EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
Additional file 3: MeDALL expert meeting for the definition of
classical phenotypes of IgE associated diseases
Participants:
Mariona Pinart1,2,3, Isabella Annesi-Maesano4, Charles Auffray5, Claus Bachert6, Kai-Håkon Carlsen7,
Judith Garcia Aymerich1,2,3,8, Cynthia Hohmann9, Francine Kauffmann10,11, Karin C L Carlsen7, Isabelle
Momas12,13, Thomas Keil9, Marek Kowalski14, Manolis Kogevinas1,2,3,15, Dirkje Postma16, Renato T
Stein1,17, Jordi Sunyer1,2,3,8, Alkis Togias18, Magnus Wickman19, Torsten Zuberbier20, Ferran
Ballester3,21,22, Xavier Basagaña1,2,3, Marta Benet1,2,3, Eleni Fthenou23, Elena Gimeno-Santos1,2,3,
Bénédicte Jacquemin10,11, Jocelyne Just12,24, Marjan Kerkhof25, Gerard Koppelman26, Inger Kull27,28, Iris
Lavi1,2,3, Christian Lupinek29$, Erik Melén27,30, Joaquim Mullol31, Christophe Normand32, Leyla
Namazova-Baranova33, Martijn C Nawijn34, Sam Oddie35,36, Henriette A Smit37, Valerie Siroux38, Rudolph
Valenta29$, Raphaelle Varraso10,11, Carlos Zabaleta39, Jean Bousquet10,40,41, Josep Maria Antó1,2,3,8
$
: connected by webcam
Location:
CREAL-Centre for Research in Environmental Epidemiology, Parc de Recerca Biomèdica de Barcelona,
Doctor Aiguader 88, Barcelona, Spain
In collaboration with the WHO Collaborating Center of Asthma and Rhinitis (Montpellier)
Participant addresses
12345678910111213141516171819202122232425262728-
Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
Hospital del Mar Research Institute (IMIM), Barcelona, Spain
CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
EPAR U707 INSERM, Paris and EPAR UMR-S UPMC, Paris VI, Paris, France
Functional Genomics and Systems Biology for Health, CNRS Institute of Biological Sciences, Villejuif, France
URL (Upper Airways research Laboratory), University Hospital Ghent, Ghent, Belgium
Department of Paediatrics, Oslo University Hospital and University of Oslo, Oslo, Norway
Department of Experimental and Health Sciences, University of Pompeu Fabra (UPF), Barcelona, Spain
Institute of Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Berlin, Germany
INSERM, CESP Centre for research in Epidemiology and Population Health, U1018, Respiratory and Environmental
Epidemiology team, Villejuif, France.
Université Paris Sud 11, UMRS 1018, F-94807, Villejuif, France
Department of Public health and biostatistics, Paris Descartes University, EA 4064
Paris municipal Department of social action, childhood, and health, Paris, France
Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Lodz, Poland
National School of Public Health, Athens, Greece
Department of Respiratory Medicine, Beatrix Children’s Hospital, GRIAC Research Institute, University Medical Center
Groningen, University of Groningen, Groningen, the Netherlands
School of Medicine, Pontifícia Universidade Católica RGS, Porto Alegre, RS - Brazil
National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
Sachs’ Children’s Hospital, Stockholm; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Allergy-Centre-Charité at the Department of Dermatology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Secretary
General of the Global Allergy and Asthma European Network (GA2LEN)
Division of Environment and Health, Centre for Public Health Research-CSISP, 46020 Valencia, Spain
School of Nursing, University of Valencia, 46010 Valencia, Spain, Valencia
Division of Morphology, Department of Histology, School of Medicine, University of Crete, Heraklion, Greece
Groupe Hospitalier Trousseau-La Roche-Guyon, Centre de l'Asthme et des Allergies, APHP, Université Paris 6, France
Department of Epidemiology, GRIAC Research Institute, University Medical Center Groningen, University of Groningen,
Groningen, the Netherlands
Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, GRIAC Research Institute,
University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Center for Allergy Research, Karolinska Institutet, Stockholm, Sweden
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
29- Christian Doppler Laboratory for Allergy Research, Division of Immunopathology, Department of Pathophysiology and
Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
30- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
31- Unitat de Rinología i Clínica de l’Olfacte, Servicio de ORL, Hospital Clínic, IDIBAPS, CIBERES, Barcelona, Spain
32- Inserm Transfert, Paris, France
33- Scientific Center of children’s health of Russian Academy of Medical Sciences, Moscow
34- Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, GRIAC Research Institute,
University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
35- Bradford Institute for Health Research, Bradford Teaching Hospitals Foundation Trust, Bradford, UK
36- Bradford Neonatology, Bradford Royal Infirmary, Bradford, UK
37- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
38- INSERM, U823, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Université Joseph
Fourier, Grenoble, France
39- Servicio de Pediatría, Hospital de Zumarraga, Gipuzkoa, Spain
40- WHO Collaborating Center for Asthma and Rhinitis, Montpellier, France
41- University Hospital of Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France
This work was supported by the European Commission’s Seventh Framework Programme
under grant agreement No. 261357 (MeDALL).
