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Severe chronic allergic (and related) diseases: a uniform approach a MeDALL-GA 2 LEN-ARIA Position Paper In collaboration with the WHO Collaborating Center for Asthma and Rhinitis

Corresponding author

Jean Bousquet Centre Hospitalier Universitaire, Montpellier 34295-Montpellier-Cedex 05 Phone : +33-611-42-88-47 Email : jean.bousquet@inserm.fr

Abstract

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different.

Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria, atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as co-morbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.

Key words

IgE, allergy, severity, control, risk, asthma, rhinitis, rhinosinusitis, urticaria, atopic dermatitis

Introduction

Allergic diseases represent the world's most common chronic disease. Several mechanisms are involved, but many result from IgE-mediated reactions [START_REF] Johansson | Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003[END_REF]. Not all sensitized patients are symptomatic [START_REF] Bousquet | Factors responsible for differences between asymptomatic subjects and patients presenting an IgE sensitization to allergens. A GALEN project[END_REF] and symptom severity varies from mild to severe and from intermittent to persistent whereas exacerbations may occur in any patient regardless of severity. Most patients have an early onset of symptoms but the clinical phenotypes of allergic diseases may vary with age (3).

Acute, IgE-mediated, severe reactions (e.g. anaphylaxis (4)) occurring in patients sensitized to drugs [START_REF] Demoly | Important questions in Allergy: 1--drug allergy/hypersensitivity[END_REF], foods [START_REF] Sicherer | Food allergy[END_REF] or hymenoptera venoms ( 7) may be life-threatening. Many types of acute non-IgEmediated allergic diseases or non-allergic diseases (1) such as aspirin hypersensitivity, hereditary angioedema [START_REF] Zuraw | Clinical practice. Hereditary angioedema[END_REF], cold urticaria [START_REF] Krause | Modern approaches to the diagnosis and treatment of cold contact urticaria[END_REF] or skin reactions such as DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) or Lyell syndrome [START_REF] Roujeau | Clinical heterogeneity of drug hypersensitivity[END_REF] may also be life-threatening. Acute allergic (and related) diseases will not be considered in this document.

Major IgE-mediated chronic diseases include rhinitis (and conjunctivitis) [START_REF] Bousquet | Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)[END_REF], asthma [START_REF] Bousquet | Global surveillance, prevention and control of Chronic Respiratory Diseases. A comprehensive approach. Global Alliance against Chronic Respiratory Diseases[END_REF], atopic dermatitis [START_REF] Bieber | Atopic dermatitis[END_REF] and gastro-intestinal diseases. However, allergy is not the only mechanism involved [START_REF] Pearce | How much asthma is really attributable to atopy?[END_REF][START_REF] Weinmayr | International variation in prevalence of rhinitis and its relationship with sensitisation to perennial and seasonal allergens[END_REF][START_REF] Bousquet | Geographical distribution of atopic rhinitis in the European Community Respiratory Health Survey I[END_REF][START_REF] Bousquet | Important research questions in allergy and related diseases: nonallergic rhinitis: a GA2LEN paper[END_REF]. The present document will propose the definition of the severity of allergic and related (nonallergic origin) diseases: asthma, rhinitis (conjunctivitis), rhinosinusitis [START_REF] Fokkens | EP3OS. European position paper on rhinosinusitis and nasal polyps[END_REF][START_REF] Bachert | Important research questions in allergy and related diseases: 3-chronic rhinosinusitis and nasal polyposis -a GALEN study[END_REF][START_REF] Hastan | Chronic rhinosinusitis in European underestimated disease. A GA(2) LEN study[END_REF], atopic dermatitis and chronic urticaria [START_REF] Zuberbier | EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria[END_REF][START_REF] Zuberbier | EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria[END_REF]. Occupational diseases will not be considered in this document. Atopic and vernal conjunctivitis are severe diseases which may affect the vision. They will be considered in an update of this document.

Co-morbidities play a major role in severity, adding to the complexity of the disease and its management [START_REF] Bousquet | Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)[END_REF]. However, in the current document, each disease will be considered separately since certain patients may have a severe disease (e.g. rhinitis) associated with a milder one (e.g. asthma).

Concepts of disease severity, activity, control and responsiveness to treatment are linked. Severity refers to the loss of function of the organs induced by the disease process. It may vary over time and needs regular follow up. Activity refers to the current level of activation of the biological network perturbations that cause the disease and their clinical consequences. Control is the degree to which therapy goals are currently met. Disease activity and control can be viewed as opposites. These concepts have evolved over time for asthma in the development of guidelines [START_REF]Expert panel report 3: Guidelines for the diagnosis and management of asthma[END_REF][START_REF] Bousquet | GINA guidelines on asthma and beyond[END_REF], task forces [START_REF]Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions[END_REF] or consensus meetings [START_REF] Taylor | A new perspective on concepts of asthma severity and control[END_REF]. Up to 2006, asthma was classified by severity alone. Then, newer GINA guidelines replaced "grading by severity" with "grading by control" using the same items. Neither classification seems adequate when employed in isolation, nor is the classification of asthma by control alone sufficient [START_REF] Taylor | A new perspective on concepts of asthma severity and control[END_REF]. The NAEPP-EPR3 guidelines [START_REF]Expert panel report 3: Guidelines for the diagnosis and management of asthma[END_REF] made key suggestions combining impairment, response to treatment and risks. This concept was adopted by GINA [START_REF]Global Strategy for Asthma Management and Prevention (GINA[END_REF]. The uniform definition of severe asthma presented to WHO [START_REF] Bousquet | Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma[END_REF] was based on the NAEPP-EPR3 approach [START_REF]Expert panel report 3: Guidelines for the diagnosis and management of asthma[END_REF].

The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO [START_REF] Bousquet | Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma[END_REF] for allergic and related diseases in order to develop a uniform definition of severity, control and risk, usable in most situations. This uniform definition will enable a better definition of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies (Table I).

