Additional file 2: Development of discussion materials for the expert
meeting
Participants of the expert meeting:
I. Annesi-Maesano, C. Auffray, C. Bachert, F. Ballester, X. Basagaña, M. Benet, E. Fthenou, J.
Garcia Aymerich, E. Gimeno-Santos, S. Guerra, C. Hohmann, B. Jacquemin, J. Just, F.
Kauffmann, T. Keil, M. Kerkhof, M. Kogevinas, G. Koppelman, M. Kowalski, I. Kull, I. Lavi,
E. Melén, I. Momas, J Mullol, L. Namazova-Baranova, M. C. Nawijn, C. Normand, S. Oddie,
M. Pinart, D. S. Postma, V. Siroux, H. A. Smit, R. T. Stein, J. Sunye, A. Togias, R. Varraso, M
Vassilaki, M. Wickman, C. Zabaleta Camino, T. Zuberbier, J. Bousquet and J. M. Anto) and
external experts (L. Namazova-Baranova, J. Mullol and A. Togias).
DEFINITION OF ATOPY AND IgE-MEDIATED ALLERGY FOR
EPIDEMIOLOGIC STUDIES – MeDALL STATEMENT
MeDALL (Mechanisms of the Development of ALLergy) (1), is an FP7 European Union
project starting in December 2010, aimed to generate novel knowledge on the mechanisms of
initiation of allergy and to propose early diagnosis, prevention and targets for therapy. In
MeDALL, a novel phenotype definition and an integrative translational approach will be
developed to understand how a network of molecular and environmental factors can lead to
complex allergic diseases. A novel, stepwise, large-scale and integrative approach will be led by
a network of complementary experts in allergy, epidemiology, allergen biochemistry,
immunology, molecular biology, epigenetics, functional genomics, bioinformatics,
computational and systems biology.
The nomenclature for allergy proposed by a WAO expert group in 2003 will be considered by
MeDALL (2). It should be used independently of target organ or patient age group and it is
based on the mechanisms that initiate and mediate allergic reactions (Table I).
Table I: Definition of allergy and atopy (2)
1)
“Hypersensitivity should be used to describe objectively reproducible symptoms or signs initiated by exposure
to a defined stimulus, at a dose tolerated by normal persons.”
2)
“Allergy is a hypersensitivity reaction initiated by specific immunologic mechanisms. When other mechanisms
can be proven, as in hypersensitivity to aspirin, the term non-allergic hypersensitivity should be used.”
3)
Atopy is a personal or familial tendency, usually in childhood or adolescence, to become sensitized and
produce IgE antibodies in response to ordinary exposures to allergens, usually proteins. As a consequence,
these persons can develop typical symptoms of asthma, rhinoconjunctivitis or eczema. The term atopy should
be reserved to describe the genetic predisposition to become IgE-sensitized to [common allergens]”
4)
“The term atopy cannot be used until an IgE sensitization has been documented …”
5)
“The umbrella for a local inflammation of the skin should be dermatitis.” It includes “eczema to replace the
provisional term atopic eczema/dermatitis syndrome….. contact dermatitis and other forms of dermatitis”.
6)
“Atopic eczema is eczema in a person of the atopic constitution”.
Major IgE-mediated chronic diseases include rhinitis (and conjunctivitis) (3), asthma (4), atopic
dermatitis (5) and gastro-oesophageal diseases. However, allergy is not always involved in
symptoms of these diseases (6-9) and some diseases such as contact dermatitis are linked with
other immune reactions. Acute, IgE-mediated, severe reactions (e.g. anaphylaxis (10) or acute
urticaria) can occur in patients sensitized to drugs (11), foods (12) or hymenoptera venoms (13)
which can induce life-threatening symptoms and death. Although rhinosinusitis (14, 15) and
chronic urticaria (16, 17) are not usually associated with allergy, they are often considered as
related diseases, partly because they may be difficult to differentiate on a clinical basis, and
partly because an allergic origin may be confirmed (acute urticaria).
IgE-associated allergic diseases are very complex since:
1. Not all sensitized patients present symptoms (18) for unclear reasons not only explained by
the level of specific IgE.
2. Specific IgE in serum and skin tests are not interchangeable in epidemiologic studies (19)
and may represent different phenotypes (Figure 2).
3. The severity of symptoms varies widely from mild to severe and from intermittent to
persistent.
4. Non-allergic mechanisms are intertwined with allergic ones in many diseases.
5. Moreover, diseases tend to cluster and patients present concomitant or consecutive comorbidities adding to the complexity of the diseases.
6. In the WAO document (2), IgE directed against pan-allergens such as Staphylococcus
aureus enterotoxins are not considered (20-23), and a simplified flow chart of allergic
diseases is proposed.
Figure 2: From allergen-specific IgE to IgE-mediated disease (18)
1.
2.
3.
4.
5.
6.
7.
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(Mechanisms of the Development of Allergy): an integrated approach from phenotypes to systems
medicine. Allergy. 2011;66:in press.
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised
nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the
World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004 May;113(5):832-6.
Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its
Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization,
GA(2)LEN and AllerGen). Allergy. 2008 Apr;63 Suppl 86:8-160.
Bousquet J, Khaltaev N. Global surveillance, prevention and control of Chronic Respiratory
Diseases. A comprehensive approach. Global Alliance against Chronic Respiratory Diseases. World
Health Organization. ISBN 978 92 4 156346 8. 2007:148 pages.
Bieber T. Atopic dermatitis. N Engl J med. 2008;358(14):1483-94.
Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax. 1999
Mar;54(3):268-72.
Weinmayr G, Forastiere F, Weiland SK, Rzehak P, Abramidze T, Annesi-Maesano I, et al.
International variation in prevalence of rhinitis and its relationship with sensitisation to perennial
and seasonal allergens. Eur Respir J. 2008 Nov;32(5):1250-61.
2
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Bousquet PJ, Leynaert B, Neukirch F, Sunyer J, Janson CM, Anto J, et al. Geographical distribution
of atopic rhinitis in the European Community Respiratory Health Survey I. Allergy. 2008
Oct;63(10):1301-9.
Bousquet J, Fokkens W, Burney P, Durham SR, Bachert C, Akdis CA, et al. Important research
questions in allergy and related diseases: nonallergic rhinitis: a GA2LEN paper. Allergy. 2008
Jul;63(7):842-53.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al.
Second symposium on the definition and management of anaphylaxis: summary report--Second
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network
symposium. J Allergy Clin Immunol. 2006 Feb;117(2):391-7.
Demoly P, Pichler W, Pirmohamed M, Romano A. Important questions in Allergy: 1--drug
allergy/hypersensitivity. Allergy. 2008 May;63(5):616-9.
Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S11625.
Bilo BM, Rueff F, Mosbech H, Bonifazi F, Oude-Elberink JN. Diagnosis of Hymenoptera venom
allergy. Allergy. 2005 Nov;60(11):1339-49.
Fokkens W, Lund V, Mullol J. EP3OS. European position paper on rhinosinusitis and nasal polyps.
2007. Rhinology. 2007;45(Suppl 20):1-139.
Bachert C, Van Bruaene N, Toskala E, Zhang N, Olze H, Scadding G, et al. Important research
questions in allergy and related diseases: 3-chronic rhinosinusitis and nasal polyposis - a GALEN
study. Allergy. 2009 Apr;64(4):520-33.
Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Gimenez-Arnau A, et
al. EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria.
Allergy. 2009 Oct;64(10):1417-26.
Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Gimenez-Arnau AM, et
al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy. 2009
Oct;64(10):1427-43.
Bousquet J, Anto JM, Bachert C, Bousquet PJ, Colombo P, Crameri R, et al. Factors responsible for
differences between asymptomatic subjects and patients presenting an IgE sensitization to allergens.
A GALEN project. Allergy. 2006 Jun;61(6):671-80.
Bousquet PJ, Castelli C, Daures JP, Heinrich J, Hooper R, Sunyer J, et al. Assessment of allergen
sensitization in a general population-based survey (European Community Respiratory Health Survey
I). Ann Epidemiol. 2010 Nov;20(11):797-803.
Semic-Jusufagic A, Bachert C, Gevaert P, Holtappels G, Lowe L, Woodcock A, et al.
Staphylococcus aureus sensitization and allergic disease in early childhood: Population-based birth
cohort study. J Allergy Clin Immunol. 2007 Feb 8.
Bachert C, Zhang N, Patou J, van Zele T, Gevaert P. Role of staphylococcal superantigens in upper
airway disease. Curr Opin Allergy Clin Immunol. 2008 Feb;8(1):34-8.
Bachert C, Zhang N, Holtappels G, De Lobel L, van Cauwenberge P, Liu S, et al. Presence of IL-5
protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with
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determinants of severe/refractory asthma (SRA): association with Staphylococcal superantigenspecific IgE antibodies. Allergy. 2011 Jan;66(1):32-8.
