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Position Paper: Allergen standardization and skin tests

Article in Allergy · May 2008

DOI: 10.1111/j.1398-9995.1993.tb04756.x

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 Position Paper: Allergen
standardization and skin tests
Editors: S. Dreborg, A. Frew

Introduction

During the annual meeting in Glasgow, July 1990, the Executive Committee of the
European Academy of Allergology and Clinical immunology (EAACI) decided to transform
the Subcommittee on Skin Tests to the Subcommittee on Allergen Standardization and Skin
Tests. Furthermore, the Business meeting of this Subcommittee decided to produce a revised
version of the 1989 Position Paper on skin tests used in type I allergy skin testing and
include in the new version a chapter on “Allergen standard ization by in vitro and in vivo
methods”, replacing the chapter on “Biologic standardization”. The new chapter includes a
general description of factors which affect the potency and composition of allergen extracts
and a second part focusing on standardiza tion of allergenic extracts used for skin testing. The
subcommittees on immunotherapy, provocation tests, and in vitro tests are responsible for
preparing position papers on the Academy’s view on standard ization of allergens for
immunotherapy, in vivo provocation tests, and in vitro tests, respectively. When outlining
Chapter 4, we have been in contact with these subcommittees.
This position paper does not cover skin tests used for the study of immune complex
diseases and delayed-type hypersensitivity.
The different chapters of the position paper on Allergen standardization and skin tests
have been worked out by members of the Steering Committee of the Subcommittee on
Allergen Standardization and Skin Tests. Draft chapters were circulated to all members and
other interested parties and were discussed during a special session at the annual meet ing in
Zurich in May 1991. The final version was discussed and approved by the subcommittee and
then by the EAACI Executive Committee during the Congress held in Paris in May 1992.
During recent years, methods and goals for aller gen standardization have been the subject
of intense discussions within the Academy, and among author ities and industries, and,
recently, the EC regulatory authority has approved directives and guidelines for registration
of allergenic preparations in Europe. These directives and guidelines will soon be imple-
mented by member countries.
There is an international system for allergen standardization and a number of WHO/IUIS
International Standards (IS) labeled in arbitrary interna tional Units (IU). The Academy
stresses the importance of assessing the potency of allergenic preparations, intended for all
types of use, in LU, giving the method for calibration of potency against these IS, in order to
allow comparison of different materials used in scientific investigations and to give an idea
of the difference in potency between mate rials prepared by different manufacturers.
The Academy also promotes the use of biologically relevant units suitable for labeling
commercially available extracts used for diagnosis, since such units allow better and more
reliable diagnosis of sensiti zation and atopic disease.
A number of company-specific units have been launched: some of these units are
equivalent to units prescribed by authorities; that is, the Nordic Biological Unit (BU/ml) and
the US Allergy Unit (AU/ ml). Other units are less well documented. For scientific purposes,
it is essential that well-standardized extracts or pure allergenic components of such extracts
he used.
 Methods of skin testing vary among regions and also among medical specialties. At
present, the skin prick test method using a laneet with 1-mm tip is the method of choice for
routine diagnosis, especially among pediatricians. In contrast to results obtained by
laboratory methods, skin test results are often presented without giving any details of the
potency of the allergen preparation used, the method of test ing, or reproducibility in the
hands of the investiga tor. This fact reduces the value of most published studies using skin
tests. It is our hope that the rec ommendations in this position paper on the per formance,
evaluation, and use of skin tests in diag nosis, standardization, and epidemiologic studies, will
be followed by European allergologists and, es pecially, by editors of scientific journals.
Finally, we hope that this edition of the position paper will stimulate scientific work within
the field.
Sten Dreborg
Anthony Frew
July 1992

