VOORHORST 1958).

Fig. 1. Migration of eosinophil cells into the peritoneal cavity of sensitized and of nonsensitized
mice after intraperitoneal injection of ascaris allergen.

94 Voorhorst
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The periferal eosinophilia which will be studied in clinical

practice mostly as an eosinophilia of secretions (nasal-mucus, sputum)
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does not necessary belong to atopic reactions.
Several other circumstances, presumably when histamine or
protein-disintegration products are liberated, can be the cause of
an eosinophil infiltration. The eosinophilia in malign tumours and
chronic inflammation processes is well-known. If these circumstances
can be excluded (which is not so easy especially in regard to chronic
inflammations) then the secretion-eosinophilia is, according to our
experience, typical for a manifest atopic reaction.

Central Eosinophilia

The eosinophilia of bone-marrow and blood (= central

eosinophilia) which is found in atopic patients is presumably controlled
by other mechanisms than the periferal.
The number of eosinophil cells which circulates in blood is, as
has already been mentioned above, the resultant on the one hand
of the production of new cells by the bone-marrow and on the
other hand of the loss of cells to the tissues and through the phagocytosis
of the reticulo-endothelial system.
A typical example of the influence of the migration of eosinophil
cells into the tissues is found in patients with extensive urticaria
or Quincke's oedema. The number of eosinophil cells of the
blood in these patients is very frequently lower than 100/mm3.

Table II
Eosinophil leucocytes in blood of 99 cases of urticaria :

The strong eosinophilia, described by us (VOORHORST 1959),

which originates in mice on the 3th day after an intraperitoneal
injection of 50 X 109 germs of hemophilus pertussis, is thought to
be dependent on a blocking of the RES, also because no corresponding
change of bone-marrow eosinophils could be demonstrated,
(fig- 2).

The Eosinophil Cell and its Role in Allergy arid in Infection 95

Though many factors influence the number of blood-eosinophils

and though it would be better to study the central eosinophilia
by examination of the bone-marrow itself, this method is for
large groups of slightly diseased patients too radical, so that in
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Fig. 2. Strong blood eosinophilia in mice on the third day after an intraperitoneal injection
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of 50 X 109 germs of haemophilias pertussis without reaction of the eosinophils in
bone-marrow.

spite of many drawbacks the study of the number of circulating

eosinophils is the obvious method to get an impression of the production
of these cells in bone-marrow. Repeatedly it has been
demonstrated (DRUKKER 1946, HABELMANN 1940, DEBRÉ 1936)
that in atopic allergy (e.g. asthma) there is a considerable bonemarrow
eosinophilia (10-20%), but exact data are very scarce in
the literature. In practice many objections, which should make the
eosinophil cells in blood a questionable indicator of the medullary
eosinophilia, appear to be only theoretical. If the blood-eosinophils
of patients are counted on successive days, it is remarkable how
very well these numbers agree in most cases. There are patients,
however, who show strong variations in number of eosinophils, but
often there is an explanation for this (e.g. variation in exposure to
allergens, infection, etc.). Nevertheless it is advisable in the investigation
of the number of eosinophil cells in the blood to keep all
circumstances which can influence this number as constant as
possible, e.g. by pricking the patients always at the same time of the

96 Voorhorst

day. A perfect counting-technique of the eosinophil cells (in the

counting-chamber) is also required.

Age-influence

There is not much data on the normal number of eosinophil

cells, counted under basal circumstances. From recent investigations
of VEENING'S (1958) it appeared that the number of eosinophil
cells in normal young children is rather high, but this number
gradually decreases with age.
His average numbers of blood-eosinophils counted under "basal
circumstances" are:

Table III

According to him the number of eosinophils would remain

constant at an adult age. We made investigations into the number
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Fig. 3. Number of eosinophils in blood of healthy prisoners under "basal circumstances".

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The Eosinophil Cell and its Role in Allergy arid in Infection 97

Fig. 4. Eosinophil cells in blood from 92 untreated hay-fever patients during the hay
fever season.