Corresponding author
Josep M Antó, MD, PhD
CREAL- Centre for Research in Environmental Epidemiology
Barcelona Biomedical Research Park
Dr. Aiguader, 88
08003 Barcelona
Spain
Tel. +34 93 2147380
Fax + 34 932147302
E-mail: jmanto@creal.cat
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
Abbreviations
AAI: Adrenaline Auto-Injector
AEDS: atopic eczema/dermatitis syndrome
ALSPAC: Avon Longitudinal Study of Parents and Children
AR: Airway Hyperresponsiveness
ARIA: Allergic Rhinitis and its Impact on Asthma
BD: Bronchodilator
BHR: Bronchial hyperresponsiveness
BP: Blood Pressure
CD: Contact Dermatitis
COPD: Chronic Obstructive Pulmonary Disease
DBPCFC: Double-blind Placebo-Controlled Food Challenge
DRACMA: Diagnosis and Rationale for Action against Cow‘s Milk Allergy
DRS: dose-response slope
EASI: Eczema Area and Severity Index
ECA: Environment and Childhood Asthma
ECRHS: European Community Respiratory Health Survey
EDEN: European Dermato-Epidemiology Network
EiAN: exercise-induced anaphylaxis
FA: Food Allergy
GA2LEN: Global Allergy and Asthma European Network
GINA: Global Initiative for Asthma
IgE: Immunoglobulin E
ISAAC: International Study of Asthma and Allergies in Childhood
LRIs: Low Respiratory Illnesses
MeDALL: Mechanisms of the Development of ALLergy
NIAID: National Institute of Allergy and Infectious Diseases
PD20: provocative dose causing 20% decrease in FEV1
PEF: Peak Expiratory Flow
PF: Peak Flow
POEM: Patient-oriented Eczema Measure
Q (1-6): Question 1-6
RSV: Respiratory Syncytial Virus
SCORAD: Severity Scoring of Atopic Dermatitis
SPT: Skin Prick Test
WAO: World oAllergy Organization
WP: Work Package
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
Introduction
The MeDALL (1) expert meeting, corresponding to task 2.2 in WP2, was held following the
specifications of the protocol. According to this protocol the general aims were:
 To redefine the different IgE-associated allergic diseases and their phenotypes (called classical
phenotypes) from birth to adolescence by consensus among experts.
 To agree on the working definitions corresponding to the classical phenotypes of the different
IgE-related disease, from birth to adolescence that will be applied to the birth cohorts in
MeDALL.
 To agree on the relevant classic phenotypes that will be used to define samples to be assayed
in WPs 5, 6, 7, 8 and 9.
 To identify research needs regarding the definition of the IgE-associated allergic diseases that
could be approached in the context of MeDALL.
 To plan publications of phenotypes definitions and systematic review.
In addition to the previous aims, a paper developing a tentative uniform definition of severe allergic
diseases was presented for discussion. The paper has been accepted for publication in International
Archives of Allergy and Immunology.
The process of redefining the classical phenotypes of IgE associated allergic diseases was based on
reviewing/discussing the classical phenotypes as described in the literature for which, reviews of
relevant international guidelines had been produced. Most frequently the reviews included clinical
definitions to be used for diagnostic purposes. In addition to reviewing phenotype definitions, a
working definition applicable to the birth cohorts was discussed for each phenotype.
During the meeting it was apparent that clinical and epidemiological interpretations of the definitions
may differ as they often serve different purposes (individual diagnosis in clinical settings versus
individual classification in populations) (2).
As Francine Kauffmann (FK) noted, confusion may occur in verbal and written discourse among
physicians because of lack of agreement on how diseases should be defined, especially when the
aetiology of the disease is not fully understood (3). The name and the definition of a disease may
change as new knowledge is acquired. It was also observed that the difficulties in establishing and
agreeing with a given phenotype definition may vary substantially from one phenotype to another.
(See note 1 in the Appendix)
ATOPY
Speakers: Jean Bousquet (JB), F Kauffman (FK)
Review of the classical phenotypes
JB started his presentation by introducing the World Allergy Organization (WAO) definitions of allergy:
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]” (1)
JB made the following statements in order to deal with the complexity of allergic diseases (1):
i) Sensitization is characterized by the presence of specific IgE to environmental allergens and can
be demonstrated by serum-specific IgE or skin prick test (SPT)
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
ii) Not all sensitized patients present symptoms (4),
iii) Serum-specific IgE or SPT do not have the same clinical relevance and patients with dissociated
tests may represent different phenotypes (5),
iv) Allergic and non-allergic mechanisms have been described for the same target organ and may
even coexist in the same patient (e.g. allergic and non-allergic rhinitis (6). Whereas allergic and
non-allergic rhinitis may be differentiated by symptoms (“sneezers and runners” may be allergic
and non-allergic whereas “blockers” are never allergic), this is not the case for asthma in which
there is no specific sign or symptoms for allergy.
v) The level of total serum IgE has little relevance in the diagnosis of allergic diseases as many
patients have low total IgE levels and many non-allergic factors are increasing total IgE levels.
vi) Family history is inconstantly associated with allergic diseases.
vii) Several diseases may co-exist in the same patients.
viii) The definition of atopy by Coca and Cooke has been proposed in 1923 (7) and included a genetic
determinant.
ix) The definition of atopy by Pepys (8) is “that form of immunological reactivity of the subject in
which reaginic antibody, now identifiable as IgE antibody, is readily produced in response to
ordinary exposure to common allergens of the subject environment. This does not imply the
presence of symptoms and is a description of the immunologic reactivity of the subject”.
FK highlighted that the term allergic phenotype has been used to denote the allergic origin of the
phenotype. However, the causal link between exposure to allergens and development of asthma and
the directionality of the relationship remains unclear (See note 2 in the Appendix).
In addition, the evidence that genes related to atopy are relevant for associated diseases such as
asthma may raise serious concerns with the classical Coca and Coke paradigm (See note 3 in the
Appendix).
Following the previous arguments JB proposed that the term allergy should be only used when there is
evidence of specific IgE and/or SPT sensitization whereas the term atopy should be considered only
when allergy goes together with a positive family history.
On the other hand, FK suggested either to remove the genetic predisposition as a requisite of the
definition of «atopy» or not to use the term and always speak more analytically, such as skin prick test
positive or specific IgE greater than X phenotype.