Abbreviations
AU, allergy unit; BS, biologic standardization; BU, biologic unit; CGRP, calcitonin
gene-related pep-tide; ECF(ECA), eosinophil chemotactic factor (activity); ECP, eosinophil
cationic protein; ELISA, enzyme-linked immunosorbent assay; EPR, imme diate- or
early-phase reaction(s); FDA, Food and Drug Administration, Bethesda, MD, USA; HETE,
hydroxyeicosatetranoic acid; histamine HO, hista mine dihydrochloride; I-IRF,
histamine-releasing fac tor(s); ICT, intracutaneous skin test(s) (intraderinal skin test(s)); IHR,
in-house reference preparation; IL, interleukin(s); IMP, intermediate product; ISP,
international standard preparation(s); IT, immuno therapy; LPR, cutaneous late-phase
reaction(s); MBP, major basic protein; MC, mast cell(s); OBRR, Office of Biologies
Research and Review (FDA); PAF, platelet-activating factor (PAF acether); 51-5, short-term
sensitizing antibodies; SPT; skin prick (puncture) test(s); ST, skin test(s); VIP, vasoactive
intestinal peptide.

1. Pathophysiology of skin tests

J. Bousquet

Studies of the mechanisms by which allergens and nonspecific agents induce skin reactions
began over 50 years ago when Lewis and Grant described the “triple response”, but in recent
years there has been a major improvement in our understanding of the pathophysiology of
skin tests. The IgE-mediated al lergic reaction of the skin results immediately in a dermal
response which is marked by a wheal and flare reaction, and which is dependent on both
chemical and neurogenic mediators (immediate reaction). This is often, but not always,
followed by a late-phase reaction (LPR) developing over the next 3—5 h, peaking at 6—12 h,
and resolving in approximately 24 h. The LPR appears as an ill-defined edematous reaction
which is related temporally to an influx of inflammatory cells.
1.1. The type I hypersensitivity reaction

The ability to mount an IgE-mediated response to allergens is a prerequisite for the

development of positive allergen skin tests. Some investigators have suggested that IgG
antibodies have anaphylactic properties; others have questioned the existence of IgG
short-term sensitizing antibodies. Other factors influencing skin reactivity to an allergen
include the amount of allergen injected; the number, degree of sensitization, and releasability
of cutaneous mast cells; and the reactivity of the skin to mediators re leased from the mast
cells, particularly histamine.
Skin tests can also be performed with vaso active agents or mast cell degranulating agents.
Histamine induces only a wheal and flare reaction, whereas kinins, PAF-acether, and mast
cell secret agogues elicit both an immediate and a late-phase reaction.

1.2. Histology of the normal skin

T lymphocytes are scattered in the skin, whereas there are no B cells. T cells are present
mainly around the superficial dermal vascular plexus, and occasion ally in the epidermis and
interstitial dermis. The main antigen-presenting cells (APC) in the skin are the Langerhans
cells in the epidermis and the macropha ges in the dermis. There are 5000—12000 mast cells
per mm3, evenly distributed and frequently observed in close anatomic association with
blood vessels and nerves, suggesting that they may be involved in the neuronal control of
skin blood flow (4). These mast cells are predominantly of the formalin-sensitive type and
contain tryptase and chymase (25). Only very few granulocytes are present in the normal
skin, usu ally around superficial venules.
Epidermal changes associated with aging include flattening of the underside of the
epidermis, reduc tion in the number of Langerhans cells and melano cytes, and decline in the
number of melanosomes synthesized. Dermal changes include reductions in the collagenous
and elastic fibers, fibroblasts, mast cells, and macrophages (22). These differences may
explain age-dependent variation in skin reactivity to allergen and vasoactive amines.

1.3. Pathology of type I hypersensitivity reactions

After allergen injection, histopathologic studies of the skin show an influx of fluid within 5
mm, fol lowed by the appearance of inflammatory cells, mainly neutrophils (10 mm after
allergen injection) and eosinophils (later onset). Dunsky and Zweiman have developed a skin
chamber technique to study the skin response to allergen: in this technique the epidermis is
denuded by inducing a skin blister, after which the dermis is covered with a chamber so that
mediators and cells can be recovered.