Fig. 5. Eosinophil cells in blood from 234 asthma-patients, who were atopic to 0.1%
house-dust extract. The patients are divided into age groups.

of eosinophils in normal male prisoners from 18 to 65 years and

could find little age influence either (fig. 3).
In contrast with normal persons, there is also in atopic patients
at an adult age an undeniable age-influence on the number of
eosinophil cells (fig. 4 and 5).

98 Voorhorst

As it appears (fig. 6) that also the number of patients with

hay-fever and house-dust positive asthma, who visited the allergic
department decreases with age, one should be inclined to combine
both facts and conclude that the "manifestness" of atopy decreases
with age.

Fig. 6. The number of asthma-patients with positive skin-reactions to 0.1 % house-dust

extract (who visited the Department of Allergology) decreases with age.

This agrees well with the clinical observation of numerous

hay-fever patients who report that their individual complaints decrease
when they grow older and it also agrees well with the experience
of every pediatrician, who sees that the greater part of
children's asthma heals during puberty and adolescence.

Correlation between Blood-eosinophilia and Atopic Skin-reactions

In a large number of patients with so called "allergic" rhinitis

and/or asthma who are examined by means of skin-reactions, it

The Eosinophil Cell and its Role in Allergy and in Infection 99

Fig. 7. Correlation between skin-reactions to different dilutions of house-dust extract

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and the number of eosinophil cells in the blood of 266 asthma-patients. - On the left :
The average reaction to different concentrations of house-dust expressed in + marks is
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plotted against the tenfold allergen dilutions.

appears that they can roughly be divided into two groups: with
and without positive skin-reactions. Those positive reactions can be
called the atopic ones. At least for our country the greatest majority
of positive skin-reactions are found to house-dust (and human
dander). Though this does not hold good for every individual
patient, for larger numbers of patients there is a nice correlation

Figure 8

Fig. 8. Correlation between the skin-reactions to different tenfold dilutions of human

dander-extract and the number of eosinophil cells in blood from 220 rhinitis and /or
asthma patients.

Table IV

between the number of eosinophil cells in blood and the strength

of the skin reaction (fig. 7 and 8).
In a relatively large group of asthma patients (143 patients)
there existed an "astronomically significant" correlation between

The Eosinophil Cell and its Role in Allergy arid in Infection 101

the presence of a reaction of the eosinophil system and the presence

of positive skin-reactions to house-dust (table IV).

Eosinophila and the Exposure to Allergens

The relation between the reaction of the eosinophil system and

the exposure to allergens, to which patients are atopic, can best be
studied in hay-fever patients, because we know exactly the period
when grasspollen occurs in the air, when the exposure begins and
when it ceases. For the two most common allergens, house-dust
and human dander, the latter occurs the whole year round. Though
the amount of house-dust allergen is strongly influenced by climatological
circumstances, nevertheless the house-dust allergen is seldom
altogether lacking.
Moreover house-dust and human dander atopy occur generally
in the same patients together, so that these patients can not be used
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without more ado in the study of the influence of the exposure to

allergens on the eosinophil cells.
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Figure 9

Fig. 9. Eosinophil cells in the blood of the same hay-fever patients both during and out
of the hay-fever seasons of the years 1957, 1958 and 1959.

Fortschritte der Hals-Nasen-Ohrenheilkunde, Vol. 10 (1961) 8

102 Voorhorst

Figure 10

Fig. 10. Eosinophil cells in blood of treated and untreated hay-fever patients in summer
and winter.

The Eosinophil Cell and its Role in Allergy arid in Infection 103

Figure 11

Fig. 11. Eosinophil cells in nasal mucus from treated and untreated hay-fever patients
in summer and winter.

104 Voorhorst

It appears from fig. 9 that in most hay-fever patients an increased

number of eosinophil cells in the blood can be found only in
the hay-fever season (half May to 1st August), and this disappeared
when the exposure has ceased. According to our clinical experience
there is also a correlation between the severity of the hay-fever
complaints and the degree of eosinophilia during the season. Hayfever
patients with a normal number of eosinophil cells during
summer have as a rule relatively few complaints, so that it is mostly
unnecessary to treat them by desensitization. The observation (fig.
10) that desensitized patients (mostly with good clinical results)
have in the hay-fever season fewer eosinophil cells in the blood than
the untreated ones is an indication in the same direction.
The same facts can be observed in respect to the eosinophil
cells in the nasal mucus (fig. 11).
Further there exists (as can be seen from fig. 12) for the whole
group of hay-fever patients a nice quantitative correlation between
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the degree of blood-eosinophilia and the quantity of eosinophil

cells in the nasal mucus.
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Fig. 12. Correlation between the numbers of eosinophil cells in blood and nasal mucus
in 67 hay-fever patients during the season.

