Essentials of Allergy - 1st Edition

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Although every effort is made to ensure that drug doses and other information are presented
accurately in this publication, the ultimate responsibility rests with the prescribing physician.
Neither the publishers nor the authors can be held responsible for errors or for any consequences
arising from the use of information contained herein.
© 2001 Martin Dunitz Ltd, a member of the Taylor and Francis group
This edition published in the Taylor & Francis e-Library, 2003.
First published in the United Kingdom in 2001 by
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Contents

Foreword v
Preface vii
1 Diagnostic tests in allergy 1
2 Asthma 15
3 Rhinitis 29
4 Urticaria and angioedema 53
5 Anaphylaxis 77
6 Insect venom allergy 85
7 Drug allergy 95
8 Food allergy 107
9 Atopic dermatitis (eczema) 129
10 Immunotherapy 145
11 Latex allergy 161
12 Eosinophilic lung diseases 167
13 Extrinsic allergic alveolitis 181
Index 191
Foreword

Atopy, a predisposition to IgE-mediated allergic

disorders, is defined as the presence of a positive skin
test and/or raised serum allergen-specific IgE to one or
more common inhaled allergens. Atopy affects some
30–40 per cent of the population of westernised
countries. Approximately half these individuals develop
clinically significant allergic disorders, which include
allergic rhinitis, conjunctivitis and bronchial asthma.
Allergic rhinitis is particularly common and, although
often trivialized, may have a major impact on quality of
life with impaired performance at work/school, poor
sleep quality and interference with leisure pursuits. Less
common but potentially life-threatening conditions
include anaphylaxis to certain foods and to the venom of
stinging insects.

Essentials of Allergy covers the diagnosis and clinical

management of the common allergies. The less common
eosinophilic lung diseases and extrinsic allergic alveolitis
are also expertly covered. The text is easy to read and
complemented by the many tables and illustrations. The
diagnostic algorithms and detailed information on drugs
vi Foreword

and doses are particularly helpful. particular interest to general practitioners,

Frequently, allergic disorders coexist. nurses and organ-based specialists and
Whereas the first port of call for patients will be a valuable teaching aid for
with multiple allergies is, quite rightly, the allergists.
general practitioner, such patients may
benefit from the multidisciplinary Professor Stephen R Durham
approach offered by an allergy specialist. Professor of Allergy and Respiratory
In this sense, Essentials of Allergy ‘fills Medicine
the gap’ by providing a timely and Upper Respiratory Medicine
comprehensive account of the common National Heart & Lung Institute
allergic disorders. The book should be of London
Preface

Most medical specialties are focused on specific organs,

while others, such as immunology, cover a series of
interdependent events relating to the host and its ability
to protect itself against the environment. The practice of
allergy falls somewhere between the two: strong organ-
based expression (e.g. asthma, atopic eczema) but often
extending to other systems. The definition of ‘allergy’
also leads to confusion – on the one hand, meaning a
group of hypersensitivity disorders with well-defined
immunological mechanisms and, on the other, covering
a range of intolerances to various environmental factors
for which clear mechanisms have not been defined.

Different health systems provide services to allergy

patients through both the primary and secondary care
sectors, with large variations between countries.
Because of the high prevalence of allergic disease, its
rising trend over time and the appearance of new
allergens to which patients react, we felt there was a
need for an easily digestible text on the subject, which
was highly accessible to those wishing to obtain a good
background relatively easily. We have targeted the book
viii Preface

towards both primary and secondary There is a pressing need to improve the
health care. The text is divided into 13 quality of care that patients with allergic
chapters covering different aspects of disease receive. It is with this in mind that
hypersensitivity responses. Thus, the we hope that this text provides a useful
book is clinically oriented and should be and accessible source of practical
valuable to trainees in allergy, respiratory information.
medicine and general (internal) medicine,
as well as to general practitioners and the M Thirumala Krishna
professions allied to medicine. George Mavroleon
Stephen T Holgate
 1

Diagnostic tests in allergy

1 Introduction
Although there is no substitute for a good history in
clinical medicine, laboratory tests are often required to
strengthen the clinical diagnosis and to provide a means
of, objectively, evaluating the disease, its severity and its
response to treatment. This chapter focuses on various
in vivo and in vitro tests employed in the investigation
and diagnosis of allergic disease. Some of these tests are
used mostly as research tools but, nevertheless, they
provide useful clinical information.