Severity, control, response to treatment and risk in asthma

The stratification and grading of asthma severity includes several components (Table 2). The most useful concept of asthma severity is based on the intensity of the treatment required to obtain control [START_REF] Taylor | A new perspective on concepts of asthma severity and control[END_REF].

Control

The level of asthma control incorporates current clinical control and exacerbations over the past 6 to 12 months [START_REF] Taylor | A new perspective on concepts of asthma severity and control[END_REF]. The measurement of current asthma control may be assessed by individual outcome measures such as daily or nocturnal symptoms, symptoms linked to activities or exercise, monitoring of peak flow or pulmonary function, as-needed use of relievers, and exacerbations. Used individually, these measures cannot accurately assess asthma control. A composite measure reflecting all key endpoints is more relevant [START_REF] Humbert | Asthma control or severity: that is the question[END_REF] and has been used in guidelines (23, 2008 #27059, 31) (Table 3).

Several scores for the control of asthma have been validated and translated into many languages in adults and adolescents. Examples are:

• The Royal College of Physicians' three questions [START_REF] Thomas | Assessing asthma control in routine clinical practice: use of the Royal College of Physicians '3 Questions[END_REF].

• The Juniper's Asthma Control Questionnaire (ACQ), based on 6 questions (ACQ6) and FEV 1 (ACQ7) [START_REF] Juniper | Development and validation of a questionnaire to measure asthma control[END_REF]. ACQ6 is more predictive than ACQ7 for asthma control [START_REF] Juniper | Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire[END_REF].

• The Asthma Control Test (ACT), based on 5 questions [START_REF] Nathan | Development of the asthma control test: a survey for assessing asthma control[END_REF][START_REF] Thomas | The Asthma Control Test (ACT) as a predictor of GINA guideline-defined asthma control: analysis of a multinational cross-sectional survey[END_REF].

In children, a few asthma control questionnaires have been validated [START_REF] Juniper | Asthma Control Questionnaire in children: validation, measurement properties, interpretation[END_REF][START_REF] Liu | The Childhood Asthma Control Test: retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma[END_REF].

None of these questionnaires appropriately assess exacerbations that are of importance in the assessment of the control of asthma and deserve further attention.

Biomarkers hold promise to capture complementary information regarding diagnosis and risk, but need to be validated with regard to control. Biomarkers are either not readily available or completely unavailable in most practice settings [START_REF]British Guideline on the Management of Asthma[END_REF].

Although asthma therapy is primarily aimed at controlling the disease, the control level of asthma is independent of the step of asthma treatment. Control can be achieved at any severity level. A patient under total control may still have severe disease (e.g. an oral corticosteroid-treated patient). Patients achieving control with treatment have a lower risk of exacerbation than those who are uncontrolled [START_REF]British Guideline on the Management of Asthma[END_REF].

Response to treatment

Responsiveness to treatment has been demonstrated in studies assessing risk reduction during treatment. Studies at the community level show a considerable reduction of hospitalizations and deaths using appropriate management [START_REF] Haahtela | A 10 year asthma programme in Finland: major change for the better[END_REF]. Successful studies have been carried out in low-and middleincome countries (LMICs) [START_REF] Souza-Machado | Rapid reduction in hospitalisations after an intervention to manage severe asthma[END_REF][START_REF] Andrade | A pediatric asthma management program in a low-income setting resulting in reduced use of health service for acute asthma[END_REF] or in deprived populations [START_REF] Evans | A randomized clinical trial to reduce asthma morbidity among inner-city children: results of the National Cooperative Inner-City Asthma Study[END_REF]. The concept is therefore applicable to all populations and all countries. In the NAEPP-EPR3 guidelines [START_REF]Expert panel report 3: Guidelines for the diagnosis and management of asthma[END_REF], resistance to therapy is defined as uncontrolled asthma despite high-dose inhaled corticosteroids. For the INNOVATE trial (omalizumab), the European Medical Agency requested the assessment of asthma control in patients treated by inhaled corticosteroids and long-acting ß-agonists [START_REF] Humbert | Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE[END_REF].

Risk

The concept of asthma risk ( 23) is intended to capture:  The likelihood of future asthma exacerbations.

 Progressive loss of pulmonary function over time (or for children, reduced lung growth).

 Risk of adverse effects from treatment, which should always be considered carefully.

These domains respond differentially to treatment. The assessment of risk domain is more difficult than the evaluation of control.

Definition of asthma severity and control

The definition of asthma severity, control and exacerbations proposed to WHO (28) took guidelines [START_REF]Expert panel report 3: Guidelines for the diagnosis and management of asthma[END_REF][START_REF] Bousquet | GINA guidelines on asthma and beyond[END_REF] and the 2008 ATS/ERS Task Force report into consideration (26) (Figure 1). The recent consensus by U-BIOPRED (Unbiased BIOmarkers for the PREDiction of respiratory disease outcomes) from the Innovative Medicines Initiative (IMI) distinguishes severe asthma from alternative diagnoses by providing a stepwise algorithm to single out severe refractory asthma from difficult asthma based on insufficient therapy, poor treatment adherence and/or co-morbidity [START_REF] Bell | Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicines Initative (IMI)[END_REF].

In patients appropriately diagnosed, severe asthma is defined by the level of current clinical control and risks as: "Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)" [START_REF] Bousquet | Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma[END_REF]. This proposal also includes wheezing disorders in pre-school children although there is dispute as to the age at which the label "asthma" can properly be applied [START_REF] Castro-Rodriguez | A clinical index to define risk of asthma in young children with recurrent wheezing [In Process Citation[END_REF][START_REF] Devulapalli | Severity of obstructive airways disease by age 2 years predicts asthma at 10 years of age[END_REF]. A consensus has been proposed [START_REF] Brand | Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach[END_REF], but the conclusions are still under discussion.