The Eosinophil Cell and its Role in Allergy arid in Infection 105

The same effect is seen in respect to the eosinophil cells in the

nasal mucus and sputum in patients with vasomotor rhinitis and
asthma (fig. 13).
For atopic asthma patients we found the same correlation
between blood- and nasal-mucus eosinophilia. Moreover there appeared
to be a correlation between the quantity of eosinophils in
nasal mucus and sputum (fig. 14).
In conclusion we can say that all these observations support
our view that a reaction of the eosinophil system occurs after the
exposure to allergen, and that the degree of this reaction corresponds
to the degree of atopic reaction.

Fig. 13. Correlation between the number of eosinophil cells in the blood of rhinitis and
asthma patients and the amount of eosinophil cells in nasal mucus and sputum.

Fig. 14. Correlation between the content of eosinophil cells of nasal mucus and sputum.

Autonomous Process of Development of Eosinophil Cells

Studies in the development of the eosinophil cells in blood

(and in bone-marrow) can hardly be done in atopic patients. For
instance, in pollinosis the exposure to pollen comes gradually in the
second half of May. Practically all the known hay-fever patients
are treated and show a much slighter eosinophilia during season
than the untreated ones, so that they cannot be used for bone-marrow

106 Voorhorst

investigations. The untreated patients come too late in the season

for a study of the start of a reaction of the eosinophil system.
In respect to the beginning of the eosinophilia therefore we
made experiments with mice which we fed infectious eggs of ascaris
suis (VOORHORST 1958). We think it right to consider the ascaris
allergy as predominantly atopic. (The delayed type allergy is left
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out of consideration). As in atopic allergy we find in men with

ascaris infestations positive skin-reactions, transferable by Pr. K.
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technique and depending on thermolabile reagins to ascaris products.
Furthermore there is in ascaris infestations a strong reaction
of the eosinophil system.
The only difference with other forms of atopy is that the sensitization
in the atopic sense by ascaris is so strong, that the constitutional
factor, generally required for these sensitizations, plays only
an inferior rôle.
For the technique of contaminating mice with ascaris and the
counting of eosinophils in mice etc., the reader is referred to the
relevant paper (VOORHORST 1958). After contaminating mice orally
with a certain number of infectious eggs of ascaris suis the larvae
come out of the shell because of the action of digestive juices and
penetrate the intestinal wall. At first most larvae can be found in
the liver, but later, when the cycle, which biologically speaking is
broken, comes to an end they are found in the lungs (SPRENT 1949,
1951). After such an infection (generally after a latent period of
10-15 days) the number of blood eosinophils increases rather suddenly

Fig. 15. Eosinophil cells in mouse-blood after administration of 30000 fertile eggs of
ascaris suis per os.

The Eosinophil Cell and its Role in Allergy and in Infection 107

Fig. 16. Eosinophil cells in mouse-blood after administration of 30000 fertile eggs of
ascaris suis per os (five series of experiments).

Fig. 17. Eosinophil cells in blood and in bone-marrow of mice after administration of
30000 fertile eggs of ascaris suis per os.

108 Voorhorst

to a very high number, so that very often values can be found

of 3500 eos. per mm3 (fig. 15 and 16).
The appearance of a peak of eosinophil elements in bonemarrow
precedes the peak of blood eosinophils by two days (fig. 17).
There is a nice correlation between the numbers of eosinophil
cells in bone-marrow and blood (fig. 18).

Fig. 18. Correlation between the highest number of eosinophil cells in blood and in
bone-marrow of mice after administration of fertile eggs of ascaris suis per os. Each
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point represents the average values of 5 mice.

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After a second exposure to ascaris larvae we saw that the
number of eosinophil cells increases again, and again we see a
peak between the 10th and 15th day (fig. 19). The second time
the bone-marrow reaction preceded the blood reaction again by
two days.