In vivo tests
Skin prick tests
Skin prick tests (SPT) (Figure 1.1) have been, and will
remain, the gold standard in the diagnosis of allergy. The
basic principle of this test is to detect the presence of
specific IgE bound to the surface of mast cells and
basophils. Upon challenge with the allergen, there is
cross-linking between the specific IgE and allergen on
2 Essentials of Allergy

Figure 1.1
Skin prick test for
standard panel of
airborne allergens. Note
positive responses
(wheals) to house dust
mite (HDM) and cat.
⫹: positive control
(histamine);
⫺: negative control
(saline).
Source: Courtesy of Dr
Lisa Hosking, Clinical
Research Fellow,
University of
Southampton.

the surface of the mast cell/basophil, and punctured by means of a 1 mm sterile

inducing a process of signal transduction lancet or a 25 gauge sterile hypodermic
and degranulation. This process results in needle. The excess solution is absorbed
the release of mast cell products, after 30 seconds with an absorbent tissue
including histamine, leukotrienes and and the reaction is evaluated after 15–20
prostaglandin (PGD2), which cause the minutes. The response is measured as the
local wheal and flare response. largest diameter of the wheal and its
orthogonal diameter. In the absence of a
A drop of the allergen extract and controls reaction to the negative control, a reaction
(positive (histamine 1–10 mg/ml) and of ⱖ3 ⫻ 3 mm is considered as a positive
negative (saline or diluent)) are placed on response. It has been shown that a true
the skin of the volar aspect of the forearm wheal diameter of 3 mm represents 10
 Diagnostic tests in allergy 3

times as much specific IgE as a 2 mm of variation of 15% in experienced hands

response. If there is a reaction to the and up to 40% in inexperienced hands,
diluent due to irritation or especially when the wheal diameter is
dermographism, this value should be <5 mm. Therefore, it has been
subtracted from the responses to the recommended that these tests are
allergens. The results of the SPT should be performed in duplicate or quadruplicate.
interpreted carefully, together with the
clinical history. Positive tests can be Intradermal tests are widely used in the
present in an asymptomatic individual USA as an alternative to skin tests and in
and this represents a ‘latent allergy’ if instances where the clinical history of
there is no airway eosinophilia, or termed allergy is strong but the SPT are negative.
‘subclinical allergy’ when airway This involves injecting 0.02–0.05 ml of
eosinophilia is present. It has been shown the extract intradermally to produce a
that, in an asymptomatic individual with a bleb approximately 3 mm in diameter,
positive reaction to grass pollen, the risk and a wheal response of >5 mm is
of developing seasonal allergic rhinitis is considered to be positive. It has been
10-fold greater than in someone who does suggested that the response is measured
not demonstrate a positive reaction. as an erythema rather than a wheal since
Caution should be exercised, particularly the former gives a steeper dose-response
in the interpretation of positive responses curve. However, this has not gained
to food extracts as only a minority of widespread acceptance. Although the
these patients have a clinical history of reproducibility of intradermal testing has
food allergy. Most are able to tolerate been shown to be better than SPT, the
these foods well without any adverse former requires greater technical skill.
reactions. In conditions such as oral Several factors that affect SPT are
allergy syndrome, SPT is carried out using summarized in Table 1.1.
the ‘prick-prick method’ (i.e. the same
lancet is used for pricking the fresh
Exhaled nitric oxide (NO)
fruit/vegetable and then the skin).
Nitric oxide (NO) is a cytotoxic and
Although SPT are a rapid and sensitive cytostatic agent and has been shown to
means of diagnosing allergy, several possess immunomodulatory properties. It
studies have shown that reproducibility of is a highly reactive molecule with high
the response varies, showing a coefficient affinity for iron and iron-sulphur
4 Essentials of Allergy

Table 1.1
Factors affecting SPT. Factor Comment

Age The distribution of skin mast cells is less

in the elderly and this can lower the
response
Drugs Antihistamines,* leukotriene receptor
antagonists and topical steroids applied
to the skin can lower responsiveness.
A short course of oral steroids does not
affect response
Dermographism A false positive result

Note:
* With the exception of astemizole (half-life 9.5 days), for
other antihistamines it is sufficient to discontinue 4 days
prior to SPT. Astemizole must be discontinued for 4
weeks.

containing moieties; consequently it has been shown to be significantly upregulated

the capacity to bind to haem, to the in the bronchial epithelium of nonsteroid-
enzymes of mitochondrial respiration and treated asthmatics as opposed to healthy
DNA synthesis. NO per se can exert nonatopic controls and steroid-treated
damaging effects on the cells or could asthmatics. Little or only minimal
react with superoxide to form immunoreactivity of iNOS was detectable
peroxynitrite, a powerful oxidant that can in the bronchial epithelium of healthy
then exert cytotoxic effects. controls. More recently, several groups
have validated the measurement of NO in
Although the precise role of NO in asthma exhaled air using a chemoluminiscent
is not known, recent studies have analyser (Figure 1.2), and have shown
confirmed that it could be potentially that the level of NO is significantly
important. The expression of inducible elevated in nonsteroid-treated asthmatics
nitric oxide synthase (iNOS), an enzyme as opposed to healthy controls and
important in the generation of NO, has steroid-treated asthmatics (Figure 1.3).
 Diagnostic tests in allergy 5

Figure 1.2
Measurement of exhaled
nitric oxide in the
laboratory using a
chemiluminiscent
analyser.
Source: Courtesy of Mrs C
Eames, Research Nurse,
University of
Southampton.

Figure 1.3
Comparison of exhaled 20
NO in asthmatics vs
controls. Exhaled NO was
15
significantly elevated in
Exhaled NO (ppb)

the asthmatic group.