1.3.1. Immediate reaction

The immediate reaction is dependent on mast cells that are rapidly degranulated after
allergen challenge (10) or injection of morphine. Mast cells in the skin apparently differ from
those in the lung and intestine in being activated for histamine release by endoge nous
neuropeptides and morphine (15). Histamine release begins about 5 mm after allergen
injection and peaks at 30 mm. Tryptase is also released with a similar time course (27).

1.3.2. Late-phase reaction (LPR)

The LPR occurring after allergen challenge is due to lgE antibodies. Biopsies of the LPR
reveal a mixed cellular infiltrate, predominantly made up of mono nuclear cells hut also
including eosinophils, haso phils, and neutrophils, and an extensive deposition of fibrin (7,
26). The same cellular pattern, however, can also be found after an immediate wheal and
flare reaction that does not lead to a macroscopic LPR. Eosinophils are found to be activated,
and the size of the LPR is correlated with the number of acti vated eosinophils (9). There is
also extracellular dep osition of eosinophil major basic protein (MBP), eosinophil-derived
neurotoxin (EDN), and neutro phil granule proteins (elastase) in the skin during LPR (19).
Activated T lymphocytes are also present, and there is a strong correlation between the num-
bers of CD4 + cells and activated eosinophils (9). There is indirect evidence that basophils
cause the persistent release of histamine during continuous an tigen administration in the skin,
since such release is unaccompanied by release of tryptase or POD, (re leased from mast cells
but not basophils), does not occur after codeine challenge (which activates mast cells but not
basophils), and is inhibited by steroids (which inhibit the accumulation and release of his-
tamine from basophils but not mast cells) (1).
Several mediators have been recovered from skin blister fluids after allergen challenge
during the immediate and the late-phase reaction (11, 23, 28, 31). These include histamine (5
mm to 4 h), tryptase, kallikrein, thromhoxane B, POD, (release starting 30 mm after
challenge; peak at 6 h after challenge), LTC 4 (peak 2—4 h after challenge), and minimal
concentrations of LTB4 and PAF-acether (peak 5—6 h after challenge). Uncharacterized
histamine-releasing factors have also been detected in skin blis ter fluids (29).

1.4. Injection into the skin of inflamma tory mediators released during type
I hy persensitivity reactions

Histamine mimics the allergen-induced wheal and flare reaction when injected into the skin
by prick tests or intradermal reactions. However, injection of histamine never produces an
LPR, in contradistinc tion to allergens or mast cell secretagogues. Hista mine is the major, but
not exclusive, mediator of the wheal and flare reaction. In contrast, histamine ac counts for a
limited portion of the LPR (11).
Sulfidopeptide leukotrienes, injected intrader mally, induce a burning, erythematous wheal
and flare reaction persisting for up to 4 h, with a char acteristic central pallor supposedly
caused by arte riolar constriction. Histologically, the wheal and flare reaction is associated
with dermal edema and marked dilation of venules and capillaries.
LTB4 injected intradermally in human skin has been shown to induce a transient wheal
and flare reaction followed by an LPR whose histopathology demonstrates a
polymorphonuclear leukocyte influx and some fibrin deposition.
POD, induces an asymptomatic wheal and flare reaction resolving within 2 h.
Histologically, POD, injection causes dermal edema and vessel dilation, with a subsequent
neutrophil infiltration beginning 2 h after challenge and lasting for a further 4 h. Top ical
application of 12-HElL (l2-hydroxy-5,8,10, 14-eicosatetraenoic acid) produces erythema and
accumulation of neutrophils and monocytes in human skin. Blood flow is increased at 6 and
24 h (30). Cyclooxygenase products, such as prostaglandins and thromboxanes, probably
contribute to IgE dependent skin reactions, both as modulators of me diator release and as
vasoactive mediators (11).
Platelet-activating factor (PAL) administered in tradermally has both acute and delayed
effects, with a wheal and flare reaction that resolves within 30—60 mm and that is followed
by an LPR persisting for several hours (21). The wheal and flare reaction is due to the direct
or indirect vasoactive properties of the autacoid. However, since PAF-acether is rapidly
metabolized in vivo by fluid-phase and cell-associated phospholipases, its delayed effects can
be explained only by its potent. chemotactic activity, especially affecting eosinophils, or its
effects on the release of IL-I and tumor-necrosis factor. By a skin chamber technique, it was
found that the prolonged exposure to this mediator induced the migration of neutrophils and
basophils. Henocq & Vargaftig(14) showed that PAF-acether was able to attract eosinophils
but only in allergic subjects. Moreover, PAF-acether is the most potent eosinophilotactic
mediator, so its re lease induces an influx of various cells which can participate in cutaneous
late-phase inflammation. The vasoactive and chemotactic effects of PAF ap pear to act locally
on a small area, producing a highly focused inflammatory response (16).
A number of preformed mediators have been shown to be capable of activating the
coagulation, fibrinolytic, and bardykinin pathways. The intrader mal injection of a bradykinin
analog leads to a late-phase reaction characterized by a cell infiltrate similar to that induced
by allergen (18), whereas bradykinin itself causes vasodilation and vasoper meability but
without inflammation.