The Eosinophil Cell and its Role in Allergy arid in Infection 109

If we should accept that the reaction of the eosinophil cells is

a consequence of a contact with an allergen after atopic sensitization,
the curve of fig. 19 cannot be explained.

Fig. 19. Eosinophil cells in blood of mice after two administrations of 30000 fertile eggs
of ascaris suis in succession.

The animals are certainly sensitized during the first phase of

eosinophilia (as appears from the liability to react with shock after
intravenous injection of an ascaris extract). After a second contact
the eosinophilia ought then to come earlier, because the time for
the sensitization is not required in the second infection.
The supposition just put forward therefore cannot be true;
and we must conclude that the development of eosinophil cells is
a process with a proper autonomy, which is surely not the consequence
of a former sensitization. It is very attractive to suppose,
seeing the strong correlation between the reaction of the eosinophil
system and atopy, that this autonomy is involved in some manner
in the production of reagins. This hypothesis is supported to a
certain extent by our observation that shock reactions after intravenous
injection of ascaris products cannot be provoked before there
has been a bone-marrow eosinophilia (fig. 20).
Eosinophilia in non-atopic vasomotor rhinitis and/or asthma both in
the infective and in the infectious phases.

Acute infectious processes and delayed type allergic reactions

are not characterized by eosinophil infiltrations. Acute processes as

110 Voorhorst

a rule cause (partly by a stimulation of the adrenal cortex, Israels

1952) an eosinopenia.
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More or less important eosinophil infiltrations, however, are

nevertheless found fairly often in chronic inflammatory processes
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(cholecystitis, appendicitis, chronic otitis media etc.) and also in
nasal mucus and sputum of distinctly non-atopic patients with

Fig. 20. Shocks and numbers of eosinophil cells in blood of different mice after administration
of fertile eggs of ascaris suis per os. Curve : average numbers of eosinophil cells in
the bone-marrow.

asthma and/or vasomotor rhinitis. There must be some mechanism

of attraction of eosinophil cells quite different from the atopic one,
though both mechanisms may have a common path.
A number of pathologists have recorded the presence of mast
cells in inflammation, and have stated that they may be especially
numerous during chronic inflammations. It has been observed that
prolonged inflammatory conditions are favourable for the increase
of the numbers of lymphocytes and plasma cells, and also for the
number of mast cells (KELSALL and CRAB 1959). MESSERKLINGER
(1960) observed that during acute inflammatory processes of the
respiratory organs no cells with typical metachromatic granules
are found. However in cases of hyperplasia of the nasal mucous

The Eosinophil Cell and its Role in Allergy arid in Infection 111

membranes (thus in cases mostly of non-atopic origin) the number

of mast cells is distinctly increased and they can often be found in
small groups. MESSERKLINGER observed that if eosinophils are
present, the mast cells are coloured far less distinctily than in cases
with little eosinophil infiltration. It may be presumed that mast
cells with less distinctly coloured metachromatic granules have lost
their histamine (and heparin) content to their surrounding and this
may be one cause of the attraction of the eosinophil cells. The same
combination of mast cells and eosinophil cells is seen in cases of
urticaria pigmentosa if the mast cells are damaged.
In respect to the increased number of blood eosinophils in
cases of non-atopic vasomotor rhinitis and asthma, there must also
be some relation.
Though the blood eosinophilia in these non-atopic diseases is
far less typical than in atopic ones, there is nevertheless a significant
difference from the number of bloodeosinophils in normal people.
As we can also see in atopic asthma and rhinitis vasomotoria, the
eosinophils are more numerous in the asthma cases.
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In the same way as in normal persons the frequency of an increased

number of eosinophils is higher in young people under 20.
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We can characterize the eosinophilia in the non-atopic rhinitis and
asthma patients as being an intermediate between the atopic and
the normal values.
We might ask ourselves whether there are some allergens still
undiscovered which might cause certain patients to be reclassified
from the non-atopic group to the atopic. At the moment, however,
we have no means of knowing of the existence of any other allergens
than the conventional ones and we are much more inclined to
think of some quite different factors which might increase the number
of circulating eosinophil cells. Neglecting worminfestations, we
think first of a hypofunction of the hypophysis-adrenal system,
which is known to work in these patients at a low level. We do this
especially because the eosinophilia in the non-atopic patients is as
a rule not very high.