Uniform approach to the severity of chronic allergic (and related) diseases

Severe allergic (and related) diseases include 7 groups, each carrying different public health perspectives and challenges (Figure 2):  Diagnosis is the first step, but it is not always easy as certain diseases may overlap (e.g.

wheezing in preschool children).

 Control should be monitored in all patients with a diagnosis of chronic allergic disease using available tests. Control should be regularly evaluated and treatment adapted to its level.

 Responsiveness to treatment is the ease with which disease control is achieved by therapeutic interventions. For asthma or allergic rhinitis, effective treatments are available for most patients. Some diseases (e.g. some phenotypes of non-allergic rhinitis or urticaria) are more difficult to control.

 Availability and affordability of the treatment: The management of allergic disease depends on the context of national (or regional), economic and health provider settings and facilities, the health system as well as individual and societal variables (beliefs, cultural and socioeconomic determinants). In high-income countries, treatments are available and, for most patients, affordable. However, in many LMICs and in some deprived areas of high-income countries, essential medicines may be available but are rarely affordable [START_REF] Cameron | Medicine prices, availability, and affordability in 36 developing and middle-income countries: a secondary analysis[END_REF] although they should be in formularies. Even if medications are affordable, health professional knowledge concerning their optimal use is fragmented and requires training. Furthermore, the health system often lacks infrastructure for early diagnosis, follow up and education as well as legislation for appropriate referral.

 Re-assessment of the diagnosis of the disease: In patients who are uncontrolled despite optimal treatment, all reasonable efforts to eliminate other diagnoses must be made. Patients may suffer from a mild disease that is considered to be severe because it is underlined by another disease (e.g. wheezing in cystic fibrosis). It may be difficult to ascribe the differential severity to the allergic disease or the underlying one. On the other hand, there may be a degree of overdiagnosis which could lead to a false impression of severe disease.

 Difficult-to-treat severe disease represents a category in which partial or poor response to treatment reflects factors other than the disease alone. Issues to address in such cases include:

• Poor adherence to treatment.

• Incorrect inhalation technique.

• Adverse environmental circumstances such as passive smoke or allergen exposure.

• Psychosocial issues.

• And co-morbidities which cannot be controlled.

Any or all of these factors can be very important in any chronic disease.

 Patients with treatment-dependent severe disease are those who require the highest level of recommended treatment to maintain control. This requirement for high doses of medication and multiple medications suggests a component of treatment resistance or insensitivity. Although the disease is controlled, the patients are at risk of exacerbations if treatment is inappropriately reduced or becomes unavailable.

 Patients with treatment-resistant severe disease are those who are partially or poorly controlled despite the highest recommended treatment provided according to the guidelines existing in the country (or if guidelines do not exist, the highest controller medications available in the country). This insensitivity may not be an absolute phenomenon, but varies from patient to patient and with time.

 Severity should be re-assessed at regular intervals as it may change over time.

Severe allergic and related diseases

Allergic and non-allergic rhinitis (and rhino-conjunctivitis)

Allergic rhinitis is an IgE-mediated reaction of the nasal mucosa. It is often associated with conjunctivitis (rhino-conjunctivitis) [START_REF] Bousquet | Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)[END_REF]. Non-allergic rhinitis represents a group of heterogeneous diseases in which no IgE-mediated reaction can be demonstrated [START_REF] Bousquet | Important research questions in allergy and related diseases: nonallergic rhinitis: a GA2LEN paper[END_REF]. Unmet clinical needs are clear in allergic and non-allergic rhinitis (51).

Control

Control and severity are not well delineated in rhinitis. Using the new definition, measures of the control of allergic rhinitis include symptom scores, visual analogue scales (VAS) [START_REF] Bousquet | Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines[END_REF], objective measures of nasal obstruction such as peak inspiratory flow measurements, acoustic rhinometry and rhinomanometry [START_REF] Ragab | Nasal nitric oxide in objective evaluation of chronic rhinosinusitis therapy[END_REF], a recent modification of the ARIA severity classification [START_REF] Valero | A new criterion by which to discriminate between patients with moderate allergic rhinitis and patients with severe allergic rhinitis based on the Allergic Rhinitis and its Impact on Asthma severity items[END_REF], or patients' reported outcomes such as quality-of-life [START_REF] Bousquet | Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)[END_REF][START_REF] Baiardini | Recommendations for assessing Patient-Reported Outcomes and Health-Related quality of life in clinical trials on allergy: a GA(2)LEN taskforce position paper[END_REF][START_REF] Baiardini | Recommendations for assessing patient-reported outcomes and health-related quality of life in clinical trials on allergy: a GA(2)LEN taskforce position paper[END_REF]. More recently, a score with several items was proposed (57). It appears in rhinitis that a simple measure such as VAS may be sufficient to appreciate the control of the disease [START_REF] Bousquet | Change in visual analog scale score in a pragmatic randomized cluster trial of allergic rhinitis[END_REF] and is particularly relevant to primary [START_REF] Ryan | Primary care: the cornerstone of diagnosis of allergic rhinitis[END_REF] or pharmacy care [START_REF]ARIA in the pharmacy: management of allergic rhinitis symptoms in the pharmacy. Allergic rhinitis and its impact on asthma[END_REF]. The level of control of allergic rhinitis is assessed independent of the treatment step (52, 61).

Responsiveness to treatment

Most patients with allergic rhinitis can be controlled using guideline-based treatment. However, among patients with moderate to severe symptoms who comply with an adequate treatment according to guidelines, up to 20% continue to be impaired by their symptoms. The GA²LEN-ARIA-WAO task force has proposed the new appellation of Severe Chronic Upper Airways Disease (SCUAD) for these cases where patients' symptoms are not sufficiently controlled despite their pharmacological treatment [START_REF] Bousquet | Unmet needs in severe chronic upper airway disease (SCUAD)[END_REF][START_REF] Bousquet | Uncontrolled allergic rhinitis during treatment and its impact on quality of life: a cluster randomized trial[END_REF]. However, SCUAD applies to all nasal diseases irrespective of the allergic component.