3
DEVELOPING A WORKING DEFINITION OF A CLASSICAL
ASTHMA PHENOTYPE FOR ITS USE IN MEDALL.
A general description of asthma
There is no agreed definition of asthma and the different existing approaches to measure asthma
cannot be validated against an accepted gold standard. Several definitions have been proposed
for the past 60 years (1, 2).
According to GINA (GINA guideline) (3): “Asthma is a chronic inflammatory disorder of the
airways in which many cells and cellular elements play a role. The chronic inflammation is
associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing,
breathlessness, chest tightness, and coughing, particularly at night or in the early morning.
These episodes are usually associated with widespread, but variable, airflow obstruction within
the lung that is often reversible either spontaneously or with treatment. This operational
description has been widely accepted. The Expert Panel Report 3 (USA) has adopted a very
similar one (4). However, the definition of asthma depends on the age of the patients (5).
The ERS taskforce (6) suggests that “the term asthma should probably not be used in preschool
children because data regarding underlying inflammation are lacking. By contrast, the BTS
guideline (7) recommends that “based on a clinical assessment it should be possible to
determine the probability of a diagnosis of asthma. With a thorough history and examination, a
child can usually be classed into one of three groups: high, intermediate and low probability of
having asthma”. Similar to the BTS, the GINA guidelines for children 5 years and younger (8)
state that “a diagnosis of asthma can be made based largely on symptoms patterns and on
careful clinical assessment of family history and physical findings.”
Symptoms of asthma
All guidelines agree that the clinical expression of asthma is characterized by the occurrence of
one or more of the following symptoms:
 wheezing,
 breathlessness,
 chest tightness
 and cough.
According to the BTS asthma guidelines (with no graded evidence assigned to the references)
(7), these symptoms tend to present with the following pattern:
 are frequent and recurrent (9) (10, 11),
 are worse at night and in the early morning (12),
 tend occur in response to, or are worse after, exercise or other triggers, including indoor
and outdoor allergens or non-specific irritants such as, cold or damp air, emotions or
laughter (no ref provided) and occur apart from cold (9).
 When symptoms present the characteristics described above the probability of asthma
increases.
Similar definitions have been proposed by GINA (13).
The role of objective markers of asthma
Because there is no clear definition of the asthma phenotype, researchers studying the
development of this complex disease turn to characteristics that can be measured objectively,
such as atopy (manifested as the presence of positive skin-prick tests or serum allergen-specific
IgE and the clinical response to common environmental allergens), airway hyper-responsiveness
(the tendency of airways to narrow excessively in response to triggers that have little or no
effect in normal individuals).
4
The role of allergy and atopy in the definition of asthma
The probability of asthma increases when:
 asthma related symptoms occur in children with a family history of atopy in the first
degree relatives and especially in the mother (evidence 2++ according to the BTS
guidelines) (7).
 When symptoms of asthma coexist with other antecedents or presence of other atopic
diseases such as eczema or rhinitis (evidence 2++ according to the BTS guideline) (7).
 Presence of a positive skin test and or specific IgE to wheat, eeg, house dust mites or cat
predicts later childhood asthma (evidence 2++ according to the BTS guideline) (7).
 The presence of atopy or allergic sensitization provides additional predictive support as
early allergic sensitization increases the likelihood that a wheezing child will have
asthma (14).
According to GINA (13), the main limitation of methods to assess allergic status is that a
positive test does not necessarily mean that the disease is allergic in nature or that it is causing
asthma, as some individuals have specific IgE antibodies without any symptoms (15) and it may
not be causally involved. The relevant exposure and its relation to symptoms must be confirmed
by patient history as for any other allergic disease (16).
Measurement of total IgE in serum has no value as a diagnostic test for atopy.
Allergic and non-allergic asthma
Despite the strong association between asthma and atopy most of guidelines do not use the term
allergic asthma (or atopic asthma) with the exception of the WAO guideline for prevention of
allergy and allergic asthma (WAO guideline) (17, 18).
According to WAO (18), allergic asthma is the basic term for asthma mediated by
immunological mechanisms. When there is evidence of IgE-mediated mechanisms the term IgEmediated asthma is recommended. IgE antibodies can initiate both an immediate and a late
asthmatic reaction. IgE may be directed against pan-allergens such as Staphylococcus aureus
enterotoxin (19). Moreover, as in other allergic disorders, T-cell associated reactions seem to be
of importance in the late and delayed reactions. Depending on duration of symptoms, asthma
can be referred to as either intermittent or persistent (20).
Non-Allergic Asthma is the preferred term for nonimmunological types of asthma. It is
recommended that the old terminologies, ‘extrinsic’, ‘intrinsic’, ‘exogenous’ and ‘endogenous’
should no longer be used to differentiate between the allergic and non-allergic sub-groups of
asthma.
Preschool wheezing and its relation with asthma
Wheezing during infancy and childhood is most commonly due to upper respiratory tract
infections and asthma. The diagnosis of asthma is however challenging in preschool children
both in research and in the clinical practice, when episodes of wheezing due to viral infections
are more frequent and guidelines do not agree on whether a diagnosis of asthma can be
proposed in preschool childhood. Taking into account the difficulties of identifying asthma
during childhood it is not a surprise that GINA has released a guideline specific for preschool
children (8) and that the ERS has arranged a taskforce to produce a guideline for the treatment
of wheezing in children aged 6 years and younger (6). Often, diagnosis of asthma in this age
group can only be made during follow up.
Birth cohort studies have described the occurrence patterns and natural history of preschool
wheezing and concluded the existence of different phenotypes (21-23). There is wide agreement
that, as first shown in the Tucson birth cohort (21), preschool wheezing can be classified in
three different phenotypes:
5
i) Transient wheeze: symptoms begin and end before the age of 3 years. There is consistent
evidence that asthma occurs rarely in children with transient wheeze.
ii) Persistent wheeze: symptoms begin before the age of 3 years and continue beyond the age of
6 years.
iii) Late-onset wheezing: symptoms begin after the age of 3 years.
There is wide agreement that this classification is appropriate for its use in research and to
describe the natural history of wheezing. However, because it is time dependent is not
applicable to classifying wheezing in children up to the age of 6 when persistence can not yet be
assessed and newer definitions have been proposed using cluster analysis or free scale networks
making the concept quite complex.
To overcome this limitation an episode-based classification of wheezing has been proposed. The
following classification of wheezing in children has been recently agreed by an ERS Taskforce
(6):
i) Episodic (viral) wheeze: Wheezing during discrete time periods, often in association with
clinical evidence of a viral cold, with absence of wheeze between episodes. Episodic (viral)
wheeze most commonly declines over time, disappearing by the age of 6 yrs, but can continue
as episodic wheeze into school age, change into multiple-trigger wheeze or disappear at an older
age (21, 24).
ii) Multiple-trigger wheeze: Wheezing that shows discrete exacerbations, but also symptoms
between episodes. Although a viral respiratory tract infection is the most common trigger factor
for wheeze in preschool children, some young children also wheeze in response to other
triggers. Although many believe that multiple-trigger wheeze in preschool children reflects
chronic allergic airway inflammation (and could, therefore, be classified as asthma), there is
little evidence to support this.
The ERS taskforce members agreed that all three transient, persistent and late-onset wheezing
phenotypes can present as episodic viral wheeze and or multiple-trigger wheeze and a study has
shown that this classification often changes over time when children are followed up.
Defining asthma in epidemiological studies
In contrast to clinical studies and most of trials, epidemiological studies use questionnaires to
classify asthma with the potential problems due to subjectivity and recall bias. To make the
measure of asthma more objective epidemiological studies use to combine questionnaires with
tests of bronchial hyperresponsiveness (BHR) (20, 25, 26).
Most of recent epidemiological studies of asthma in children have used the ISAAC
questionnaire (27). A commonly used definition of wheezing has been based on the question
“Have you had wheezing or whistling in the chest in the last 12 months. The ISSAC study also
used a video asthma questionnaire that showed clinical signs and symptoms of asthma followed
by questions, which was strongly recommended for use in older children (13-14 years). The
video sequence showing wheezing at rest was at least as sensitive and specific for predicting
bronchial hyper-responsiveness as the written questionnaire, and more repeatable (28-30).
Despite the lack of an agreed gold standard of asthma, the performance of the different
epidemiological measures of asthma is usually assessed in validation studies and expressed in
terms of sensitivity, specificity and positive and negative predictive values The instrument with
the highest Youden's Index ((sp + se) -1) provides the most valid estimate of the prevalence
6
whereas the instrument with the highest positive predictive value provides the most valid
estimate of the prevalence ratio (31).