Agreement
It was widely agreed not to use the term Atopic phenotype of whichever diseases but to use the
expression “specific IgE- associated phenotype”.
Discussion
There were concerns that by throwing out the word atopic, we are saying that we leave out genetic
predisposition (genes related to atopy are relevant for associated diseases such as asthma) and family
history, which are the strongest risk factors that we currently have.
It was suggested that the agreed use of the term atopy may not be realistic taking into account that
according to clinicians atopic dermatitis is a well established phenotype. Moreover, a new guideline
from the European Dermatological Society and supported by GA(2)LEN, which is coming out soon, is
using the term “atopic” to describe current eczema (clinical consensus) (9).
ASTHMA/WHEEZING
Speakers: J Sunyer (JS), F Kauffman, D Postma (DP), RT Stein (RS), JM Antó (JMA)
Review of the classical phenotypes
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
JS started his presentation by recognizing that there is no agreed clinical definition of asthma. Instead
GINA has developed a widely used description of asthma (GINA guideline, 1995 to 2010) (10, 11) which
includes a reference to the underlying mechanisms of the disease. Regarding its clinical expression, all
guidelines agree that asthma is characterized by the occurrence of one or more of the following
symptoms: wheezing, breathlessness, chest tightness and cough. In asthma, these symptoms tend to
be frequent and recurrent and in some cases worse at night and early in the morning. The presence of
sensitization provides additional predictive support as early allergic sensitization increases the
likelihood that a wheezing child will have asthma.
The most widely accepted phenotypical classification of childhood asthma is the one provided by the
Tucson group (12):
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. There is often no atopy or family history of atopy.
iii) Late-onset wheezing: symptoms begin after the age of 3 years, often with atopy and/or eczema.
FK pointed out that age and variability are important aspects of the definition of asthma. As previously
described, age of onset is key in the Tucson taxonomy (12). This notion was supported by recent
research showing that using unsupervised statistical methods starting asthma at or before the age of 4
led to different genetic determinants (13). Regarding variability, FK noted that short-term variability of
airflow which presence can be traced by several indicators including BHR, BD and peak expiratory flow
(PEF) variability could result from triggers (14) and be relevant at different periods of the day (day –
night) or life (e.g. puberty).
DP elaborated the notion of combined phenotypes. Clusters of risk factors may lead to joint
mechanisms. Including the role of environment in the phenotype definition may be important. The
Dutch hypothesis stipulated that asthma and COPD have common genetic and environmental risk
factors (allergens, infections, smoking), which ultimately lead to clinical disease depending on the
timing and type of environmental exposures (15). Thus, a particular group of shared genetic factors
may lead to asthma when combined with specific environmental factors that are met at a certain stage
in life, whereas combination with other environmental factors, or similar environmental factors at a
different stage in life, will lead toward COPD (16). DP recognized that despite being in favour of
phenotype definitions which include all the relevant characteristics (both genetic and environmental),
other pragmatic approaches like defining asthma as doctor-diagnosed and/ or asthma treatment in
questionnaires may work well.
RS reviewed the genesis of the Tucson wheezing taxonomy and its recent replication by an
unsupervised analysis of the ALSPAC cohort (17). Lung function and BHR are important traits of
childhood asthma. Lung function is preserved during the first year of life in children with persistent
wheezing (who will later on be more likely to be asthmatics). By contrast, airways responsiveness (AR)
is increased in infancy and persists into childhood associated with male gender, early Lower
Respiratory Illnesses (LRIs), maternal smoking and asthma. AR in childhood is better measured by peak
flow (PF) variability than by BHR tests. Other relevant events that at the first year of life may
contribute to induce asthma are respiratory syncytial virus (RSV) bronchiolitis which, interestingly, may
share genetic determinants with atopy (18) but more data are needed (19). RS insisted that the
association between allergy and asthma may not be causal (20).
Proposed working definitions for the MeDALL study
To facilitate discussion the following options were presented.
Option 1: Current asthma at 6 years old in the younger cohorts and current asthma at 6 and or later in
the older cohorts. This definition would be roughly equivalent to persistent and late onset asthma.
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
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?”.
Option 2: Current asthma at 6 and or later like in option 1, but increasing specificity by adding an
additional question on a doctor diagnosis of asthma ever.
Option 3: Allergic asthma defined as option 2 plus a positive skin prick test or specific IgE.
Agreement
After an overall discussion, the following definition was agreed:
Questions from GA2LEN (only 2 are required) (21, 22):
i) Doctor-diagnosed asthma ever.
ii) Asthma medication in the past 12 months.
iii) Wheezing in the past 12 months according to ISAAC parental core questionnaire (23).
Some participants were concerned with some doctors that treat children with medication for asthma
without confirmation of diagnosis of asthma to the parents. Also asking for wheezing attacks in the
past 12 mo will include people that should be left out.
For this reason it was agreed to include another question related to asthma symptoms:
 Shortness of breath in the past 12 months.
So, asthma will be defined by GA2LEN modified criteria (only 2 are required):
i) Doctor-diagnosed asthma ever.
ii) Asthma medication in the past 12 months.
iii) Wheezing in the past 12 months according to ISAAC parental core questionnaire (23) AND/OR
breathing difficulties (chest tightness and shortness of breath) in the past 12 months.
Discussion
Karin L Carlsen (KLC); Marek Kowalski (MKo); Jordi Sunyer (JS); Josep Maria Antó (JMA); Jet Smit (HS);
Gerard Koppelman (GK); Manolis Kogevinas (MK); Judith Garcia-Aymerich (JGA); Isabelle Momas (IM).