Allergic conjunctivitis is frequently associated with pollen-induced rhinitis but it is more difficult to control than rhinitis [START_REF] Bousquet | Implementation of guidelines for seasonal allergic rhinitis: a randomized controlled trial[END_REF].

The efficacy of the treatment of non-allergic rhinitis is variable [START_REF] Bousquet | Important research questions in allergy and related diseases: nonallergic rhinitis: a GA2LEN paper[END_REF]. It is heterogeneous in etiologies and inconsistently benefits from treatments which are effective in allergic rhinitis [START_REF] Webb | Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia[END_REF][START_REF] Greiner | Pharmacologic rationale for treating allergic and nonallergic rhinitis[END_REF].

Re-assessment of the diagnosis of the disease

Many different conditions can mimic allergic and non-allergic rhinitis [START_REF] Bousquet | Allergic rhinitis and its impact on asthma[END_REF]. Local allergic reactions with nasal but not systemic IgE antibodies (67) may be more important than initially thought.

Misdiagnosis (e.g. nasal tumors, granulomas, cerebrospinal rhinorrhea) may lead to adverse outcomes if the patient is not appropriately re-assessed and reviewed.

Risk

Allergic rhinitis impairs work [START_REF] Dykewicz | Executive Summary of Joint Task Force Practice Parameters on Diagnosis and Management of Rhinitis[END_REF][START_REF] Bousquet | Severity and impairment of allergic rhinitis in patients consulting in primary care[END_REF] and school performance [START_REF] Blaiss | Allergic rhinitis and impairment issues in schoolchildren: a consensus report[END_REF][START_REF] Simons | Learning impairment and allergic rhinitis[END_REF]. Moreover, sedation may be enhanced using H 1 -antihistamines with sedative properties [START_REF] Church | Risk of first-generation H(1)-antihistamines: a GA(2)LEN position paper[END_REF]. The major long-term risk of allergic and non-allergic rhinitis is the development of asthma (73).

Chronic rhinosinusitis (CRS)

Control

Control and severity are not well delineated in CRS. Using the new definition, it is proposed that an overall symptom score measured by VAS may more accurately monitor control, and could be combined with disease specific [START_REF] Fokkens | EP3OS. European position paper on rhinosinusitis and nasal polyps[END_REF][START_REF] Lim | The relationship between subjective assessment instruments in chronic rhinosinusitis[END_REF] and generic health status assessment instruments (18).

Responsiveness to treatment

Responsiveness to treatment differs in CRS without nasal polyps (CRSsNP) and in CRS with nasal polyps (CRSwNP) [START_REF] Van Zele | Differentiation of chronic sinus diseases by measurement of inflammatory mediators[END_REF][START_REF] Zhang | Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease[END_REF][START_REF] Van Bruaene | TGF-beta signaling and collagen deposition in chronic rhinosinusitis[END_REF]. The principle of SCUAD also applies to CRS [START_REF] Bousquet | Unmet needs in severe chronic upper airway disease (SCUAD)[END_REF].

The pathophysiology of CRSsNP is poorly understood [START_REF] Bachert | Important research questions in allergy and related diseases: 3-chronic rhinosinusitis and nasal polyposis -a GALEN study[END_REF] and treatment options are limited to topical corticosteroids [START_REF] Fokkens | EP3OS. European position paper on rhinosinusitis and nasal polyps[END_REF]. According to clinical experience and reports, sinus surgery improves symptoms in the short-term in 65-90% of the cases.

In CRSwNP, symptoms may be controlled by topical corticosteroid treatment in mild to moderate localized disease [START_REF] Stjarne | The efficacy and safety of once-daily mometasone furoate nasal spray in nasal polyposis: a randomized, double-blind, placebo-controlled study[END_REF][START_REF] Mullol | Corticosteroid treatment in chronic rhinosinusitis: the possibilities and the limits[END_REF][START_REF] Vaidyanathan | Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids: a randomized trial[END_REF]. However, in severe polyposis and asthma co-morbidity, repeated courses of intranasal and/or oral corticosteroids are usually insufficient in controling symptoms. Repeated sinus surgeries may be needed with inconsistent clinical benefits (81).

Re-assessment of the diagnosis of the disease

The differential diagnosis includes all forms of rhinitis, as well as underlying sinus diseases such as cystic fibrosis, primary ciliary dyskinesia, non-invasive fungal sinusitis, allergic fungal sinus disease and invasive forms [START_REF] Fokkens | EP3OS. European position paper on rhinosinusitis and nasal polyps[END_REF]. Sinus headache needs to be differentiated from neurological, ocular or facial pains. Other rare diagnoses are Wegener´s, other granulomas disease, cocaine abuse or lymphomas.

Any unilateral obstruction, pain and bleeding has to be investigated by a specialist to exclude malignancies, inverted papilloma, meningoceles and other serious conditions (82).

Risk

Very rarely, acute complications with a spread of the disease into the orbit, the meninges, the brain or frontal bone (osteomyelitis) may develop in the course of acute exacerbations of the disease.

Mucoceles develop slowly as long-term complications after surgery, but can also develop spontaneously.

About 10-15% of the CRSsNP and up to 45% of the CRSwNP patients present or will develop comorbid asthma, which may be severe [START_REF] Bachert | Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma[END_REF]. CRSwNP may also develop into a systemic disease such as aspirin-exacerbated respiratory disease [START_REF] Kowalski | Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) -classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*[END_REF], or Churg-Strauss syndrome [START_REF] Fuchs | Granulomatous disorders of the nose and paranasal sinuses[END_REF]. Allergic fungal sinus disease may be accompanied by allergic bronchopulmonary aspergillosis (ABPA).

Repeated courses of oral corticosteroids in patients with persistent CRS may affect bone metabolism and lead to HPA-axis dysfunction (79, 86).