Pekkanen et al (31) reviewed population-based studies in children which have validated
symptom-based definitions of asthma against physician's assessment of asthma. Remes et al,
studying a sample of 247 children (7-12y) reported a 85% Youden index (Sen 88%, Sp 97%)
and a 53% PPV for a doctor diagnosis of asthma ever or "attacks of wheezing" or
"breathlessness" in the last 12 months (32). In the same study, the corresponding figures for a
doctor-diagnosed asthma ever the corresponding figures were YI 76 (Sen 82, Sp 99 ) and PPV
76. In another study of 96 children with the same age group Steen-Johnsen et al (33) reported a
YI of 62% (Sen 63, Spe 99) and PPV 92% respectively. In the Sears et al. study the values for a
measure of BRH were 34% and 53% respectively (34). Other population-based studies have
compared BHR tests with a self-report of doctor-diagnosed asthma ever in life with specificities
of approximately 90%, sensitivities of 20-50% and a Youden index of approximately 40%
(reviewed in Pekkanen J table 4, (31)). Jenkins et al (35), in a study of 168 children (7-13 y)
reported the corresponding values for a symptom-based definition (wheezing or whistling in last
12 months), a hypertonic saline test and a combined definition and reported a YI of 43, 66 and
41 respectively and a PPV 64, 61 and 74 respectively.
In their review, Pearce and Pekkanen (31) conclude that no single method of detecting
asthmatics will suit all epidemiological studies. In cohort and case control studies, specific
methods for detecting asthmatics, such as severe symptoms, diagnoses of asthma or
symptomatic bronchial hyperresponsiveness, are most useful. They also recommend symptoms
and bronchial hyperresponsiveness be analysed separately rather than combined due to the poor
agreement between bronchial hyperresponsiveness and clinical asthma.
Developing a working definition of a classical asthma phenotype for its use in MeDALL.
The research strategy of MeDALL includes a double approach (classical and novel) to be
developed in six steps, the first consisting in the comparison of the well-characterised classical
and novel phenotypes of IgE-associated allergic diseases (WP2) (36). One of the aims WP 2 is
to re-define the different IgE-associated allergic diseases and their phenotype (called classical
phenotypes), from birth to adolescence, by consensus among experts (see the protocol Expert
meeting class phenotypes 02032011). The resulting classical phenotypes will then be the basis
for omics assessments in MeDALL. As agreed in the protocol for the expert meeting: “from the
recent guidelines and consensus reports a panel of MeDALL experts will prepare working
definitions of the included phenotypes”. These definitions will be sent to the MeDALL
participants for initial discussion and the answers collated and integrated in a discussion paper
which will be the basis (together with a systematic review) for the Expert meeting.
In order to facilitate the discussion here we suggest several alternatives:
Option 1
Current asthma at 6 in the younger cohorts and current asthma at 6 and or latter in the older
cohorts. This definition would be roughly equivalent to persistent and late onset asthma.
Defined as a positive answer to the question “Have you had wheezing or whistling in your chest
in the last 12 months” at the age of 6 and / or later.
Limitations:
Non-asthma wheezing is common in presence of a cold.
Children in the younger cohorts have not reached the age for defining persistent and late onset
7
The PPV is low
Option 2
Current asthma at 6 and or latter like in option 1, but increasing specificity by adding an
additional question on a doctor diagnosis of asthma ever.
Limitations
Though the PPV will be higher it may be influenced by underdiagnosis.
It could increase the geographical heterogeneity of the definition.
Option 3
Allergic asthma defined as option 2 plus a positive skin test or specific IgE.
Limitations:
Though it may seem consistent in a project like MeDALL none of the guidelines reviewed here
with exception of the WAO has proposed to use this category of asthma.
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the prevalence of bronchial hyper-responsiveness in children. Int J Epidemiol. 1995;24(3):597602.
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Shaw RA, Crane J, Pearce N, Burgess CD, Bremner P, Woodman K, et al. Comparison
of a video questionnaire with the IUATLD written questionnaire for measuring asthma
prevalence. Clin Exp Allergy. 1992;22(5):561-8.
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associated with bronchial hyperreactivity. Clin Exp Allergy. 1997;27(5):540-5.
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Pekkanen J, Pearce N. Defining asthma in epidemiological studies. Eur Respir J. 1999
Oct;14(4):951-7.
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Remes ST, Korppi M. Asthma and atopy in schoolchildren in a defined population.
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Steen-Johnsen J, Bolle R, Holt J, Benan K, Magnus P. Impact of pollution and place of
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residence on atopic diseases among schoolchildren in Telemark County, Norway. Pediatric
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12
DEVELOPING WORKING DEFINITIONS OF ALLERGIC AND
NON-ALLERGIC RHINITIS FOR EPIDEMIOLOGIC STUDIES – A
MeDALL STATEMENT
Introduction
According to ARIA (1, 2), allergic rhinitis is a symptomatic disorder of the nose induced after
allergen exposure due to an IgE-mediated inflammation of the membranes lining the nose
Allergic rhinitis was defined in 1929 (3): “The three cardinal symptoms in nasal reactions
occurring in allergy are sneezing, nasal obstruction and mucous discharge.” Allergic rhinitis is
characterized by nasal symptoms including anterior and/or posterior rhinorrhea, sneezing, nasal
blockage and/or itching of the nose. These symptoms occur during two or more consecutive
days for more than one hour on most days (4).
Preschool children may just have nasal obstruction and there is no guideline-defined definition.
Patients with allergic rhinitis are usually classified as “sneezers and runners” (3, 5-8). Post-nasal
drip mainly occurs either with profuse anterior rhinorrhea in allergic rhinitis (9) or without
significant anterior rhinorrhea in chronic rhinosinusitis (10, 11).
Allergic rhinitis is subdivided into "intermittent" or "persistent" disease. The severity of allergic
rhinitis can be classified as "mild" or "moderate/severe" (2).
Objective tests for the diagnosis of IgE-mediated allergy (skin prick test, serum specific IgE)
can also be used (12-14). However, these two measurements do not have the same value in
epidemiologic studies (15). Moreover, un certain number of allergens needs to be tested to
assess allergy in a general population (16). The diagnostic efficiency of IgE, skin prick tests and
Phadiatop® was estimated in 8,329 randomized adults from the SAPALDIA. The skin prick test
had the best positive predictive value (48.7%) compared to the Phadiatop® (43.5%) or total
serum IgE (31.6%) for the epidemiologic diagnosis of allergic rhinitis (17).
There is no objective test for the diagnosis of rhinitis which has been validated and can be used
easily in epidemiologic studies.
Definitions for epidemiologic studies
Adults:
The clinical definition of rhinitis is not difficult to use in the epidemiologic settings of large
populations but when it is impossible to obtain the (skin test or laboratory) evidence of each
immune response, allergic rhinitis cannot be defined. However, the standardization of the
definition of rhinitis in epidemiological studies is of crucial importance, especially when
comparing the prevalence between studies.
Initial epidemiologic studies have assessed allergic rhinitis on the basis of simple "working
definitions". Various standardized questionnaires have been used to this effect (18, 19).
 The first questionnaires aiming at the assessment of seasonal allergic rhinitis dealt with
"nasal catarrh" (British Medical Research Council, 1960) (20) and "runny nose during
spring" (British Medical Research Council, 1962) (21).
 Questions introducing the diagnostic term of "seasonal allergic rhinitis" were successively
used: "Have you ever had seasonal allergic rhinitis?" or "Has a doctor ever told you that you
suffer from seasonal allergic rhinitis?"
 In the ECRHS full-length questionnaire, the question asked on rhinitis was: "Do you have
any nasal allergies including "seasonal allergic rhinitis"?" (22). In order to identify the
responsible allergen, the ECRHS study has included potential triggers of the symptoms (14,
23, 24). However, this question is not sensitive enough and some patients with non-allergic
rhinitis answer “yes” (25, 26).
 There are however problems with questionnaires. Many patients poorly perceive nasal
symptoms of allergic rhinitis, some of them exaggerating symptoms them whereas many
others tend to dismiss the disease (27). Moreover, a large proportion of rhinitis symptoms
are not from allergic origin (26, 28, 29). In the SAPALDIA study, the prevalence of current
13



seasonal allergic rhinitis varied between 9.1% (questionnaire answer and a positive skin
prick test to at least one pollen), 11.2% (questionnaire answer and presence of atopy) and
14.2% (questionnaire answer only).
Diagnostic criteria affect the reported prevalence rates of rhinitis (30, 31).
A score considering most of the features (clinical symptoms, season of the year, triggers,
parental history, individual medical history, perceived allergy) of allergic rhinitis has been
proposed (SFAR: Score For Allergic Rhinitis) (32). Using the doctor’s diagnosis (based on
questionnaire, examination and skin tests to common aeroallergens) as a gold standard,
these scores had good positive and negative predictive values (84% and 74%, respectively)
in the identification of patients suffering from allergic rhinitis. Symptoms of perennial
rhinitis have been defined as frequent, non-seasonal, nasal or ocular ("rhinoconjunctivitis").
In 6 African countries, the SFAR presented a close match with the gold standard (the
physician's diagnosis of AR backed up by SPT where necessary) in terms of various
performance parameters (33). In particular, it showed high sensitivity (0.84) and specificity
(0.81). Compared to the ISAAC questionnaire, the SFAR had greater sensitivity and equal
specificity.