It is useful to take the information provided by unsupervised studies (e.g. Tucson study 1995 (12)) to
re-define classical phenotypes. The phenotypes that came out in the Tucson study, are considered the
classical phenotypes for wheezing.
KLC: it is better to use cross-sectional studies than retrospective studies (e.g. Tucson study 1995) so
that we can transfer these definitions into real life (clinical definitions)
The current debate in the literature is: time-dependent vs trigger/viral
M Ko: The definitions should be based on a prospective approach. ALSPAC (16) vs. Tucson (12). ALSPAC
got a more complex picture because they had more contacts.
KLC: How much can we learn from the classical phenotypes? Main aim of MeDALL: to compare
classical versus novel phenotypes. Then we can make a contribution and add input to the current
definitions in the literature.
JS: We need a practical definition to select the samples for analysis.
JMA: Two things: to agree on common terms and to reach a consensus so that we can use these
definitions for the sampling strategy.
HS: We need to talk about feasibility and technology. e.g. there is high variability in measurements on
bronchodilator response.
KLC: Asthma outcomes are very important: we need to talk about anti-asthma medication and not
medication for wheezing (misleading). Medication on asthma is a very good criteria and precise. You
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
want to pick up asthmatics rather that subjects that may have wheezing episodes once or twice and
then stop having them.
GK: We need to focus on establishing criteria to identify asthmatics and feasibility-all cohorts should
use the same technology.
JMA: According to the preliminary results of the novel phenotypes we have over 8000 children but
there are two problems: 1) lots of missing data and so we had to do lots of imputations; 2) the more
ambitious we are the harder the analysis will be due to a low sample size if we add too many variables.
MK: With the new questionnaire we will have less missing data and more interesting information for
unsupervised analyses.
MKo: We assume that the definitions won’t be easy but it is not necessary to have now a definition. It
is better to think of variables for MeDALL studies since we can’t reinvent the wheel.
JMA: Disagrees since it goes against the a priory hypothesis. We don’t want to accommodate novel
phenotypes to several classical phenotypes.
JGA: We need to agree on definitions that should be transferred to the real data (questionnaires).
JS: Controls should be discussed as well.
IM: To add chronic cough.
KLC: Disagrees because it goes against the rationale since although useful for the novel phenotypes it
doesn’t provide relevant information on classical phenotypes. We should ask for asthma medications
(not only steroids but also bronchodilators).
RHINITIS
Speakers: J Bousquet, KCL Carlsen, A Togias (AT), C Bachert (CB)
Review of the classical phenotypes
JB said that in adults the clinical definition of rhinitis is not difficult since symptoms are very clear
though “allergic rhinitis” cannot be defined without evidence of positive IgE and/or SPT (24). Various
standardized questionnaires including the ECRHS and ISAAC have been used (23, 25). However, the use
of questionnaires poses some problems as many subjects poorly perceive nasal symptoms of allergic
rhinitis or exaggerate the symptoms or dismiss the disease.
Questionnaire-based prevalence without IgE or SPT tends to be largely overestimating prevalence of
“true” allergic rhinitis (26, 27). A combined 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 (28).
In children and adolescents, ISAAC questionnaire has been used to assess rhinitis (6-7 years and 13-14
years) (29, 30). In a validation study, the specificity of the various questions was high but the sensitivity
was low (31). Agreement between reported rhinitis symptoms and hay fever was only moderate.
Some drawbacks were identified including a seasonal effect on responses to questions on rhinitis
symptoms and the need of an accurate translation of questionnaires.
In preschool children the diagnosis of rhinitis is difficult since children cannot report symptoms,
symptoms may differ between age groups and the exact origin of rhinitis is unclear. Moreover, it
seems that it is very difficult to assess rhinitis symptoms before 2 years or age in birth cohorts. In preschool children the diagnosis of rhinitis was used in a cohort (31) using the following questions: “Has
your child had problems with sneezing, or a runny, or blocked nose when he/she DID NOT have a cold
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
or the flu” and “In the past 12 months, has this nose problem been accompanied by itchy-watery
eyes?” coupled with a positive SPT, even though it may not be relevant.
According to ARIA (24, 32), 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. In the MAS birth
cohort, ARIA classification of allergic rhinitis (AR) was the following (33):
i) Intermittent: each episode of AR <1 month
ii) Persistent: each episode of AR >1 month
iii) Mild: no impairment of daily activities
iv) Severe: impairment of daily activities
KLC described the ECA study on current rhinitis (34) and concluded that current rhinitis is accompanied
by co-morbidites such as conjunctivitis, current asthma, current wheeze and previous or current atopic
eczema. Children with current rhinitis had higher levels of PD20 metacholine and Dose-Response Slope
(DRS). In fact, boys had significantly more often current asthma, rhinitis, and wheeze as well as higher
DRS compared to the girls. Monosensitisation was rare and polysensitisation to inhalant allergens or
food allergens was common. Boys were significantly more often sensitized to perennial, seasonal and
food allergens than the girls.
In the ECA study, current rhinitis was present in a child reporting at least one of the following
symptoms runny nose, blocked nose, or sneezing during the last 12 months without a cold. Current
Conjunctivitis required a report of itchy/runny eyes within the last 12 months. Most of reported
triggers corresponded to allergen exposure (pollen and furry pets). Children with unknown triggers
were more likely to have symptoms throughout the year and less likely to be sensitized.
AT indicated that the diagnosis of rhinitis based on symptoms has a problem of sensitivity and
highlighted some of the difficulties in the diagnosis of rhinitis. First, he said that it should be a
temporal agreement between the presence of symptoms and positive IgE/SPT. So, he reckoned that it
is important to add a question of seasonality in addition to the questions used to define current
rhinitis. Second, the association between rhinitis and asthma depends on the severity of symptoms of
rhinitis. Finally, he considered that, when possible, it is also important to include immunological
knowledge beyond IgE and use the broadest spectrum of tests (T cell response, T reg cell response,
etc.)