Chronic urticaria

Urticaria describes the spontaneous or inducible occurrence of wheals and flares often accompanied by pruritus which generally subside within hours, while new lesions occur. Chronic urticaria is a group of spontaneous or inducible diseases characterized by symptom persistence or reoccurence over 6 weeks [START_REF] Zuberbier | EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria[END_REF][START_REF] Kaplan | Pathogenesis of chronic urticaria[END_REF] with several clinical unmet needs [START_REF] Maurer | Unmet clinical needs in chronic spontaneous urticaria. A GA(2) LEN task force report(1)[END_REF]. Angioedema describes a deep swelling in the dermis which can be accompanied by pain and predominantly involves soft tissues, e.g. in the face (eyelids, lips) or genital area.

Control

Control and severity are not well delineated in chronic urticaria [START_REF] Maurer | Unmet clinical needs in chronic spontaneous urticaria. A GA(2) LEN task force report(1)[END_REF]. Using the new definition, control can be assessed by the daily number of wheals and by the intensity of the pruritus as assessed using the weekly urticaria activity score (UAS7) [START_REF] Mathias | Development of a daily diary for patients with chronic idiopathic urticaria[END_REF] and/or the chronic urticaria quality of life questionnaire (CU-Q2oL) [START_REF] Mlynek | How to assess disease activity in patients with chronic urticaria?[END_REF][START_REF] Baiardini | Allergic diseases and their impact on quality of life[END_REF]. Patient diaries and health-related quality of life instruments can be used.

Responsiveness to treatment

In chronic urticaria, symptomatic treatment is the rule since causal treatment is rarely effective [START_REF] Zuberbier | EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria[END_REF][START_REF] Maurer | Unmet clinical needs in chronic spontaneous urticaria. A GA(2) LEN task force report(1)[END_REF]. Chronic urticaria can be fully controlled in a minority of patients by following the guidelinerecommended step-up approach. The aim of the treatment in chronic urticaria is the absence of symptoms, i.e. the complete protection from the reoccurrence of wheals, pruritus, and angioedema. This can be achieved in less than half of all patients by using licensed doses of non-sedating oral H 1antihistamines, the guideline-recommended first step therapy and only in-label treatment option (92).

Re-assessment of the diagnosis of the disease

Urticaria vasculitis and auto-inflammatory disorders (e.g. cryopyrin-associated periodic syndrome (CAPS) [START_REF] Neven | Cryopyrinopathies: update on pathogenesis and treatment[END_REF], Schnitzler syndrome (94)), mastocytosis [START_REF] Valent | The European Competence Network on Mastocytosis (ECNM)[END_REF] and hereditary or other complement associated disease (8) must be considered in patients with chronic spontaneous urticaria who present with wheals and signs of systemic inflammation or recurrent angioedema without wheals. These diseases are associated with a high risk of severe morbidity and mortality.

Risk

The risks in chronic inducible urticaria are different from those in chronic spontaneous urticaria and are specific for each inducible urticaria. In general, low thresholds for trigger intensity and for trigger exposure time are indicators of high disease activity [START_REF] Magerl | The definition and diagnostic testing of physical and cholinergic urticarias--EAACI/GA2LEN/EDF/UNEV consensus panel recommendations[END_REF].

Some inducible urticarias such as cold urticaria and exercise-induced urticaria can induce severe systemic reactions including anaphylactic shock which may lead to death (e.g. swimming in cold water).

Chronic spontaneous urticaria patients are at risk of developing comorbidities such as autoimmune disorders (e.g. autoimmune thyroiditis) [START_REF] Dreskin | The thyroid and urticaria[END_REF].

Since many patients cannot be controlled using recommended doses of medications, uncontrolled patients often develop depression and anxiety [START_REF] Willemsen | Alexithymia and dermatology: the state of the art[END_REF].

Many chronic urticaria patients are at risk of experiencing adverse effects of their therapy since they often receive doses higher than those recommended as well as the off-label use of other medications. Impaired QOL is common in AD, both in children (patients and caregivers) and adults. Impaired QOL may be observed in infants (105). Several QOL measures (disease-specific and generic) have been used (106).

Responsiveness to treatment

Most cases of patients seemingly resistant to the treatment are certainly explained by a lack of correct implementation of the guidelines (107, 108). This can be improved by an intense treatment under supervision and adapted educational programs. Thus, as in other chronic diseases, the responsiveness and control of the disease is tightly dependent on the compliance of the patients/parents. However, truly therapy-resistant AD severe cases exist, which may be explained by a particular genetic predisposition. There are currently no studies available having addressed this issue, but it is estimated that no more than 5% of AD belong to this group (13).

Re-assessment of the diagnosis of the disease

Depending on the age of onset, AD can be misdiagnosed (107, 108). In preschool children, the spectrum of differential diagnosis is very wide including either common diseases such as psoriasis or rather rare conditions such as Schwachman Diamond's syndrome (also named Burke-Syndrome) agammaglobulinaemia, ataxia telangiectasia (109) and histiocytic disorders (110). In adults, other diseases such as seborrheic dermatitis or cutaneous T cell lymphoma have to be excluded (111).

Risk

Atopic dermatitis during infancy is a risk factor for other atopic diseases occurring later in childhood (112-114). This is probably the case for about 30% of AD patients, mostly with early onset, i.e. in infancy. During the first year of life, atopic dermatitis is mostly related to food allergy, but very often spontaneously improves after one to two years. Children with early onset, a filagrin mutation and having food allergy (mainly peanut) have almost a 100% risk of developing allergic asthma (115).

On the other hand, about 30% of adult patients seem to develop specific IgE against self-proteins, suggesting an autoimmune form of AD in adulthood for which allergen avoidance is therefore meaningless (116).