In one study, the length of the disease was also taken into consideration in order to
differentiate perennial rhinitis from the "common cold" (viral upper respiratory infections)
(34).
ISAAC study (school children and adolescents)
 In children aged 13-14 and 6-7, several dozens of studies have been reported using the
ISAAC questionnaire (29, 35-42).

The validation of a rhinitis symptom questionnaire (ISAAC core questions) in a population
of Swiss school children visiting the school health services (43). 2954 parents of 7, 10 and
14-year old children filled in an exhaustive questionnaire which included the ISAAC core
questions on rhinitis. 2120 children also underwent skin prick testing against six common
aeroallergens (grass mixture, birch, mugwort, D. pteronyssinus, cat and dog dander). The
analysis was restricted to children with both questionnaire data and skin prick test results.
RESULTS: Sensitization to any allergen was most strongly associated with reported hay
fever (OR = 5.7, 95% CI 4.4-7.4), nose problems accompanied by itchy-watery eyes (OR =
4.4, 95% CI: 3.3-5.7), symptoms occurring only during pollen season (March through
September) (OR = 4.9, 95% CI: 3.6-6.5) and a combination of these latter two symptoms
(OR = 5.8, 95% CI: 4.1-8.1). The association was stronger for a sensitization to outdoor
allergens than for indoor allergens. The specificity of the various questions was high,
ranging from 77.5% to 97.6%, but the sensitivity was low (2.6% to 42.7%). The positive
predictive value for atopy among children with symptoms was 63% for sneezing
accompanied by itchy-watery eyes, 67% for symptoms occurring only during the pollen
season and 70% for reported hay fever. However, agreement between reported rhinitis
symptoms and hay fever was only moderate. About one third of the children with symptoms
indicative of seasonal rhinitis did not report the label "hay fever". The authors concluded
that the ISAAC core questions on rhinitis are highly specific and therefore useful in
excluding atopy. In addition they have a high positive predictive value in detecting atopy
among children with symptoms, but they are not helpful for detecting atopy in a general
population of children (low sensitivity). To monitor time trends in the prevalence of allergic
rhinitis in Switzerland, questions on rhinitis symptoms as well as on the diagnostic label
"hay fever" have to be included in a questionnaire because they contain complementary
information since under-diagnosis of allergic rhinitis is common.

Cross-sectional studies of stratified random samples of 8 to 12-year-old children (n = 7461)
used the standardized methodology of Phase II of the International Study of Asthma and
Allergies in Childhood (ISAAC) (40). Symptoms of rhinitis were ascertained by parental
questionnaires. 6 aeroallergen SPTs and measurements of serum total IgE and sIgE were
14
performed. In nonaffluent countries, a higher proportion of children with positive SPT had
no detectable sIgE (range 37-61%) than in affluent countries (0-37%). Total serum IgE was
associated with all disease outcomes among children with both positive SPT and sIgE (P <
0.001), but only with self-reported eczema in children with negative SPTs and negative
sIgE.

Some drawbacks were identified.
o There is a seasonal effect on responses to questions on rhinitis symptoms
suggesting a recall bias relating to recency of symptoms (44).
o Translations of questionnaires should follow a consistent protocol in global
epidemiological research as shown in ISAAC Phase III (45). Cultural norms need to
be considered when evaluating back-translations into English, as disease labels are
not available in every language, nor are they understood in the same way.
Deviations from literal translations of English should be permitted if the intent of
the original meaning is retained. A web-based tool of medical terminology would
be useful for international research requiring the use of translations.
o The requirement for active consent for population school-based questionnaire
studies can impact negatively on response rates, particularly English language
centres, thus adversely affecting the validity of the data (46).
Birth cohorts
Several birth cohorts have studied nasal symptoms and allergic rhinitis from birth to
adolescence (47-51).
One study attempted to describe the natural history and burden of allergic rhinitis according to
the new ARIA criteria in a population-based birth cohort study (MAS) of children up to 13 yr
(49). They defined symptoms as « severe » (impairment of daily activities) or « mild » (no
impairment) and « persistent » (duration > 1 month) or « intermittent » ( < 1 month) using
annual questionnaires. Serum Ig E to five common aero-allergens was determined at six time
points. The complete follow-up data were analyzed from 467 children (54% boys). The 12month prevalence of AR quadrupled from 6% (at age 3 yr) to 24% (at age 13 yr) in children
with non-allergic parents and more than tripled from 13% (3 yr) to 44% (13 yr) in children with
at least one allergic parent. Over half of the children with allergic rhinitis had « severe
persistent » symptoms.
Table: ARIA classification in the MAS birth cohort (49)
Intermittent: each episode of AR <1 month.
Persistent: each episode of AR >1 month.
Mild: no impairment of daily activities.
Severe: with impairment of daily activities.
Preschool children
As for asthma, in the clinic, the diagnosis of rhinitis in preschool children is difficult since the
patients cannot report symptoms, symptoms may differ in this age group by comparison to later
in life and the exact origin of rhinitis is unclear. Moreover, it seems that very difficult to assess
rhinitis symptoms before 2 yrs or age in birth cohorts (49, 52).
Several birth cohorts have studied rhinitis and nasal symptoms in preschool children (52-67).
In the MAS cohort (64) “current rhinitis was defined as parents answering the question “has
your child had a congested or runny nose since our last follow up?” and not to the question
“Were these symptoms during a cold?” until the age of 2 yrs. After this time, it was defined
answering “yes” to the following question “Did your child have sneezing attacks (at least 5
consecutive) or a congested or a runny nose without a cold or an infection during the last 12
months?” Only parent-reported reports were used since a physician’s diagnosis of rhinitis may
under-report rhinitis (59, 60). Marinho et al defined rhinitis at the age of 5 yrs as “sneezing or a
runny nose or blocked nose when the child did not have a cold or chest infection.” (59, 60).
15
Very few studies compared allergic and non-allergic rhinitis in this age group. Chawes et al (68)
investigated 255 children at six years of age from the Copenhagen Prospective Study on Asthma
in Childhood birth cohort assessing rhinitis history, specific immunoglobulin E relevant to
rhinitis symptoms, nasal eosinophilia and nasal airway patency by acoustic rhinometry before
and after decongestion (68). Allergic rhinitis was significantly and directly associated with
irreversible nasal airway obstruction (reduced decongested nasal airway patency) (P = 0.004),
whereas nonallergic rhinitis was not. Both allergic rhinitis (P = 0.000) and nonallergic rhinitis
(P = 0.014) were directly and significantly associated with nasal eosinophilia, but this
association was stronger for allergic rhinitis.
Working definition of allergic and non-allergic rhinitis
The research strategy of MeDALL includes a double approach (classical and novel) to be
developed in six steps, the first consisting in the comparison of the well-characterised classical
and novel phenotypes of IgE-associated allergic diseases (WP2) (69). One of the aims WP 2 is
to re-define the different IgE-associated allergic diseases and their phenotype (called classical
phenotypes), from birth to adolescence, by consensus among experts (see the protocol Expert
meeting class phenotypes 02032011). The resulting classical phenotypes will then be the basis
for omics assessments in MeDALL. As agreed in the protocol for the expert meeting: “from the
recent guidelines and consensus reports a panel of MeDALL experts will prepare working
definitions of the included phenotypes”. These definitions will be sent to the MeDALL
participants for initial discussion and the answers collated and integrated in a discussion paper
which will be the basis (together with a systematic review) for the Expert meeting.
Allergic and non-allergic rhinitis: Both in children and adults, “allergic” rhinitis can only be
defined in studies with a measurement of the allergic sensitization using skin prick tests or
serum allergen-specific IgE. However, the two measurements may not have a similar value.
Thus, the terms “allergic” and “non-allergic” can only be used if sensitization measurements
have been done.
Rhinitis in adults: The terms “nasal symptoms” or “rhinitis” can be used. According to
ECRHS, "Do you have any nasal allergies including "seasonal allergic rhinitis?” can be used. It
would be important to add individual symptoms of rhinitis since many subjects with rhinitis
would answer “no” to the question.
Rhinitis in adolescents and school children: The terms “nasal symptoms” or “rhinitis” can be
used. According to ISAAC, "Do you have any nasal allergies including "seasonal allergic
rhinitis?” can be used. It would be important to add individual symptoms of rhinitis since many
subjects with rhinitis would answer “no” to the question.
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20
DEVELOPING A WORKING DEFINITION OF A CLASSICAL
PHENOTYPE OF ECZEMA FOR ITS USE IN MeDALL.
This draft includes information about the clinical diagnosis of eczema and its assessment with
epidemiological questionnaires. Information about diagnosis is mainly based on the NICE
guideline: “Atopic eczema in children management of atopic eczema in children from birth up
to the age of 12 years” which was published in Dec 2007. (1). The Guideline was produced by
the National Collaborating Centre for Women’s and Children’s Health and commissioned by
the National Institute for Health and Clinical Excellence. As all NICE guidelines it has followed
a standardized methodology which includes a systematic search of the literature, a grading of
the evidence level (EL) and an appraisal and synthesis of clinical effectiveness evidence.