CB raised the difficulty of establishing a causal link between the temporal pattern of symptoms and the
presence of IgE. He wondered whether the link between symptoms of rhinitis and IgE truly exists. A
positive response to treatment with anti-IgE could be a good indicator of a causal link. He raised some
concerns about our limited understanding of IgE.
Proposed working definitions
Rhinitis: Have you had problems with sneezing, or a runny, or blocked nose when you did not have a
cold or flu? (ISAAC questionnaire (29, 30)).
Allergic rhinitis: Have you had problems with sneezing, or a runny, or blocked nose when you did not
have a cold or flu? PLUS EITHER a positive skin prick test to environmental allergens AND/OR specific
serum IgE.
In which of the past 12 months did these nose problems occur? Jan, Feb, March….Dec may be useful to
be added.
Agreement
Rhinitis:
i) Have you had problems with sneezing, or a runny, or blocked nose when you did not have a cold or
flu? Yes/No (ISAAC questionnaire)
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
ii) If YES: in the past 12 months has this nose problem been accompanied by itchy-watery eyes?
PLUS: either Skin prick tests AND/OR specific IgE to define allergic rhinitis.
Discussion
Jean Bousquet (JB); Joaquim Mullol (JM); Marek Kowalski (MKo); Renato Stein (RT); Karin L Carlsen
(KLC).
JB: We should avoid doctor-diagnosed allergic rhinitis. We need to focus on symptoms (in MeDALL
only 2 cohorts have the symptoms correct).
JM: To add loss of smell in the new core questionnaire linked to the severity of the disease. MW:
Disagrees because we should be conservative for the definition of classical phenotypes.
MKo: It is important to look at seasonality of symptoms.
RS: How much information do we have for rhinitis medication?
JB: If the patient doesn’t have allergic rhinitis, I don’t know what it is. Thus, better to define allergic
rhinitis.
KLC: We should ask symptoms outside colds. In addition, we can ask for symptoms of conjunctivitis.
JB: We can use ISAAC Q 2 for conjunctivitis (Have you had problems with sneezing, or a runny, or
blocked nose when you did not have a cold or flu? Yes/No).
KLC: It is important to look at the TRIGGERS and COMORBIDITIES
KLC: She thinks we should eliminate any seasonality for the definition of classical phenotypes.
Rationale: seasons are different in the different regions of Europe.
We need to add though, as many questions as possible so that the computer can pick up the most
relevant (novel phenotypes)
JB: Not to put allergy if you don’t have evidence!
ECZEMA
Speakers: I Momas (IM), HA Smit (HS)
Review of the classical phenotypes
IM provided the definition of atopy and eczema from the WAO. Atopy is a personal and/or familial
tendency to become sensitized and produce IgE antibodies in response to ordinary exposure to
allergens and Eczema aggregates several skin diseases sharing common clinical characteristics and
involving a genetically determined skin barrier defect (35). Despite the existence of several definitions
of atopic eczema, still the term “atopic” remains confusing. Atopic eczema is eczema in a person of the
atopic constitution. In 2003, the WAO expert group revised the nomenclature for allergy and divided
dermatitis in 3 forms:
1) Eczema (now the agreed term to replace the transitional term atopic eczema/dermatitis syndrome
(AEDS)) 2) Contact Dermatitis (CD) and 3) other forms of dermatitis. Eczema in turn, is subdivided in
atopic and non-atopic eczema whilst Contact Dermatitis is subdivided in allergic and non-allergic CD
(36). The American Academy of Dermatology (37) and the National Institute for Health and Clinical
Excellence (38) defined eczema as a chronic inflammatory itchy skin condition triggered by irritants or
allergens which can come and go (episodes of disease followed by relapse) or may be persistent in
severe cases.
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
The location of eczema varies over a lifetime. Infants can have eczema spread in the whole body
whereas children and adults eczema lesions are localised in the folds of the elbows, behind the knees,
in front of the ankles, under the buttocks or around the neck, ears or face (39). The cutaneous
manifestations of atopy in preschool children often represent the beginning of the atopic march.
Children with atopic eczema may develop in the future asthma, particularly with severe atopic eczema,
or allergic rhinitis.
Diagnostic criteria for eczema based on signs and symptoms, are often not validated. There are only
three outcome measurements for the assessment of severity of eczema that work adequately:
i) SCORAD index (Severity Scoring of Atopic Dermatitis) validated in 14 studies (40),
ii) EASI (Eczema Area and Severity Index) (41),
iii) POEM (Patient-oriented Eczema Measure) (42).
Finally IM exposed criteria to define eczema epidemiologically by means of the ISAAC questionnaire
(lifetime prevalence, onset of eczema, period (last year) prevalence and severity) (23).
HS emphasised that in order to diagnose eczema we need both standardised ISAAC questions (itchy
skin condition) and physical examination in 3 steps: 1)Question ‘itchy skin condition’ and if the
response is positive 2) Physical examination for signs of flexural dermatitis and if the response is
positive 3) Scoring of severity (POEM or SCORAD). There are several caveats though since it deals with
a complex phenotype with no clear markers of disease and symptoms of eczema that come and go.
Thus a diagnosis based on ISAAC questions only, will produce a period prevalence with a relatively high
sensitivity and low specificity and thus overestimate of the prevalence. A diagnosis based on physical
examination will produce a point prevalence with higher validity, but it will underestimate the period
prevalence. A direct question on ‘do you have eczema?’ is not to be preferred since this will lead to
misclassification due to translations into different languages (cultural bias). Guidelines for clinical
diagnosis of eczema (UK Working party based on Hanifin and Rajka) (43) require three major signs and
3 minor signs. A major sign is itchy rash and a minor sign can be history of flexural dermatitis, history
of dry skin, onset under 2 years, history of asthma or rhinitis, visible flexural dermatitis. There is often
a trade-off in epidemiological studies between validity of diagnosis and reliability of prevalence
estimate. However the more persistent and the more severe the eczema, the smaller the discrepancy
will be.