1.5 Pharmacologic studies

Indirect evidence of the role of different mediators in allergic skin reactions can be obtained
in studies of the modulation of reactions by pharmacologic or therapeutic agents. Concerning
the immediate skin reaction, croniolyn does not inhibit codeine-induced histamine release,
while antihistamines inhibit some of the components of the wheal and flare reaction but have
no effect on the LPR. The LPR is blocked by prior administration of topical or systemic corti-
costeroids. Topical application of ETYA (eicosatet raynoic acid) can block both the
cyclooxygenase and the lipoxygenase pathways of arachidonic acid me tabolism and induce a
small but significant reduction of the LPR. Cyclooxygenase inhibitors incompletely alter
edema formation and dazoxiben, a selective inhibitor of thromhoxane synthesis, increases the
wheal and flare reaction and has some part in de creasing the LPR. Topical indomethacin,
another cyclooxygenase inhibitor, decreases the flare without any effect on the wheal.
PAF-antagonists decrease skin tests to PAF-acether and, to a lesser extent, those to allergens.

1.6. Cytokines

Cytokines arc glycoproteins which are synthesized and secreted by various cells, bind to
specific recep tors, and regulate the activation, proliferation, and differentiation of immune as
well as nonimmune cells. Keratinocytes are capable of secreting various immunomodulating
cytokines or secretory regulatory peptides (IL-i alpha, IL- 1 beta, IL-6, IL-8,
colony-stimulating factors, tumor-necrosis factor alpha, growth factors (transforming growth
factor beta) and suppressor factors (epidermal cell-contrainterleukin-i)) involved in
inflammation as well as in healing and repair processes. Many cells of the der mis are also
capable of releasing cytokines: further studies are needed to clarify the role of different
cytokines in the cutaneous allergic reaction and to elucidate the lymphokine cascade in vivo
(20).
lnterleukin-l promotes cell recruitment and influences allergic mediator release, and is
released at sites of allergen-induced cutaneous reactions in human subjects 1 h and 10—12 h
after allergen chal lenge (5). A histologic study of the LPR gained in-. direct evidence of
cytokine secretion, as suggested by increased expression of HLA-DR on endothelial cells and
tie novo expression of the CD4 antigen on epidermal Langerhans cells (9). In a recent study
using in situ hybridization, Hamid et al. (12) have observed that cells infiltrating the site of
allergen-induced LPR transcribe mRNA for genes encoding for IL-3, IL.4, IL-5, and GM-CSF
cluster, possibly representing the human equivalent of the murine Th2 cell phenotype.
In animals, recombinant (r) IL-i alpha, IL-i beta, TNF alpha, 11,-2, and IFN-gamma have
been in jected subcutaneously. Acute (6 h), resolving (48 h) inflammation was induced by the
following cytokines in order of potency: rIL-1 alpha, rIL-1 beta, and rTNF alpha, whereas
rIFN gamma had no effect (6). In human subjects, IFN-gamma injection induces a moderate,
perivascular, lymphohistiocytic infiltrate and intense keratinocyte HLA-DR expres sion (24).
However, IFN-gamma appears to suppress mast-cell-dependent skin reactions. Quantita tive
skin prick tests with allergen were done before and after 20 injections of either recombinant
IFNgamma (100 jig each) or placebo in 30 patients. TFN gamma reduced skin wheal area
significantly but had no effect on allergic bronchoconstriction (3).
Taken together, these studies appear to establish the importance of cytokines in the
generation of the LPR, hut further studies are required to clarify their role.