Information about the epidemiological definitions based on questionnaires is based on a
Medline non-systematic narrative review.
The term eczema is used as proposed by the World Allergy Organization (2) as equivalent to
other labels as atopic dermatitis or atopic eczema. However the NICE guideline uses the term
atopic eczema.
Summary of the NICE guideline.
Atopic eczema (atopic dermatitis) is a chronic inflammatory itchy skin condition that develops
in early childhood in the majority of cases. It is typically an episodic disease of exacerbation
(flares, which may occur as frequently as two or three per month) and remissions, except for
severe cases where it may be continuous.(3). Certain patterns of atopic eczema are recognised.
In infants, atopic eczema usually involves the face and extensor surfaces of the limbs and, while
it may involve the trunk, the napkin area is usually spared. A few infants may exhibit a discoid
pattern (circular patches). In older children flexural involvement predominates, as in adults (4).
As with other atopic conditions, such as asthma and allergic rhinitis, atopic eczema often has a
genetic component. In atopic eczema, inherited factors affect the development of the skin
barrier, which can lead to exacerbation of the disease by a large number of trigger factors,
including irritants and allergens. Many cases of atopic eczema clear or improve during
childhood while others persist into adulthood, and some children who have atopic eczema `will
go on to develop asthma and/or allergic rhinitis; this sequence of events is sometimes referred to
as the ‘atopic march’.
Development of diagnostic tools of atopic eczema based on signs and symptoms
The diagnosis of atopic eczema relies on the assessment of clinical features because there is no
laboratory marker or definitive test that can be used to diagnose the condition. In 1980, Hanifin
and Rajka, categorised signs and symptoms of atopic eczema into four major criteria and more
than 20 minor criteria; a diagnosis of atopic eczema required the presence of at least three
criteria from both categories. (5) The validity and reliability of this definition was not tested. (6,
7).
In 1994, the UK Working Party criteria were developed by comparing observations made by
two observers (dermatology registrars or senior registrars) using 31 of the Hanifin and Rajka
criteria, with the definitive diagnosis of atopic eczema being made by a physician with an
interest in dermatology
According to the UK Working Party (8, 9), six criteria were found to provide good separation of
atopic eczema cases from controls, namely:
• history of flexural dermatitis
• history of dry skin
21
• onset under the age of 2 years
• history of a pruritic skin condition (‘presence of an itchy rash’)
• personal history of asthma
• visible flexural dermatitis.
The proposed composite criteria (itchy skin as a major criterion, with three or more of the other
five criteria) were validated in studies undertaken in outpatient settings. [EL = DS Ib] The
populations considered were dermatology outpatients (27% of whom were children aged 10
years or under) and paediatric outpatients. From these studies, the composite criterion of itch
plus three or more other criteria was regarded as providing the best diagnostic information (that
is, providing the best separation of cases from non-cases).
Compared with a dermatologist’s diagnosis, the composite criterion provided the following
diagnostic accuracy statistics:
• sensitivity 70%, specificity 93%, PPV 47%, NPV 97% in London schoolchildren (10)
• sensitivity 74%, specificity 99%, PPV 63%, NPV 99% in Romanian schoolchildren. (11).
The results show that the level of agreement for a negative diagnosis is high. The relatively low
PPVs reflects the low prevalence of atopic eczema in the study populations. It is expected that
in clinical situations where the diagnostic criteria are to be used that the prevalence would be
much higher and therefore the PPV would also increase.
The study in London schoolchildren also considered the retest reliability of the questionnaire in
73 cases. Kappa scores were above 0.85, indicating a good level of agreement between first and
second questionnaires. (10).
The validation study of infants in Scotland considered level of agreement (percentage and kappa
scores) between a parent’s and a nurse’s diagnosis of atopic eczema in cases and controls using
the UK Working Party’s criteria (n = 108). [EL = 2+] Parents completed a postal questionnaire
listing the criteria. The percentage agreement for five of the six criteria ranged from 88% to
97% (kappa scores 0.75 to 0.94). (The criterion ‘onset in age under 2 years’ is irrelevant in this
study because the entire study population was aged under 2 years). The levels of agreement
between mothers and nurses for composite criteria were 96% for itch plus three or more other
criteria, and 94% for itch plus all UK criteria. (12)
NICE Evidence statement for diagnosis
A range of diagnostic criteria for atopic eczema in children has been described in the literature,
but only the UK Working Party criteria have been assessed adequately for validity and
repeatability. The use of composite criteria of itch plus another three or more of the five criteria
is considered to provide optimal separation of children with or without the condition. In
validation studies in European children aged 1–12 years, the UK Working Party criteria
provided a valid tool for diagnosing atopic eczema in community settings. [EL = 2+/DS II]. In
the South African study, the composite criteria did not distinguish cases from non-cases
adequately, although the single criterion of visible flexural eczema did. [EL = DS III] The high
specificity in all of the validation studies means that the false positive rate is low and therefore a
diagnosis of atopic eczema according to the UK working party criteria should be believed.
In Asian, black Caribbean and black African children, atopic eczema can affect the extensor
surfaces rather than the flexures, and discoid (circular) or follicular (around hair follicles)
patterns may be more common. The UK diagnostic criteria have not been tested extensively in
non-white ethnic groups in the UK
22
Atopic eczema should be diagnosed when a child has an itchy skin condition plus three or more
of the following:
• visible flexural dermatitis involving the skin creases, such as the bends of the elbows or behind
the knees (or visible dermatitis on the cheeks and/or extensor areas in children aged 18 months
or under)
• personal history of flexural dermatitis (or dermatitis on the cheeks and/or extensor areas in
children aged 18 months or under)
• personal history of dry skin in the last 12 months
• personal history of asthma or allergic rhinitis (or history of atopic disease in a first-degree
relative of children aged under 4 years)
• onset of signs and symptoms under the age of 2 years (this criterion should not be used in
children aged under 4 years).
The epidemiological definitions used in the ISAAC study.
Te International Study of Asthma and Allergies in Childhood (ISAAC) developed an eczema
questionnaire using some of the UK Working Party (UKWP) criteria and a set of photographs
(13)
In the first phase of the ISAAC study, a cross-sectional questionnaire survey was conducted on
random samples of schoolchildren aged 6 to 7 years and 13 to 14 years from centers in 56
countries throughout the world. Those children with a positive response to being questioned
about the presence of an itchy relapsing skin rash in the last 12 months that had affected their
skin creases were considered to have atopic eczema. Children whose atopic eczema symptoms
resulted in sleep disturbance for 1 or more nights per week were considered to have severe
atopic eczema. Complete data was available for 256,410 children aged 6 to 7 years in 90 centers
and 458,623 children aged 13 to 14 years in 153 centers. The prevalence range for symptoms of
atopic eczema was from less than 2% in Iran to over 16% in Japan and Sweden in the 6 to 7
year age range and less than 1% in Albania to over 17% in Nigeria for the 13 to 14 year age
range. Higher prevalences of atopic eczema symptoms were reported in Australasia and
Northern Europe, and lower prevalences were reported in Eastern and Central Europe and Asia.
Similar patterns were seen for symptoms of severe atopic eczema. (14).
Following the development of the ISAAC eczema questionnaire several validation studies have
reported in different countries. In overall, studies carried out in developed countries have shown
higher sensitivity and specificity (7, 10, 11, 15-18). By contrast studies performed in low and
middle income countries have found poorer validity (19, 20, 21, 22, 23, 24). In these studies the
type of reasons potentially explaining limited sensitivity and specificity have included the
following: study characteristics, different reference standards, different periods of prevalence to
establish the diagnosis of eczema, high prevalence of scabies, exclusion of “visible flexural
dermatitis” from the criteria, translation and cultural issues (such as the interpretation of
pruritus), low prevalence of eczema and different methodological strengths (25)
To compare the performance of a validated eczema symptom questionnaire and a standardized
skin examination protocol employed in the second phase of the International Study of Asthma
and Allergies in Childhood (ISAAC) a total of 30,358 schoolchildren aged 8-12 years from 18
countries were examined for flexural eczema. Parents also completed an eczema symptom
questionnaire. Prevalence estimates at the population level based on the questionnaire vs.
physical examination were compared. Authors also compared the skin examination and the
ISAAC questionnaire in making a diagnosis of flexural eczema. The point prevalences for
23
flexural eczema at centre level based on a single examination were lower than the questionnairebased 12-month period prevalences (mean centre prevalence 3.9% vs. 9.4%). Correlation
between prevalences of both outcome measures was high (r = 0.77, P < 0.001). At the individual
level, questionnaire-derived symptoms of 'persistent flexural eczema in the past 12 months'
missed < 10% of cases of flexural eczema detected on physical examination. However, between
33% and 100% of questionnaire-based symptoms of 'persistent flexural eczema in the past 12
months' were not confirmed on examination. Authors concluded that
ISAAC questionnaire-derived symptom prevalences are sufficiently precise for comparisons
between populations. By contrast, where diagnostic precision at the individual level is
important, questionnaires should be validated and potentially modified in those populations
beforehand, or a standardized skin examination protocol should be used (26).