Summary

For a satisfactory discussion of the problems concerning the

eosinophil leucocyte and rhinitis vasomotoria and asthma it is necessary
to distinguish in these diseases an atopic and a non-atopic
form. The atopic form is closely connected with the reactions of the

112 Voorhorst

eosinophil cells. First there is an attraction of eosinophil cells to the

places where the allergens come into contact with the reagins fixed
to the cells of the mucous membranes. In the second place, in
atopic patients there is a central (bone marrow and blood) eosinophilia
during the time that the patients come into contact with
the allergens to which they are atopic. In the patients with nonatopic
vasomotor rhinitis and asthma, a certain degree of reaction
of the eosinophil system may exist, but this is usually much weaker
than in the atopic cases. These weaker forms of eosinophilia are
difficult to explain. For local eosinophilia, we think first of the
liberation of protein disintegration products and of histamine, the
latter by mast cells, which are very numerous in the mucous
membranes of these patients. As for the increased number of blood
eosinophils, it is possible that the low level function of the hypophysis-adrenal
system favours their development.
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Zusammenfassung
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Für eine befriedigende Diskussion des Problems der eosinophilen
Leukozyten und der Rhinitis vasomotoria sowie des Asthmas
ist es nötig, bei diesen Krankheiten zwischen einer atopischen und
nichtatopischen Form zu unterscheiden. Die atopische Form ist eng
mit den Reaktionen der eosinophilen Zellen verbunden. Zuerst
erfolgt eine Anlockung der eosinophilen Zellen zu den Stellen der
Schleimhaut, wo die Allergene mit den an den Zellen fixierten
Reaginen in Kontakt kommen. In zweiter Linie tritt bei atopischen
Patienten in der Zeit während welcher sie Kontakt mit
den Allergenen, zu welchen sie atopisch sind, haben, eine Eosinophilie
auf (Knochenmark, Blut). Bei Patienten mit nicht atopischer
vasomotorischer Rhinitis und Asthma kann ein gewisser Grad von
Reaktion des eosinophilen Systems existieren, aber gewöhnlich ist
sie viel schwächer als bei den atopischen Fällen. Diese schwächeren
Formen von Eosinophilie sind schwierig zu erklären. Bei lokaler
Eisinophilie denken wir zuerst an freiwerdende Proteinabbauprodukte
und an Histamin, welch letzteres aus den in den Schleimhäuten
dieser Patienten reichlich vorhandenen Mastzellen stammt.
Was die Bluteosinophilie anbetrifft, so ist es möglich, daß die niederschwellige
Funktion des Hypophysen-Nebennieren-Systems deren
Entstehung begünstigt.

The Eosinophil Cell and its Role in Allergy arid in Infection 113

Résumé

La discussion du problème de l'éosinophilie dans la rhinite vasomotrice

et dans l'asthme ne peut être résolue convenablement qu'en
distinguant dans ces maladies une forme atopique et une forme non
atopique. La forme atopique est étroitement liée avec les réactions
des éosinophiles. Il y a tout d'abord une concentration de cellules
éosinophiles aux endroits où des allergènes entrent en contact avec
les réagines fixées aux cellules des muqueuses. Puis, chez les
malades atopiques, survient une éosinophilie centrale (moelle
osseuse et sang) durant aussi longtemps qu'il y a contact avec les
allergènes. Chez les sujets non atopiques atteints de rhinite vasomotrice
et d'asthme, le système éosinophilique peut réagir en une
certaine mesure, mais beaucoup moins fortement que dans les cas
atopiques. Cette forme légère d'éosinophilie est difficile à expliquer.
En ce qui concerne l'éosinophilie locale, l'auteur pense en premier
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lieu à la libération des produits de désintégration des protéines et

de l'histamine, la dernière des cellules basophiles tissulaires qu'on
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rencontre en grand nombre dans les muqueuses de ces malades. En
ce qui concerne l'augmentation du nombre des éosinophiles du
sang, il est possible que la fonction diminuée du système adrénalinohypophysaire
favorise leur développement.

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