Source: Courtesy of Dr A 10
M Zurek, University of 15.0
Southampton. 5
7.1

0
Controls Asthmatics
(n ⫽ 23) (n ⫽ 71)
6 Essentials of Allergy

In addition, the levels of exhaled NO are measured by conventional spirometry at 3

markedly elevated during acute asthma and 5 minutes after each step. The test is
exacerbations and, following treatment terminated when a 20% decline in FEV1 is
with corticosteroids, this drops achieved, and the bronchoconstriction is
significantly. Thus exhaled NO has been reversed by administration of a short-
shown to be a useful surrogate marker in acting ␤2 agonist such as salbutamol. PC20
asthma and could be employed for is then calculated by interpolation of the
monitoring response to treatment. last two concentrations that resulted in
However, exhaled NO is not specific for ⱖ20% drop in FEV1. Figure 1.4 illustrates
asthma since it has been shown to be the bronchial hyper-reactivity test
elevated in patients with adult respiratory graphically in an asthmatic subject. PC20
distress syndrome, fibrosing alveolitis and is usually ⱕ8 mg/ml of histamine or
pneumonias. methacholine in asthma, and several
studies have shown an inverse association
between disease severity and PC20, and
Bronchial reactivity testing
eosinophil numbers in the airways and
Nonspecific bronchial hyper- PC20, suggesting that PC20 could be a
responsiveness (BHR) is a characteristic reliable marker for disease severity.
feature of asthma. Several agents
(including cold air, carbachol, histamine
and methacholine) have been used to
Sputum induction
study bronchial hyper-responsiveness in In recent years, sputum induction (Figure
asthma. This is mainly a research tool but, 1.5) with hypertonic saline has been used
nevertheless, is used in certain clinical extensively as a research tool to
situations where the clinical diagnosis of investigate airway inflammation in asthma
asthma is not straightforward. Bronchial and chronic obstructive pulmonary
reactivity is measured as the dose disease. The main advantage of this
(cumulative or noncumulative) of procedure is that it is relatively
bronchoconstrictor, usually histamine or inexpensive, is safe and is less time-
methacholine that induces a 20% fall in consuming than fibreoptic bronchoscopy.
FEV1 (PC20 (mg/ml)). During this Moreover, sputum induction could be
provocation test, gradually escalating performed safely in severe asthmatics in
doses of histamine or methacholine are whom bronchoscopy might not be
nebulized into the airways and FEV1 is feasible. Recent studies have shown strong
 Diagnostic tests in allergy 7

Figure 1.4
0 0.03 0.06 0.13 0.5 1 2 4 8 16
Histamine challenge test 0
in normal and asthmatic
airways to calculate
PC20 (concentration of ⫺5
histamine required to
induce a 20% fall in FEV1
from baseline). Note that ⫺10
in normal human airways
% drop in FEV1

even a concentration of
32 mg/ml of histamine ⫺15
induced only a maximum
of 2% drop in FEV1. This
⫺20
is in contrast to asthmatic
airways where bronchial
hyperresponsiveness is a ⫺25
characteristic feature.
Note that in the severe
asthmatic patient a 20% ⫺30
drop occurred at Histamine concentration (mg/ml)
⬍0.5 mg/ml of
histamine in comparison
to the patient with mild normal subject
asthma where this mild asthmatic
occurred at between 4
severe asthmatic
and 8 mg/ml of
histamine.

correlations between biomarkers of eosinophilia) when the diagnosis of

inflammation measured in the sputum, asthma is not straightforward or when
bronchial wash and bronchoalveolar monitoring the response to treatment,
lavage fluid. Although induced sputum is especially in chronic severe asthmatics on
mainly used for research purposes, it low-dose cyclosporin.
could provide useful information (such as
demonstration of lower airway After premedication with salbutamol, a 3%
8 Essentials of Allergy

Figure 1.5
Induced sputum of an
asthmatic subject. Note
the eosinophilia.
Eosinophils show bilobed
nucleus with eosinophilic
granules in the
cytoplasm.
Source: Courtesy of Dr
Lisa Hosking, Clinical
Research Fellow,
University of
Southampton.

solution of saline is nebulized by means of Dulbecco’s phosphate buffered saline. The

an ultrasonic nebulizer. Saline is inhaled sample is shaken gently and placed in a
for 5–30 minutes until an adequate shaking water bath at 37 °C for 15
quantity of sputum is expectorated. To minutes to ensure complete
prevent salivary contamination and homogenization. The suspension is then
postnasal drip, the patient is advised to filtered through a gauze (1 mm pore size),
rinse his or her mouth and blow his or her the filtrate is centrifuged at 1000 g for 10
nose, respectively. During the inhalation minutes and the supernatant is stored at
the patient is advised to cough deeply and ⫺80 °C for analysis of soluble mediators.
frequently. The procedure is terminated if The cell pellet is resuspended and the
FEV1 falls to greater than 15% of the total numbers of non-squamous cells are
baseline. Sputum is collected in a plastic counted in a modified Neubauer
petri dish and processed immediately. haemocytometer. Cytospin slides are then
Equal quantities of 0.1% dithiothreitol are prepared and stained with Diff-Quick for
added, followed by equal quantities of differential cell counts.