Due to a strongly impaired innate immunity response of the epidermal barrier in AD, these patients have a high risk of developing superinfections with bacteria such as Staphylococcus aureus, fungi such as Malassezia sympodialis or herpes simplex virus or causing eczema herpeticum, a severe complication of AD (117, 118).

The increased permeability of the skin associated with chronic inflammation may also favor sensitization to haptens, causing increasing rates of allergic contact dermatitis (119).

Application to children

Severe problematic asthma

Severe problematic asthma is probably as common in children as in adults, with approximately 4-5 % of children with asthma (120). Phenotypes of severe problematic asthma differ in children and in adults (121, 122). A proposal with a 4-step procedure for the diagnosis and assessment of severe problematic asthma in childhood has recently been published (123). The steps include (a) a full diagnostic work-up that may exclude other chronic lung diseases which may mimic severe asthma; (b) a multidisciplinary assessment to identify factors of importance including co-morbidities; (c) an assessment of the pattern of inflammation and (d) a documentation of the level of corticosteroid responsiveness.

Allergic rhinoconjunctivitis and chronic rhinosinusitis

For children, there is an increasing awareness that rhinitis may start in very early childhood, but definitions and control measures are largely lacking. Treatment challenges are frequently more pronounced in children, with sparse documentation of pharmacological intervention in severe disease, which is often part of complex atopic disease presentation.

It is difficult to diagnose allergic rhinitis/conjunctivitis in preschool children. Furthermore, children of this age have frequent infections of the upper airways, and management is challenging due to a lack of guidelines, co-morbidities and a lack of objective parameters to guide diagnosis.

There are specific problems in childhood/adolescence such as general symptoms of malaise occurring during important school and university examinations in the spring pollen season (124).

In children, it may be difficult to distinguish between persistent non-allergic rhinitis and rhinitis associated with recurrent respiratory tract infections.

Cystic fibrosis or primary ciliary dyskinesias are important to rule out in patients suspected of chronic rhinosinusitis. Phenotyping subtypes can be used to characterize and predict disease severity, progression, and response to treatment, and may help identify unique targets for treatment [START_REF] Taylor | A new perspective on concepts of asthma severity and control[END_REF]. Heterogeneity also exists within each dimension of the disease (e.g. eosinophils and asthma severity) (129, 130), across diseases (e.g. eosinophils in asthma and COPD) and in relation to co-morbidities (131, 132). Phenotypes may also change over time.

Importance of a uniform approach

Phenotype heterogeneity may reflect a priori defined hypotheses or lead to the generation of novel hypotheses through multiple logistic regression (131, 133), cluster analysis (126, 132) or free scale networks. However, a uniform definition applied worldwide is needed, and then detailed subphenotyping of severe allergic diseases may be approached [START_REF] Bousquet | Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma[END_REF].

Clinical practice

A uniform definition provides a framework to decide who needs targeting for treatment or improved treatment [START_REF] Bousquet | Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma[END_REF]. It will help in the delivery of appropriate health care through better organization for diagnosis and treatment in primary care and/or specialist clinics. A multidisciplinary approach is recommended in patients with severe allergic diseases [START_REF]British Guideline on the Management of Asthma[END_REF]. For this, the use of a common language across primary, secondary and tertiary care is important. A major challenge is that their functional differentiation of level of care turns into a segregation of patient flows. The use in guidelines of the same definitions and criteria across the board of health care will facilitate a smooth transfer of patients from primary care to more specialized care and back, according to their needs. Communication with patients or parents of patients should be focused on providing information on the need for therapy and the consequent use of therapy, as well as on the risks of not complying with these recommendations.

Personalized medicine

The main challenge for allergic diseases in the 21 st century is to understand their complexity.

Identification of the underlying mechanisms will help the prognosis, diagnosis and treatment of disease [START_REF] Bousquet | Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine[END_REF] as well as the transition to predictive, preventive, personalized and participatory (P4) medicine (134). The uniform approach of severity is perfectly embedded within this new paradigm.

Registries for severe allergic (and related) diseases

Severe asthma registries provide a foundation upon which to generate a greater understanding of public health needs, to define phenotypic heterogeneity to inform the design of research studies and to improve overall clinical care [START_REF] Bousquet | Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma[END_REF]. Registries will help in the surveillance of severe allergic diseases.

Data from the registries may provide evidence of inadequacies in the control of diseases. The establishment of an internationally-agreed definition of severe allergic (and related) diseases will provide the opportunity to develop a single registry in order to capture core information in both developed and developing countries. This is particularly relevant to the worldwide changing demography of allergic diseases.

Clinical trials

For clinical trials, it is essential to have clarity as to what definitions have been used -severity assessed before treatment or after treatment, and in this case, which treatment was used. In addition, clinical trials should consider co-morbidities and confounding conditions necessary for the adequate assessment of clinical responses (e.g. smoking and asthma) or effectiveness of different therapeutic approaches.

Registration of medicines and reimbursement

Controlled trials designed with a uniform approach of severity (135) will be more easily evaluated by the agencies for approval and by the Health Technology Assessment agencies (such as NICE) for reimbursement.

Research on mechanisms and genetics

More research into severe allergic diseases is urgently needed. Many large collaborative studies are already ongoing for severe asthma (125-127), but not for the other diseases. A uniform definition and a collaborative approach to epidemiological, genetic and mechanistic research are important. Different levels of phenotype characterization (granularity) can be applied to assess phenotypic characterization in patients with severe allergic (and related) diseases. For the success of such approaches, it is important to develop global partnerships and platforms to ensure the application of standard methodology and protocols to promote the collection and sharing of samples and data through appropriate infrastructure in different countries [START_REF] Bousquet | Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma[END_REF].

Epidemiology

In epidemiologic population studies, standardized definitions are fundamental. It is often difficult to assess severity since many patients are undertreated. The uniform definition of severe allergic (and related) diseases accounts for these patients and articulates time frames for the appropriate assessment of severity and control. Thus, the definition will facilitate epidemiological research, understand modifiable risk factors and enable comparisons across studies in different populations. Control usually refers to events occurring recently (over the last 2-4 weeks) whereas severity refers to those occurring over a long period of time (e.g. 6-12 months).

