ATOPY - WebmedCentral.com€¦ · Web viewClusters of risk factors may lead to joint mechanisms. Including the role of environment in the phenotype definition may be important

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

1- Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain2- Hospital del Mar Research Institute (IMIM), Barcelona, Spain3- CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain4- EPAR U707 INSERM, Paris and EPAR UMR-S UPMC, Paris VI, Paris, France5- Functional Genomics and Systems Biology for Health, CNRS Institute of Biological Sciences, Villejuif, France6- URL (Upper Airways research Laboratory), University Hospital Ghent, Ghent, Belgium7- Department of Paediatrics, Oslo University Hospital and University of Oslo, Oslo, Norway8- Department of Experimental and Health Sciences, University of Pompeu Fabra (UPF), Barcelona, Spain9- Institute of Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Berlin, Germany10- INSERM, CESP Centre for research in Epidemiology and Population Health, U1018, Respiratory and Environmental

Epidemiology team, Villejuif, France.11- Université Paris Sud 11, UMRS 1018, F-94807, Villejuif, France12- Department of Public health and biostatistics, Paris Descartes University, EA 406413- Paris municipal Department of social action, childhood, and health, Paris, France14- Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Lodz, Poland15- National School of Public Health, Athens, Greece16- Department of Respiratory Medicine, Beatrix Children’s Hospital, GRIAC Research Institute, University Medical Center

Groningen, University of Groningen, Groningen, the Netherlands17- School of Medicine, Pontifícia Universidade Católica RGS, Porto Alegre, RS - Brazil18- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland19- Sachs’ Children’s Hospital, Stockholm; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden20- Allergy-Centre-Charité at the Department of Dermatology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Secretary

General of the Global Allergy and Asthma European Network (GA2LEN)21- Division of Environment and Health, Centre for Public Health Research-CSISP, 46020 Valencia, Spain22- School of Nursing, University of Valencia, 46010 Valencia, Spain, Valencia23- Division of Morphology, Department of Histology, School of Medicine, University of Crete, Heraklion, Greece 24- Groupe Hospitalier Trousseau-La Roche-Guyon, Centre de l'Asthme et des Allergies, APHP, Université Paris 6, France25- Department of Epidemiology, GRIAC Research Institute, University Medical Center Groningen, University of Groningen,

Groningen, the Netherlands 26- Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, GRIAC Research Institute,

University Medical Center Groningen, University of Groningen, Groningen, the Netherlands27- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden28- Center for Allergy Research, Karolinska Institutet, Stockholm, Sweden29- 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

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30- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden31- Unitat de Rinología i Clínica de l’Olfacte, Servicio de ORL, Hospital Clínic, IDIBAPS, CIBERES, Barcelona, Spain32- Inserm Transfert, Paris, France33- Scientific Center of children’s health of Russian Academy of Medical Sciences, Moscow34- Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, GRIAC Research Institute,

University Medical Center Groningen, University of Groningen, Groningen, the Netherlands35- Bradford Institute for Health Research, Bradford Teaching Hospitals Foundation Trust, Bradford, UK 36- Bradford Neonatology, Bradford Royal Infirmary, Bradford, UK37- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland38- INSERM, U823, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Université Joseph

Fourier, Grenoble, France39- Servicio de Pediatría, Hospital de Zumarraga, Gipuzkoa, Spain40- WHO Collaborating Center for Asthma and Rhinitis, Montpellier, France41- 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, PhDCREAL- Centre for Research in Environmental EpidemiologyBarcelona Biomedical Research Park Dr. Aiguader, 8808003 BarcelonaSpain

Tel. +34 93 2147380Fax + 34 932147302E-mail: [email protected]

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Abbreviations

AAI: Adrenaline Auto-Injector AEDS: atopic eczema/dermatitis syndromeALSPAC: Avon Longitudinal Study of Parents and ChildrenAR: Airway HyperresponsivenessARIA: Allergic Rhinitis and its Impact on AsthmaBD: BronchodilatorBHR: Bronchial hyperresponsivenessBP: Blood PressureCD: Contact DermatitisCOPD: Chronic Obstructive Pulmonary DiseaseDBPCFC: Double-blind Placebo-Controlled Food ChallengeDRACMA: Diagnosis and Rationale for Action against Cow‘s Milk AllergyDRS: dose-response slopeEASI: Eczema Area and Severity Index ECA: Environment and Childhood AsthmaECRHS: European Community Respiratory Health SurveyEDEN: European Dermato-Epidemiology NetworkEiAN: exercise-induced anaphylaxisFA: Food AllergyGA2LEN: Global Allergy and Asthma European NetworkGINA: Global Initiative for AsthmaIgE: Immunoglobulin EISAAC: International Study of Asthma and Allergies in ChildhoodLRIs: Low Respiratory IllnessesMeDALL: Mechanisms of the Development of ALLergyNIAID: National Institute of Allergy and Infectious DiseasesPD20: provocative dose causing 20% decrease in FEV1PEF: Peak Expiratory FlowPF: Peak FlowPOEM: Patient-oriented Eczema MeasureQ (1-6): Question 1-6RSV: Respiratory Syncytial VirusSCORAD: Severity Scoring of Atopic DermatitisSPT: Skin Prick TestWAO: World oAllergy OrganizationWP: Work Package

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IntroductionThe MeDALL 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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ii) Not all sensitized patients present symptoms , iii) Serum-specific IgE or SPT do not have the same clinical relevance and patients with dissociated

tests may represent different phenotypes ,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 . 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 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)


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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) 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 . 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 . 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 . RS insisted that the association between allergy and asthma may not be causal .

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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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 .

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 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 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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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)


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 . 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 . 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 .

In children and adolescents, ISAAC questionnaire has been used to assess rhinitis (6-7 years and 13-14 years) . 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 pre-school children the diagnosis of rhinitis was used in a cohort 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 or

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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 , 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 :i) Intermittent: each episode of AR <1 monthii) Persistent: each episode of AR >1 monthiii) Mild: no impairment of daily activitiesiv) 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 ).

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)ii) If YES: in the past 12 months has this nose problem been accompanied by itchy-watery eyes?

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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)


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 . 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.

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 . The cutaneous

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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 , ii) EASI (Eczema Area and Severity Index) , iii) POEM (Patient-oriented Eczema Measure) .

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) .

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 Dermato-Epidemiology Network (EDEN) , for example Hywel Williams, Carsten Flohr , 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/NoIf Yes :ii) Q2. Has your child had this itchy rash at any time in the last 12 months? Yes/NoIf Yes : 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 Þ definition of flexural eczema

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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 cohortsi) Q1. Has your child ever had an itchy rash which was coming and going for at least 6 months?

Yes/Noii) Q dry skin. Has your child had dry skin in the last 12 months? Yes/No

(WP4) birth cohortsiii) Q1. Have you ever had an itchy rash which was coming and going for at least 6 months? Yes/Noiv) 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/NoYes Þ 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 .

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.

JB: In the classical phenotypes we should not change many things; we will do so for the novel phenotypes.

FOOD ALLERGY

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Speakers: T Keil (TK), KH Carlsen (KHC)


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 IgE-mediated, 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.


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).

13


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 allergen-sensitisation 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 . 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.

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.

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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


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.


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-tongue-

uvula); 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)

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!

15


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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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.

17


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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ATOPY - WebmedCentral.com€¦ · Web viewClusters of risk factors may lead to joint mechanisms. Including the role of environment in the phenotype definition may be important