Locations of eczema in children are often in cheeks, forearms and legs. Dermatitis is a poorly
demarcated erythema with surface change. The erythema can manifest itself in different forms such as
scaling, vesicles, oozing, crusting or lichenification.
HS concluded that the optimal definition of eczema depends on the choices to be made for the
working definition: to define eczema cases, ranging from light to severe, the ISAAC questionnaire will
be optimal; but, to define severe eczema cases, a physical examination needs to be included (the 3
steps described above). HS also emphasized the value to include the expertise of well-known
dermatologist-epidemiologists in the field of atopic eczema through the European DermatoEpidemiology Network (EDEN) (42), for example Hywel Williams, Carsten Flohr (44), Joachim Smitt.
Proposed working definitions and Agreement
Current eczema
[Questions from ISAAC, Asher et al (1995)] (23)
i) Q1. Has your child ever had an itchy rash which was coming and going for at least 6 months?
Yes/No
If Yes :
ii) Q2. Has your child had this itchy rash at any time in the last 12 months? Yes/No
If Yes :
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
iii) Q3. Has this itchy rash at any time affected any of the following places: the folds of the elbows,
behind the knees, in front of the ankles, under the buttocks, or around the neck, ears or eyes?
Yes/No
Yes to Q1, Q2 and Q3  definition of flexural eczema
Atopic eczema
ISAAC Q1+Q2+Q3 + sensitization (serum-specific IgE, SPT) / familial history of atopy (See note 4 in the
Appendix)
Eczema persistence
ISAAC Q5 Has this rash cleared completely at any time during the last 12 months? Yes/No (No →
persistent eczema symptoms)
Eczema severity
ISAAC Q6 In the last 12 months, how often, on average, has your child been kept awake at night by this
itchy rash?
Never in the last 12 months (mild)
Less than one night per week (moderate)
One or more nights per week (severe)
Life-time eczema ISAAC Q1 + dry skin
(WP·3) birth cohorts
i) Q1. Has your child ever had an itchy rash which was coming and going for at least 6 months?
Yes/No
ii) Q dry skin. Has your child had dry skin in the last 12 months? Yes/No
(WP4) birth cohorts
iii) Q1. Have you ever had an itchy rash which was coming and going for at least 6 months? Yes/No
iv) Q dry skin. Have you had dry skin in the last 12 months? Yes/No
Doctor-diagnosed eczema
Q. Has your child ever been diagnosed by a physician with having eczema/atopic dermatitis? Yes/No
Yes  definition of doctor diagnosed eczema
Discussion
Torsten Zuberbier (TZ); Marek Kowlaski (MKo); Inger Kull (IK); Josep Maria Antó (JMA); Jordi Sunyer
(JS); Jean Bousquet (JB)
TZ: we need to get a uniform definition of severity of eczema if we use SCORAD. The European
Dermatological Society guideline supported by GA2LEN is coming out soon (9). The guideline says that
we shouldn’t use another word other than atopic eczema. Thus, we cannot change the terminology so
lightly!
MKo: Some people tried to replace the word atopic eczema but failed because you cannot replace a
word widely used among dermatologists.
MW: We should add a question on contact dermatitis
IK: BAMSE has 3 good questions about eczema: 1) itchy rash; 2) dry skin; 3) location of lesions (45).
TK: In the proposed definition for current eczema, WP4 do not have question 1 (coming and going for
at least 6 months…)
JMA/JS: It is better to use photos than a scoring system.
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JB: In the classical phenotypes we should not change many things; we will do so for the novel
phenotypes.
FOOD ALLERGY
Speakers: T Keil (TK), KH Carlsen (KHC)
Review of the classical phenotypes
TK started by pointing out absence of epidemiological guidelines for the definition of FA and reported
that food allergy, food allergens, food intolerances are defined based on clinical guidelines such as
NIAID-sponsored Expert Panel: “Guidelines for Diagnosis and Management of Food Allergy in the
United States” (46) and DRACMA (Diagnosis and Rationale for Action against Cow‘s Milk Allergy) (47).
According to the NIAID report food allergy is defined as an adverse health effect arising from a specific
immune response that occurs reproducibly on exposure to a given food. However, food intolerance is
defined as a non-immunologic adverse reaction to food or food components. A challenge in MeDALL is
the application of these clinical guidelines in epidemiological studies. Food-induced allergic symptoms
can affect a large number of organs and receive specific labels like cutaneous, ocular, etc.
The big limitation in epidemiological studies is that self-reported FA leads to severe overestimation of
FA prevalence. Thus, further tests are required. There are only two systematic reviews on FA
prevalence (48, 49) which concluded that population-based prevalence estimates for allergies to plant
products determined by the diagnostic gold standard are scarce, thus recommending measurements
be made by using standardized methods, if possible food challenge. The natural history of FA based on
retrospective data from patient records or cross-sectional studies are mainly focussed on hen‘s egg,
cow‘s milk but there is a paucity of data on other food items.
TK concluded that the definition of FA cannot be based on perceived adverse reactions to food and
that our knowledge of confirmed FA in the population is still limited (like asthma/rhinitis prevalence in
early 1990s, pre-ISAAC time). However, there is a multi-disciplinary European research project project
called EuroPrevall looking at “The prevalence cost and basis of food allergy in Europe” that aims to
examine prevalence and risk factors of FA based on diagnostic gold standard (50). It is likely that their
results which will be published soon may help us to define the FA phenotype. In addition, since IgEmediated, non-IgE immune mechanisms and non-immune mechanisms may co-exist, the diagnosis of
FA for clinical practice and for epidemiological studies will be definitely challenging.