Public health planning

For public health purposes, a uniform definition of severe allergic (and related) diseases is needed to identify the prevalence, burden and costs incurred by severe patients in order to improve quality of care and optimize health care planning and policies. This definition will provide support for more precise calculations on the needs and costs of medications in a country.

Developed and developing countries

A uniform definition of severe allergic (and related) diseases should be applicable to the local and geographical conditions of all countries, phenotypes, risk factors, availability and affordability to treatment differing widely around the world. Research must be planned to evaluate the phenotypes of "severe" allergic (and related) diseases from different countries.

Development of novel therapies

For treatment-resistant severe allergic (and related) diseases, more detailed cellular and molecular phenotyping is needed to identify new targets for the development of novel therapies and to improve current therapies in a cost-effective manner. Ultimately, novel therapies studied in clinical trials should help define the pathogenesis of the diseases and determine the importance of the treatment in large patient populations or in sub-populations of patients based on the concept of distinct phenotypes.

Conclusions

It is likely that a uniform definition of severe allergic diseases will help in a better understanding of phenotypes but there is a need for a validation process of the proposed definition for severe chronic allergic diseases across different populations and countries with different income, age groups and different disease phenotypes.

Table I: Goals of the current paper

 The current document develops a common strategy to the severity of chronic allergic (and related) diseases taken individually.

 It does not consider acute allergic reactions such as anaphylaxis.

 It does not take into account co-morbidities [START_REF] Bousquet | Systems medicine and integrated care to combat chronic noncommunicable diseases[END_REF].

 It is intended to be used by all stakeholders involved in the management or research of allergic (and related) diseases.

Table 2: Components contributing to asthma severity

From ( 23) and ( 28

  144-Julius Center of Health Sciences and Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands 145-National Centre Cardiology and Internal Medicine, Bishkek, Kyrgyzstan 145A-School of Medicine, Pontifícia Universidade Católica RGS, Porto Alegre, RS -Brazil 146-Dept of ENT and Paediatrics, AMC hospital, Amsterdam, the Netherlands 147-Finnish Institute of Occupational Health, Helsinki, Finland 148-Department of Obstetric and Gynecology, Axis in Reproduction, Perinatal and Child Health, Faculty of medicine, Laval University, Quebec, Canada 149-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 150-Université Paris 13, PRES Sorbonne-Paris-Cité and Assistance publique-Hôpitaux de Paris, Avicenne hospital, Bobigny, France 151-University Hospital of Mont-Godinne, Catholic University of Louvain, Yvoir, Belgium 152-Department of Primary and Community Care, Radboud University Nijmegen Medical Centre, HB Nijmegen, The Netherlands 153-CNR Institutes of Biomedicine and Molecular Immunology (IBIM), Palermo, and of Clinical Physiology (IFC), Pisa, Italy 154-Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore 155-Sachs' Children's Hospital, Stockholm; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 156-School of Pharmacy, University of North Carolina, North Carolina, USA 157-Medical University of Vienna, Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases (DIAID), Wien, Austria 158-Celal Bayar University School of Medicine Dept. of Pulmonology, Manisa, Turkey 159-The Allergy & Asthma Institute, Islamabad, Pakistan 160-Department of Paediatrics and Child Health, University of Cape Town, South Africa School of Child and Adolescent Health, Red Cross Childrens Hospital, University of Cape Town, South Africa 161-University Clinic of Respiratory and Allergic Diseases Golnik, Slovenia 162-Guangzhou Institute of Respiratory Diseases and State Key Laboratory of Respiratory Diseases, Guangzhou Medical College, Guangzhou, China 163-Secretary General of the Global Allergy and Asthma European Network (GA2LEN), Network of Excellence, Charité -Universitätsmedizin Berlin, Berlin, Germany

  Several severity tests of current atopic dermatitis (AD) have been published. Three measurements (SCORing Atopic Dermatitis [SCORAD] (99), Eczema Area and Severity Index [EASI] (100), and Patient-oriented Eczema Measure [POEM]) have been tested sufficiently and performed adequately (101). Other scoring systems such as the Langeland-Rajka score have been designed to include information about the recent past (3 months) of the disease (102). Besides the objective parameters such as erythema or excoriations, the more subjective aspect of pruritus/itching is of great importance in the evaluation of the disease since it also reflects the severity. SCORAD also includes a VAS component for this particular symptom. Furthermore, SCORAD has been used to classify AD into 3 main severity forms: mild (<15), moderate (>15 and <40) and severe (>40). Recently, a patientoriented version of SCORAD (PO-SCORAD) was proposed and validated, allowing the estimation of severity by the patients themselves or the caregivers of affected children (103). These scoring systems only provide a snapshot of the current disease situation for a given patient at a defined time point (104) and should be more appropriately considered as control tests.

5. 1 .

 1 Subphenotyping severe/uncontrolled diseases Allergic diseases represent complex multi-dimensional diseases with marked heterogeneity depending on environmental factors and socio-economic determinants. Tools to phenotype individual disease subtypes are now being developed in order to characterize the various patterns of triggers that induce symptoms, different clinical presentations of the disease, and different inflammatory markers. This is the case for asthma (US SARP: Severe Asthma Research Program (125, 126), U-BIOPRED, (45, 127) and allergic disease onset (MeDALL, Mechanisms of the Development of ALLergy, FP7, (49)) but more research is needed to identify allergic disease subphenotypes or endophenotypes (128) based on severity.