An assessment of the validity of ISAAC and UK Working Party criteria for field diagnosis of
eczema in a urban children population in Brazil was performed in the parents or guardians of
1,419 children who answered the ISAAC phase II questionnaire. Children were examined for
skin lesions (UKWP protocol). Two dermatologists examined most cases of eczema (according
to ISAAC or UKWP), and a sample without eczema. Agreement between repeat questionnaires
on the filter question was poor (kappa = 0.4). Agreement between the 2 dermatologists was fair
(kappa = 0.6). False positive reports included scabies in 39% of ISAAC cases and 33% of
UKWP cases. Sensitivity and PPV were low (ISAAC: 37.1% and 16.1%; UKWP: 28.6% and
23.8%). Specificity and NPV were high (ISAAC: 90.0% and 96.6%; UKWP: 95.3% and
96.2%). One-year prevalence of eczema was 11.3% (ISAAC), 5.9% (UKWP) and 4.9%
(adjusted dermatologist diagnosis). Point prevalence of scabies (alone or not) was 43%, 33%
and 18%, in eczemas according to ISAAC, to UKWP and to dermatologists. The reasons why
children with eczema were not identified by ISAAC or UKWP were wrongly denying dry skin,
itchy rash or personal history of atopic diseases. A limitation is that questionnaire was already
validated in Brazil, but not field tested in this specific setting. (27).
Other diagnostic instruments (also in adults)
A systematic review the evidence concerning the validity of diagnostic criteria for AD included
all data sources identified through searches on Medline, Embase and Cochrane databases. The
Quality Assessment of Diagnostic Accuracy tool (QUADAS) was used. Results are presented in
a receiver operating characteristic (ROC) plot. Out of the 20 articles that met the criteria, 27
validation studies were identified. In two studies concerning Hanifin and Rajka diagnostic
criteria sensitivity and specificity ranged from 87.9% to 96.0% and from 77.6% to 93.8%,
respectively. Nineteen validation studies of the U.K. diagnostic criteria showed sensitivity and
specificity ranging from 10% to 100% and 89.3% to 99.1%, respectively. Three validation
studies concerning the Schultz-Larsen criteria showed sensitivity from 88% to 94.4% and
specificity from 77.6% to 95.9%. In one article concerning the criteria of Diepgen, the
sensitivity ranged from 83.0% to 87.7% and the specificity from 83.9% to 87.0%. One article
studied the Kang and Tian criteria and reported 95.5% sensitivity and 100% specificity. One
article validating the International Study of Asthma and Allergies in Childhood (ISAAC)
criteria showed a positive and negative predictive value of 48.8% and 91.1%, respectively. The
study concluded that the U.K. diagnostic criteria are the most extensively validated (28, 29).
A previous study suggested the following diagnostic criteria for atopic dermatitis in the adult
Thai population: visible flexural dermatitis, a history of flexural dermatitis, a rash of more than
six months duration and visible dry skin. However these criteria were not validated against
physicians' diagnoses. In the present study, we validated these diagnostic criteria for atopic
dermatitis in the Thai population in a clinical setting. A case-controlled study was performed on
a total of 259 patients; 33 subjects with active atopic dermatitis, 26 with inactive atopic
dermatitis, 100 controls presenting with an inflammatory skin disorder other than atopic
dermatitis and 100 controls without any skin disease. Each patient was examined according to
24
the above criteria. Sensitivity, specificity, relative value, positive predictive value, and negative
predictive value were calculated for each individual criterion and for composite criteria. Our
data confirmed that in order to achieve satisfactory sensitivity and specificity for diagnosing
atopic dermatitis in Thai people older than 13 years, a patient must have a history of flexural
dermatitis plus two or more of the other mentioned criteria (30).
The validity of the International Study of Asthma and Allergies in Childhood (ISAAC) and
United Kingdom Working Party (UKWP) AD questionnaires of adult AD in Taiwan was
performed among nursing staff at a university hospital. The 1-year prevalence of AD was
assessed by ISAAC and UKWP questionnaires. Subsequently, the dermatologists' diagnosis
based on Hanifin and Rajka criteria was used as a reference for validation. The overall response
rate was 92.9%, equivalent to 1131 complete questionnaires. Ninety adult patients with AD
(8%) were identified by dermatologists' diagnosis whereas ISAAC identified 107 (9.5%);
sensitivity and specificity were 36.7% and 92.9%, respectively. UKWP identified 42 (3.7%)
patients with AD; sensitivity and specificity were 42.2% and 99.6%, respectively. Using the
receiver operating characteristic curve analysis, the UKWP criteria performed significantly
better than its ISAAC counterpart. Further analysis indicated that modification of these criteria
resulted in significant improvement in their diagnostic efficacy. More specifically, modified
ISAAC showed 90.0% and 55.2% sensitivity and specificity, respectively, whereas modified
UKWP demonstrated 82.2% and 94.2% sensitivity and specificity, respectively. Most of the
study subjects were female with a high educational background. Authors concluded that
currently available questionnaire instruments do not perform well in the identification of adult
patients with AD. Modification of the original questionnaires may allow for future large-scale
epidemiologic studies (31).
The Millenium Criteria were developed assuming that the presence of IgE antibodies in a given
patient should be a mandatory criterium for the diagnosis of atopic dermatitis.. The clinical
features described in the literature were critically evaluated, and it was proposed that in addition
to the mandatory presence of allergen-specific IgE, 2 of 3 principal criteria (pruritus, typical
morphology and distribution, chronic or chronically relapsing) should be present for such a
diagnosis. For study purposes, it was suggested that the mandatory and principal criteria are
sufficient The minor criteria originally described by Hanifin and Rajka were revised and divided
over 4 subcategories; a) related to subclinical eczema; b) related to dry skin; c) extra skin folds;
and d) ophthalmological pathology. They were suggested to be used as additional criteria only,
needed when clinical suspicion is high but the new mandatory and principal diagnostic criteria
described here are inconclusive (32, 33).
The Millennium Criteria was further refined and compared with the UK Working Party Criteria
and the Hanifin & Rajka Criteria. Data of 210 included patients were used. After multiple
logistic regression, a minimum set of five criteria was identified as best discriminators: (i)
typical morphology; (ii) early age of onset; (iii) Dennie-Morgan fold; (iv) historical and (v)
actual flexural involvement. The refined Millennium Criteria were constituted from these
criteria. When comparing the different list for validity in diagnosing atopic dermatitis, the
refined Millennium Criteria showed a sensitivity of 81.8% and a specificity of 98.8% compared
to a sensitivity of 97.7% and specificity of 72.9% of the UK Criteria and a sensitivity of 100%
and specificity of 48.8% of the Hanifin & Rajka Criteria. This refinement and validity study
shows that the refined Millennium Criteria are a valid tool to diagnose atopic and atopiform
dermatitis in a hospital-based setting and therefore could be incorporated in clinical practice and
trials.
25
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Immunol. 1999 Jan;103(1 Pt 1):125-38.
15. Girolomoni G, Abeni D, Masini C, Sera F, Ayala F, Belloni-Fortina A, Bonifazi E,
Fabbri P, Gelmetti C, Monfrecola G, et al: The epidemiology of atopic dermatitis in
Italian schoolchildren. Allergy 2003, 58(5):420-425.
16. Gu H, Chen XS, Chen K, Yan Y, Jing H, Chen XQ, Shao CG, Ye GY: Evaluation of
diagnostic criteria for atopic dermatitis: validity of the criteria of Williams et al. in a
hospital-based setting. Br J Dermatol 2001, 145(3):428-433.
17. Yamada E, Vanna AT, Naspitz CK, Solé D: International Study of Asthma and
Allergies in Childhood (ISAAC): validation of the written questionnaire (eczema
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18. Saeki H, Iizuka H, Mori Y, Akasaka T, Takagi H, Kitajima Y, Oiso N, Kawada A,
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atopic dermatitis in Japanese elementary schoolchildren. J Dermatol Sci 2007,
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19. Firooz A, Davoudi SM, Farahmand AN, et al. Validation of the diagnostic criteria for
atopic dermatitis. Arch Dermatol 1999;135(5):514–16.
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21. Marks R, Kilkenny M, Plunkett A, Merlin K: The prevalence of common skin
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GW, Yu M, Zhong NS, Williams HC; ISAAC Phase Two Study Group. Collaborators
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28
DEFINITIONS OF FOOD ALLERGY,
ALLERGENS – MeDALL STATEMENT
FOOD,
AND
FOOD
Proposed
The NAIAD-sponsored Expert Panel Report came to consensus on definitions for the
Guidelines for the Diagnosis and Management of Food Allergy in the United States. The
report and the guidelines were published in December 2010 (1, 2).