KHC said that there is a relationship between allergic sensitization and clinical food allergy. Since there
are different food allergens that can cause FA, we may differentiate phenotypes according to the
different food allergens. He presented a study conducted in Oslo (51). Clinical symptoms of food
allergens may appear in the intestines, skin (atopic eczema, urticaria or angioedema), respiratory tract
(asthma, rhinitis) or in general (anaphylaxis, exercise-induced anaphylaxis). However, whilst food
allergens (codfish) may cause atopic eczema, inhalant allergens may cause asthma from cooking fish.
Wheat allergy induced by food allergens may cause atopic eczema, anaphylaxis, urticaria or exercise
induced anaphylaxis (EIAn) whilst inhalant allergens may cause asthma (Baker’s asthma).
KHC ended his presentation by pointing out that many attempts have been made to define food
allergy. According to Boyce et al. (46) food allergy is an adverse health effect arising from a specific
immune response that occurs reproducibly on exposure to a given food. Another definition could be
IgE sensitization to food with accompanying clinical symptoms (on the skin, intestines, respiratory
tract, or generalized) and signs caused by interaction between food and specific IgE antibodies through
ingestion or inhalation of food allergens.
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EXPERT MEETING SUMMARY
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Proposed working definitions
There were no proposals for working definitions; however, both speakers raised some questions.
TK pointed out that gold standards (DB PC FC) are not available in MeDALL birth cohorts and asked
whether we shall just use sensitization to food or we shall use self-reported (or parent-reported)
adverse reactions to food).
KHC asked whether it could be useful to combine questions based on symptoms with specific IgE to
foods.
Agreement
MeDALL will try not to leave out Food Allergy.
To seek advice from EUROPREVALL: to contact Peter Burney for help in the definition of allergic
reaction to foods and also for the methodology. To discuss with them which questions should be
added in the new questionnaire.
MeDALL expects to include a combination of positive response to food allergy questions and specific
IgE/SPT to food allergens.
Discussion
Torsten Zuberbier (TZ); Jean Bousquet (JB); Magnus Wickman (MW); Karin L Carlsen (KLC); Francine
Kauffmann (FK); Jocelyne Just (JJ); Josep Maria Antó (JMA); Kai-Hakon Carlsen (KHC); Renato Stein (RS)
TZ: Very good specificity but no good sensitivity (false negatives)
JB wanted to know prevalence to FA sensitisation in cohorts.
MW: around 20% /FA-any food); <10% sensitisation to milk; 15% sensitisation to birch pollen and
peanuts
KLC: We need to start with what we can measure objectively (suggests starting with allergensensitisation to food and not food allergy)
FK: Says that because it is very difficult to draw a definition of FA, we should remove this phenotype,
not to study it in MeDALL.
JJ: Disagrees. We can study it by adding some questions.
JMA: Important to note that it is a big challenge to apply methodology to measure allergic food
reactions.
TK: He suggests contacting Peter Burney for help in the definition of allergen reactions to food and
methodology (EUROPREVALL study).
Peter Burney indicated that high levels of prediction of the results of DBPCFCs could be found in young
children seen in clinic settings (52). In principal it should be possible to use this algorithm in some
cohorts though obviously the predictive values will not be so high as in a clinical sample.
KHC: Questions plus specific IgE sensitisation.
KLC: Not to measure FA qualitatively. Better to study FA quantitatively (are you sensitised or not?)
Either we use a clinical definition + objective measurements or we just use objective measurements.
JB: Proposal: IgE sensitisation – confirmation of FA episodes.
RS: The data we have in MeDALL is useful as a predictor for other diseases but not as a phenotype.
JB: Interesting to see differences in prevalence/sensitisation etc
JMA: This is another question (we can always do these analyses). Let’s go for the understanding
mechanisms of FA.
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
KLC: We can asses an intermediate phenotype but cannot define a proper FA phenotype because it is
too difficult.
JB/TZ: We should add food challenge tests in MeDALL.
FK/JMA and more participants: To wait and talk to EUROPREVALL people to discuss what questions
should be added in MeDALL new core questionnaires.
KLC: Clinical examinations: to ask for FA symptoms.
KHC: It will be a mistake if we leave out FA or food sensitisation.
ANAPHYLAXIS
Speakers: M Wickman (MW), J Bousquet
Review of the classical phenotypes
MW started by raising the extremely low prevalence of anaphylaxis (EUROPREVALL found 4 cases of
anaphylaxis out of 12000 participants) and thus was quite reluctant to study anaphylaxis in MeDALL
(20.000 children during a 12 months period: 6 children with anaphylaxis). However, he thought it is
important to study reactions to food. MW presented a study on children with reviewed clinical records
from emergency department visits at any of the three paediatric hospitals in Stockholm, Sweden and
showed that foods were the inciting agent in 92% of anaphylactic cases. With a study population of
447.739 children/adolescents 0-18 years of age, the incidence of anaphylaxis in Stockholm in 2007 was
32 per 100.000 person years irrespective of eliciting agent and the incidence of food-related
anaphylaxis was 29 per 100 000 person years (53).
MW exposed the diagnosis of anaphylaxis according to the WAO (1). Anaphylaxis is highly likely when
any one of the following 3 criteria is fulfilled: 1) Acute onset, 2) two or more of symptoms and 3)
reduced blood pressure after exposure to known allergen.