1.7. Neuromediators

The relationship between neurogenic and cellular inflammation in the generation of the
cutaneous type I hypersensitivity reaction is beginning to be under stood. Experimental
support for the neurogenic hypothesis comes from studies which show that the indirect effect
of histamine on the cutaneous mi crovasculature (in the peripheral flare around the injection
site) is greatly diminished by prior applica tion of a local anesthetic cream (13). The skin re-
ceives a rich supply of nerve fibers, many of them being the peripheral ramifications of
primary sensory neurons involving axonal reflexes in the terminal arborizations of C-fibers
containing substance P, neu rokinin A, and calcitonin gene-related peptide (CGRP). The
physiologic significance of the anti dromic stimulation of small-diameter afferent nerve fibers
localized in the skin is still incompletely known, hut there is good evidence that some
vascular effects of inflammation in the skin are neurogenic. Substance P releases histamine
from skin mast cells and produces dose-related wheal and flare reactions in human skin.
Neurokinin A induces a wheal but lit tle or no flare and is less potent than substance P. CGRP
induces both wheal and flare but is also less potent than substance P. In addition, CGRP in-
duces a slow-onset, intense vasodilation in human skin which persists for several hours and is
associated with leukocyte infiltration, a response which is not seen with substance P. The
possibility that his tamine and mast cells play a role in neurogenic in flammation in skin is still
a matter of debate (8). However, two studies suggest that mast cell activa tion is not essential
for the initial, vascular perme ability phase of neurogenic inflammation in rodent skin (2, 17).
1.8. Schematic representation of type I hypersensitivity reactions

1.8.1. Immediate reaction

The wheal and flare reaction induced by an IgE mediated immune response is mainly due to
the ac tivation of mast cells releasing vasoactive agents, which cause both plasma
extravasation and vasodi lation. Tt is likely that cellular and neurogenic in flammation are
linked, since histamine (more than other mediators) can trigger the release of substance P by
axonal reflex, and substance P enhances the immediate reaction by causing the release of
histamine from mast cells (positive feedback loop). The close proximity of the mast cells to
vessels and nerves in the skin augments these processes.

1.8.2. Late-phase reaction

The exact mechanisms of this erythematous inflam matory reaction are less well
characterized. Mast cells appear to be the trigger cells of the reaction, since the LPR almost
never appears without a pre ceding immediate reaction. These cells release chemotactic
mediators and possibly cytokines, at tracting inflammatory cells to the site of the allergic
reaction. Tt is also possible that the release of vaso active mediators from mast cells increases
vascular permeability, facilitating the access of inflammatory cells and the exposure of these
cells to chemoattrac tant factors. It has been suggested that lymphocytes play a key role in the
generation of late-phase in flammation, and they may he more important than mast cells in the
generation of the LPR. Moreover, lymphocytes release histamine-releasing factors and other
cytokines which can facilitate the release of mediators from mast cells and other cell types.
Eosinophils are known to produce cytotoxic proteins such as MBP (major basic protein) and
ECP (eosinophil cationic protein) that have been shown to be involved in the cutaneous LPR.
They are likely to be key cells of the LPR. Macrophages and neutrophils release chemotactic
factors, cytokines, oxygen free radicals, and enzymes that are involved in the in flammatory
process. Neutrophils are the first cell type to appear in the inflammatory infiltrate after the
immediate reaction. They have been shown to be in an activated state and are thus capable of
initiating the cutaneous damage and attracting other cells, particularly eosinophils. Basophils
are possibly involved: the late release of histamine is probably due to hasophil activation, but
the exact role of these cells remains to be elucidated.

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