The same year, the DRACMA (Diagnosis and Rationale for Action against Cow’s Milk
Allergy) report was published (3, 4).
Guidelines on anaphylaxis (5 , 6) have been published but will be detailed in another paper.
As a background paper for the MeDALL review on Classical Phenotypes (7), the exact wording
of the NAIAD-sponsored Expert Panel Report (1, 2) or DRACMA was used (3, 4). This will
allow for consistency across the world.
A food allergy is defined as an adverse health effect arising from a specific immune response
that occurs reproducibly on exposure to a given food (1).
A food is defined as any substance—whether processed, semi- processed, or raw—that is
intended for human consumption, and includes drinks, chewing gum, food additives, and dietary
supplements (1).
Food allergens are defined as those specific components of food or ingredients within food
(typically proteins, but sometimes also chemical haptens) that are recognized by allergenspecific immune cells and elicit specific immunologic reactions, resulting in characteristic
symptoms (1). A phenomenon called cross-reactivity may occur when an antibody reacts not
only with the original allergen, but also with a similar allergen. In food allergy, cross-reactivity
occurs when a food allergen shares structural or sequence similarity with a different food
allergen or aeroallergen. Cross-reactivity is common, for example, among birch pollen and
different tree nuts.
Foods or food components that elicit reproducible adverse reactions but do not have established
or likely immunologic mechanisms are not considered food allergens. Instead, these nonimmunologic adverse reactions are termed food intolerances (1). For example, an individual
may be allergic to cow’s milk (henceforth referred to as milk) due to an immunologic response
to milk protein, or alternatively, that individual may be intolerant to milk due to an inability to
digest the sugar lactose. In the former situation, milk protein is considered an allergen because it
triggers an adverse immunologic reaction. Inability to digest lactose leads to excess fluid
production in the gastrointestinal (GI) tract, resulting in abdominal pain and diarrhea. This
condition is termed lactose intolerance, and lactose is not an allergen because the response is not
immune based. It should be noted that the words tolerance and intolerance are unrelated terms,
even though the spelling of the words implies that they are opposites.
Definitions of related terms.
Because individuals can develop allergic sensitization (as evidenced by the presence of allergenspecific IgE (sIgE)) to food allergens without having clinical symptoms on exposure to those
foods, an sIgE-mediated food allergy requires both the presence of sensitization and the
development of specific signs and symptoms on exposure to that food. Sensitization alone is not
sufficient to define food allergy (1).
The NAIAD-sponsored Expert Panel Report generally use the term tolerate to denote a
condition where an individual has either naturally outgrown an FA or has received therapy and
no longer develops clinical symptoms following ingestion of the food (1). This ability to tolerate
food does not distinguish between these 2 possible clinical states. Individuals may tolerate food
only for a short term, perhaps because they have been desensitized by exposure to the food.
Alternatively, they may develop long-term tolerance.
29
Definitions of specific food-induced allergic diseases.
We used the NAIAD Guidelines (1) for the definitions of the following (1):

Food-induced anaphylaxis is a serious allergic reaction that is rapid in onset and may
cause death (5 , 8).

Gastro-intestinal (GI) food allergies include a spectrum of disorders that result from
adverse immunologic responses to dietary antigens. Although significant overlap may exist
between these conditions, several specific syndromes have been described. These are
defined as follows (1):
o Immediate GI hypersensitivity refers to an IgE-mediated food allergy in which
upper GI symptoms may occur within minutes and lower GI symptoms may occur
either immediately or with a delay of up to several hours (9). This is often a
manifestation of anaphylaxis. Among the GI conditions, acute immediate vomiting
is the most common re- action and the one best documented as IgE mediated.
o Eosinophilic esophagitis (EoE) involves localized eosinophilic inflammation of the
esophagus (10 , 11, 12). Although EoE is commonly associated with the presence of
food-specific IgE, the precise causal role of food allergy in its etiology is not well
defined. Both IgE- and non-IgE-mediated mechanisms appear to be involved. In
children, EoE presents with feeding disorders, vomiting, reflux symptoms, and
abdominal pain. In adolescents and adults, EoE most often presents with dysphagia
and esophageal food impactions.
o Eosinophilic gastroenteritis (EG) also is both IgE- and non- IgE-mediated and
commonly linked to food allergy (10 , 11, 12). EG describes a constellation of
symptoms that vary depending on the portion of the GI tract involved and a
pathologic infiltration of the GI tract by eosinophils, which may be localized or
widespread. EoE is a common manifestation of EG.
o Food protein-induced allergic proctocolitis (AP) typically presents in infants who
seem generally healthy but have visible specks or streaks of blood mixed with
mucus in the stool (10). IgE to specific foods is generally absent. The lack of
systemic symptoms, vomiting, diarrhea, and growth failure helps differentiate this
disorder from other GI food allergic disorders that present with similar stool
patterns. There are no specific diagnostic laboratory tests. Many infants present
while being breast-fed, presumably as a result of maternally ingested proteins
excreted in breast milk.
o Food protein-induced enterocolitis syndrome (FPIES) is another non-IgE-mediated
disorder that usually occurs in young infants and manifests as chronic emesis,
diarrhea, and failure to thrive. Upon re-exposure to the offending food after a period
of elimination, a subacute syndrome can present with repetitive emesis and
dehydration (8, 10 ). Milk and soy protein are the most common causes. A similar
condition also has been reported in adults, most often related to crustacean shellfish
ingestion.
o Oral allergy syndrome (OAS), also referred to as pollen-associated food allergy
syndrome, is a form of localized IgE-mediated allergy, usually to raw fruits or
vegetables, with symptoms confined to the lips, mouth, and throat. OAS most
commonly affects patients who are allergic to pollens. Symptoms include itching of
the lips, tongue, roof of the mouth, and throat, with or without swelling, and/or
tingling of the lips, tongue, roof of the mouth, and throat.

Cutaneous reactions to foods are some of the most common presentations of food allergy
and include IgE-mediated (urticaria, angioedema, flushing, pruritus), cell-mediated (contact
dermatitis, dermatitis herpetiformis), and mixed IgE- and cell-mediated (atopic dermatitis)
reactions (1). These are defined as follows:
o Acute urticaria is a common manifestation of IgE-mediated food allergy, although
food allergy is not the most common cause of acute urticaria and is rarely a cause of
30
o
o
o
o
chronic urticaria. Lesions develop rapidly after ingesting the problem food and
appear as polymorphic, round, or irregular-shaped pruritic wheals, ranging in size
from a few millimeters to several centimeters. On the other hand, food allergy is
rarely involved in chronic urticaria.
Angioedema most often occurs in combination with urticaria and, if food induced,
is typically IgE mediated. It is characterized by nonpitting, nonpruritic, well-defined
edematous swelling that involves subcutaneous tissues (for example, face, hands,
buttocks, and genitals), abdominal organs, or the upper airway. Both acute
angioedema and urticaria are common features of anaphylaxis.
Atopic dermatitis (AD), also known as atopic eczema. The role of FA in the
pathogenesis and severity of this condition remains controversial. In some
sensitized patients, particularly infants and young children, food allergens can
induce urticarial lesions, itching, and eczematous flares, all of which may aggravate
AD.
Allergic contact dermatitis (ACD). Clinical features include marked pruritus,
erythema, papules, vesicles, and edema.
Contact urticaria.

Respiratory manifestations of IgE-mediated food allergy occur frequently during
systemic allergic reactions and are an important indicator of severe anaphylaxis (14).
However, food allergy is an uncommon cause of isolated rhinitis and asthma (15).

Heiner syndrome is a rare disease in infants and young children (1). Caused primarily by
the ingestion of milk, it is characterized by chronic or recurrent lower respiratory symptoms
often associated with pulmonary infiltrates, failure to thrive and iron-deficiency anemia.
Definitions of specific food-induced allergic symptoms.
Table: Symptoms of food-induced allergic reactions (from the NAIAD-sponsored Expert
Panel Report (1))
Cutaneous
Ocular
Upper
respiratory
Lower
respiratory
Immediate symptoms
Erythema
Puritus
Urticaria
Mobiliform eruption
Angioedema
Delayed symptoms
Erythema
Pruritus
Morbiliform eruption
Angioedema
Eczematous rash
Flushing
Pruritus
Conjunctival edema
Tearing
Pre-orbital edema
Pruritus
Conjunctival edema
Tearing
Pre-orbital edema
Nasal congestion
Pruritus
Rhinorrhea
Sneezing
Laryngeal edema
Hoarseness
Dry staccato cough
Cough
Cough
Chest tightness
31
Dyspnea
Dyspnea
Wheezing
Wheezing
Intercostal retraction
Assessory muscle use
GI (oral)
Angioedema of the lip, tongue
or palate
Oral pruritus
Tongue swelling
GI (lower)
Nausea
Nausea
Colicy abdominal pain
Abdominal pain
Reflux
Reflux
Vomiting
Vomiting
Diarrhea
Diarrhea
Hematochezia
Irritability and refusal with weight loss
(young children)
Cardiovascular Tachycardia (occasionally)
Bradycardia in anaphylaxis
Hypotension
Dizziness
Fainting
Loss or consciousness
Miscellaneous Uterine contractions
Sense of “impeding doom”
Symptoms of cow’s milk allergy (CMA)
In the full report of DRACMA, CMA symptoms have been reviewed (4) and reported herein:
 In a Danish birth cohort, 60% of children with CMA presented with gastrointestinal
symptoms, 50 to 60% with skin issues, and respiratory symptoms present in 20 to 30%
while 9% developed anaphylaxis (16 , 17).