Proposed working definitions
A definition of anaphylaxis based on a questionnaire is unlikely to work. The questions should recall
anaphylaxis or severe allergic reaction leading to hospital admissions or emergency room visit (not a
good one). In addition it would be necessary to identify a known allergen (but in <30% of cases the
eliciting allergen was not possible to identify due to complete meal and idiopathic anaphylaxis). Finally,
a prescription of AAI (use of AAI in the last 12 months) does not say anything about anaphylaxis.
Instead, criteria for the definition of anaphylaxis should include:
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or
both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF
THE FOLLOWING:
i) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF (Peak
Expiratory Flow), hypoxemia);
ii) Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse],
syncope, incontinence, arrhythmias)
2) Two or more of the following that occur rapidly after exposure to a likely allergen for that patient
(minutes to several hours):
i) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-tongueuvula);
ii) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia);
iii) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence);
iv) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
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EXPERT MEETING SUMMARY
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Discussion
MW: Anaphylaxis (allergic reaction including respiratory difficulty and/or hypotension, especially
accompanied by urticaria and/or angioedema) is often misclassified because people think that
anaphylaxis is angioedema and this is wrong!
JB: not to use anaphylaxis in the classical questionnaire. However, KCL says that we should be able to
identify anaphylactic cases through the questionnaire (Cohort participants understand the question of
“allergic shock”. (Have you ever suffered anaphylactic shock? Yes/No)), even though we won’t be sure.
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EXPERT MEETING SUMMARY
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APPENDIX
During the preparation of these minutes several authors hold dissenting views about some aspects of
the minutes. As the debate was often reflecting different disciplinary perspectives, the different views
have been included in the appendix.
Note 1.
In the subsequent correspondence JB did not agree with the notion that a disease definition can be
interpreted in different ways and defended the idea that definitions should be used in a very precise
way. JB pointed out that the use of different definitions for the same disease is a cause of
misunderstanding between clinicians, epidemiologists and scientists and that agreement on a precise
definition would avoid these problems. JB suggested that definitions should be unique, evidence-based
and fully agreed and that based on such definitions one can see different strategies to “identify” the
disease. JB suggested that the key point is the difference between definition and identification of the
condition as this may change over time.
On the other hand JMA defended that in some diseases it is very difficult to agree on a unique disease
definition because clinicians, epidemiologists and scientists have sometimes different aims and the
definitions should be adapted to these aims. On this regard quoted McConnell and Holgate (54) “these
sometimes complementary but often competing pressures on the agreed definition of a disease have
led to prolonged and in-depth debates over the use of the word “asthma”. In the absence of full
understanding of the condition that we now group together as “asthma”, any definition will represent
a compromise, albeit a temporary compromise”.
Note 2.
FK raised the issue of the unclear directionality in the relationship between sensitization and asthma
from Fernando Martinez (FM) presentation at the MeDALL kick-off meeting, when he suggested that is
possible that not only allergy may cause asthma, but also that asthma may cause allergy and that it
would be important to consider that possibility from a research point of view. FM mentioned S
Holgate, who hypothesized that epithelial activation may drive Th2-type inflammation and concludes
his presentation by a quote of S Holgate "Thus, rather than atopy driving asthma, we suggest that the
development of asthma, and its concomitant epithelial abnormalities may predispose the airway to
local sensitization that, when established, would have the effect of aggravating the inflammatory and
remodeling response" (55).
JB did not agree and defended that asthma cannot induce atopy. Moreover, asthma by itself cannot
induce IgE synthesis against environmental allergens. In pollen allergy, the role of the lower airways is
minimal and most patients present rhinitis. The size of the pollens is far too big to penetrate below the
pharynx, particularly in children. Thus, asthma cannot drive the IgE immune response towards pollen
allergens. If this is true for pollens, it is unlikely that it would be the case for other allergens. What is
unknown however, is why some subjects become sensitized (with or without a family history of
allergy). It is likely that the epithelium (nasal and possibly bronchial) has a key role in driving the IgE
immune response. Thus, it is not asthma that induces IgE, but an intrinsic defect of the epithelium
likely to be independent of asthma itself. Otherwise, IgE would be more associated with asthma and
not with rhinitis. This is not the case for pollen allergy.
Note 3.
JB did not agree that current evidence challenges Coca and Cooke paradigm and suggested that the
classical definition of atopy can be accepted or not but cannot be changed if there is no scientific
evidence showing that it should be changed. Coca and Cooke made a clinical definition of a disease
(they called atopy). This definition is still valid with little change. Pepys added the concept of
sensitization (specific IgE) showing that it fits well with the concept.
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EXPERT MEETING SUMMARY
Barcelona, June 29-30th 2011
JB considered that there is a problem with the way some epidemiological papers mix total and specific
IgE to measure atopy. The latter is in contrast with the clinical opinion that total IgE measurement
should be withdraw in the definition of Ig-E mediated diseases.
FK suggested that the conflict between the evidence and the classical definition of atopy could be
interpreted as a process of changing a paradigm (according to T Kuhn who introduced the term
paradigm shift in his book "The Structure of Scientific Revolutions"). JB defended that so far there has
been no study which has disputed this paradigm.
Note 4.
TZ considered that the working definition of atopic eczema does not exactly reflect our agreement. As
in the document itself and pointed out in the discussion, the whole disease is and will be in the future
consistently called atopic eczema/atopic dermatitis independent of the positive history of atopy and
independent of atopy markers. Thus the disease will be called atopic dermatitis also in those patients
who have the clear-cut morphology according to the criteria of Hanifin and Rajka but have no
detectable IgE (although, to complicate even further, in many of these patients if you look more
precisely you will find positive IgE e.g. against the yeast Pitorosporum ovale or against bacteria, or
even against auto-antigens).
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EXPERT MEETING SUMMARY
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