 In the Norwegian cohort, young infants experienced pain (48%), gastrointestinal symptoms
(32%), respiratory problems (27%), and atopic dermatitis (4.5%) (18).
 In the Finnish cohort, presentation symptoms included urticaria (45.76%), atopic dermatitis
(89.83%), vomiting and/or diarrhea (51.69%), respiratory symptoms (30.50%), and
anaphylaxis (2.54%). The same children reacted at oral food challenge with symptoms of
urticaria (51.69%), atopic dermatitis (44.06%), vomiting and/or diarrhea (20.33%),
respiratory symptoms (15.25%), and anaphylaxis (0.84%) (19).
 In a British study, infants reacted to oral food challenges with eczema (33%), diarrhea
(33%), vomiting (23.8%), and urticaria in 2 children who immediately reacted to the
challenge meal (one with wheeze and the other with excessive crying) (20, 21).
 Dutch infants with CMA from the study noted above developed gastrointestinal (50%), skin
(31%), and respiratory (19%) symptoms (22).
Thus, in DRACMA (4), it is stated that CMA appears with GI symptoms in 32 to 60% of cases,
cutaneous symptoms in 5 to 90%, anaphylaxis in 0.8 to 9% of cases. Respiratory complaints,
including asthma, are not rare. Clearly, in most of the populations studied, there are overlapping
presenting symptoms and multiple symptoms are often confirmed during challenge.
32
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Boyce JA, Assa'ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. Guidelines
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Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. Food protein-induced
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Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol. 2010 Feb;125(2
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Sicherer SH. Clinical aspects of gastrointestinal food allergy in childhood. Pediatrics.
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Simon HU, Rothenberg ME, Bochner BS, Weller PF, Wardlaw AJ, Wechsler ME, et al.
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Simon D, Wardlaw A, Rothenberg ME. Organ-specific eosinophilic disorders of the
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Warshaw EM, Belsito DV, DeLeo VA, Fowler JF, Jr., Maibach HI, Marks JG, et al.
North American Contact Dermatitis Group patch-test results, 2003-2004 study period.
Dermatitis. 2008 May-Jun;19(3):129-36.
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James JM. Respiratory manifestations of food allergy. Pediatrics. 2003 Jun;111(6 Pt
3):1625-30.
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Onorato J, Merland N, Terral C, Michel FB, Bousquet J. Placebo-controlled doubleblind food challenge in asthma. J Allergy Clin Immunol. 1986 Dec;78(6):1139-46.
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Bishop JM, Hill DJ, Hosking CS. Natural history of cow milk allergy: clinical outcome.
J Pediatr. 1990 Jun;116(6):862-7.
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Hill DJ, Bannister DG, Hosking CS, Kemp AS. Cow milk allergy within the spectrum
of atopic disorders. Clin Exp Allergy. 1994 Dec;24(12):1137-43.
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Kvenshagen B, Halvorsen R, Jacobsen M. Adverse reactions to milk in infants. Acta
Paediatr. 2008 Feb;97(2):196-200.
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Saarinen KM, Juntunen-Backman K, Jarvenpaa AL, Kuitunen P, Lope L, Renlund M, et
al. Supplementary feeding in maternity hospitals and the risk of cow's milk allergy: A
prospective study of 6209 infants. J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):457-61.
20.
Venter C, Pereira B, Grundy J, Clayton CB, Arshad SH, Dean T. Prevalence of
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34
DEFINITIONS OF ANAPHYLAXIS
STUDIES – MeDALL STATEMENT
FOR
EPIDEMIOLOGIC
Several guidelines and recommendations on the diagnosis and management of anaphylaxis have
been published since 2006 (1 , 2 , 3 , 4).
This document does not take into account the management of anaphylaxis during anaesthesia
(5 , 6, 7).
Even though anaphylaxis was first described around 100 years ago and is one of the most
alarming disorders encountered in medicine, there is waso universal agreement on its definition
or criteria for diagnosis until the second symposium on the definition and management of
anaphylaxis: Summary report—Second National Institute of Allergy and Infectious
Disease/Food Allergy and Anaphylaxis Network symposium (1). In this symposium it was
written that:
 “Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly
after contact with an allergy-causing substance.
 Participants recommended the following: ‘‘Anaphylaxis is a serious allergic reaction that is
rapid in onset and may cause death.’’
 Criteria proposed at the first symposium were revised (8), as outlined in Table I.
TABLE I. Clinical criteria for diagnosing anaphylaxis (1)
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT
LEAST ONE OF THE FOLLOWING:
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse],
syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lipstongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic
BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s
baseline
PEF, Peak expiratory flow; BP, blood pressure. *Low systolic blood pressure for children is
defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg 1 [2 3 age]) from 1
to 10 years, and less than 90 mm Hg from 11 to 17 years.
 It was acknowledged that no criteria will provide 100% sensitivity and specificity, but it
was believed that the criteria proposed are likely to capture more than 95% of cases of
anaphylaxis.
 Because the majority of anaphylactic reactions include skin symptoms (9),which are noted
in more than 80% of cases when carefully assessed, it was judged that at least 80% of
anaphylactic reactions should be identified by criterion 1, even when the allergic status of
the patient and potential cause of the reaction might be unknown.
 However, cutaneous symptoms might be absent in up to 20% of anaphylactic reactions in
children with food allergy or insect sting allergy (10).Consequently, in patients with a
35
known allergic history and possible exposure, criterion 2 would provide ample evidence that
an anaphylactic reaction was occurring.
 Gastrointestinal symptoms were included as a pertinent target response because they have
been associated with severe outcomes in various anaphylactic reactions.
 Finally, criterion 3 should identify the rare patients who experience an acute hypotensive
episode after exposure to a known allergen.
 Although participants believed that these criteria should accurately identify anaphylactic
reactions in more than 95% of cases, it was agreed that these criteria need to be subjected to
a prospective multicenter clinical survey to establish their utility and determine whether
there is need for further refinement.”
Skin tests and measurements of allergen-specific IgE are useful in determining sensitization;
however, to predict clinical reactivity, especially to a food or medication, closely monitored
incremental challenges conducted in appropriately equipped and staffed healthcare facilities
may be required (2)
36
1.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum
A, et al. Second symposium on the definition and management of anaphylaxis: summary report-Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. J Allergy Clin Immunol. 2006 Feb;117(2):391-7.
2.
Simons FE, Frew AJ, Ansotegui IJ, Bochner BS, Golden DB, Finkelman FD, et al. Risk
assessment in anaphylaxis: current and future approaches. J Allergy Clin Immunol. 2007
Jul;120(1 Suppl):S2-24.
3.
Ruggeberg JU, Gold MS, Bayas JM, Blum MD, Bonhoeffer J, Friedlander S, et al.
Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of
immunization safety data. Vaccine. 2007 Aug 1;25(31):5675-84.
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Cardona Dahl V. [Guideline for the management of anaphylaxis.]. Med Clin (Barc).
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5.
Kroigaard M, Garvey LH, Gillberg L, Johansson SG, Mosbech H, Florvaag E, et al.
Scandinavian Clinical Practice Guidelines on the diagnosis, management and follow-up of
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Jensen AG, Callesen T, Hagemo JS, Hreinsson K, Lund V, Nordmark J. Scandinavian
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Scand. 2010 Sep;54(8):922-50.
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Ewan PW, Dugue P, Mirakian R, Dixon TA, Harper JN, Nasser SM. BSACI guidelines
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2010 Jan;40(1):15-31.
8.
Sampson HA, Munoz-Furlong A, Bock SA, Schmitt C, Bass R, Chowdhury BA, et al.
Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin
Immunol. 2005 Mar;115(3):584-91.
9.
Lieberman P, Kemp S, Oppenheimer J, Land I, Bernstein I, Nicklas R, et al. The
diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin
Immunol. 2005;115 (suppl):S485-523.
10.
Braganza SC, Acworth JP, McKinnon DR, Peake JE, Brown AF. Paediatric emergency
department anaphylaxis: different patterns from adults. Arch Dis Child. 2006 Feb;91(2):159-63.
37