) 1 -

 1 Level of control  Current clinical control (impairment): Symptoms, health status and functional limitations over previous 2-4 weeks  Severe exacerbations over previous 6-12 months (use of oral or systemic corticosteroids) 2-Level of current treatment prescribed 3-Inhalation technique and compliance to treatment 4-Responsiveness to treatment 5-Exposure to aggravating factors 6-Risk

From ( 28 )

 28 (Adapted from GINA 2006 (31) and 2007 NAEPP-EPR3[START_REF]Expert panel report 3: Guidelines for the diagnosis and management of asthma[END_REF])Any of the components places the patient in the category interval since last exacerbation *: FEV1 or PEF may be ≥ 80% predicted in patients with severe persistent asthma **: * For well controlled asthma, all components should be present; for partially or poorly controlled asthma, any of the components places the patient in the category ***: At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control of severity.

Figure 2 :

 2 Figure 2: Uniform approach for the definition of severe allergic (and related) diseases (adapted from (49))

Table 3 : Level of asthma control in patients ≥ 5 years of age

 3

Acknowledgment: This paper is part of MeDALL WP2 and was completed during a meeting in CREAL, Barcelona (June 29-30, 2011), and the French Speaking Respiratory Forum (Espace Francophone de Pneumologie, Société de Pneumologie de Langue Française, Nice, July 8-10, 2011) in collaboration with the WHO Collaborating Center for Asthma and Rhinitis (Montpellier).

Member of GA 2 LEN (Global Allergy

Abbreviations


Adrien Bousseau

Non-Linear Aperture for Stylized Depth of Field

Pinhole (b) Average (c) Bilateral (d) Median

Figure 1: Compared to a traditional aperture that blurs out of focus points (b), non-linear apertures produce depth dependent non photorealistic simplifications. For example a bilateral filter smooths out details while preserving contours (c) and a median filter simplifies out of focus shapes (d).

Introduction and Related Work

Shallow depth of field is widely used by photographers to blur the background and isolate the object of interest in a picture. On conventional cameras, the amount of blur of out of focus points of the scene is controled by the size of the aperture and the distance of the objects from the plane in focus. Lightfield cameras have been proposed to allow a user to vary the size of the aperture and the plane in focus after the shot [START_REF] Ng | Light field photography with a hand-held plenoptic camera[END_REF]].

In the field of Non Photorealistic Rendering, similar attention grabing effects are obtained by removing the details of background objects with various abstraction filters. The use of different filters allows a greater variety of styles compared to the conventional out of focus blur of realistic photography. For instance, Winnemöller et al. [2006] applies a bilateral filter on images and videos to obtain a cartoon-like abstraction. However, in order to obtain depth dependent level of abstraction, a depth map is required. Such depth information can be painted by a user, which is tedious and not accurate, or estimated by vision algorithms, which is prone to errors.

We propose to combine abstraction and refocusing, and use nonlinear filters such as the bilateral filter in place of the average filter traditionally used in lightfield refocusing. Our approach is simple to integrate in existing lightfield viewers and allows depth dependant image abstraction without the need for explicit depth information.

Linear and Non-Linear Apertures

Box Filtering In traditional cameras, out of focus blur is produced by the optical integration of incoming light rays over the camera aperture. In lightfield refocusing, similar blur can be simulated by averaging the light rays over the synthetic aperture:

p = 1 W X u,v
Lu,v,s,t

where p is the resulting blurred pixel, u and v are the coordinates of the aperture samples, s and t are the coordinates of the intersection of the aperture rays with the focal plane, L is the lightfield and W is a normalization factor equal to the number of samples in the aperture. Figure 1(b) 1 illustrates this realistic refocusing. In the 1 Lightfield data from http://lightfield.stanford.edu/ following, we propose to modify the synthetic aperture equation to obtain varied stylization effects. We examplify here the median and bilateral filter.

Median Filtering

The first non-linear aperture we propose consists in substituting the integration over the aperture by a median filter that selects the median value of the incoming light rays. Although such aperture could not be manufactured in reality, it can be simulated by the following synthetic aperture:

p = medianu,v{Lu,v,s,t}
The resulting abstraction filter removes small details and simplifies shapes, as illustrated in Figure 1(d). Note that the amount of abstraction automatically increases with the distance to the plane in focus. This filter can be used as a basis for more complex stylization such as watercolor where the shape simplification mimics the use of a coarse paint brush.

Bilateral Filtering Finally, we propose to consider the aperture as the spatial support of a bilateral filter. The corresponding synthetic aperture can be expressed as:

p = 1 Wp X u,v
Gσ r (|Lu,v,s,t -Lu 0 ,v 0 ,s,t|) Lu,v,s,t

with Wp = X u,v Gσ r (|Lu,v,s,t -Lu 0 ,v 0 ,s,t|)
where Gσ r is a gaussian function defining the range support, u0 and v0 are the coordinates of the central sample of the aperture. This filter removes the low contrast features of the image while preserving the strong edges (Figure 1(c)). The spatial support of the bilateral filter varies automatically with depth.

Conclusion and Future Work

We have presented in this paper a simple yet effective method to produce depth dependent stylized abstraction of photographs using lightfield data. We believe that similar lightfield stylization methods will be of great interest in the near future when lightfield cameras will become available to the average consumer.


Husain Mubashir

Abderrezak Rehmani ⋆ ‡

⋆ Rachedi
email: rachedi@univ-mlv.fr

Stéphane Lohier
email: lohier@univ-mlv.fr

Thierry Alves
email: talves@univ-mlv.fr

Benoit Poussot
email: benoit.poussot@univ-mlv.fr

On the Feasibility of making Intelligent Antenna Selection Decision in IEEE 802.15.4 Wireless Sensor Networks

Keywords: Wireless sensor networks, IEEE 802.15.4, ZigBee, RSSI, Antenna

In this paper, we study the feasibility of making intelligent antenna selection decision in IEEE 802.15.4 wireless sensor networks. This study provides us the basis to design and implement software defined intelligent antenna switching capability to wireless sensor nodes based on link quality metric, such as Received Signal Strength Indicator (RSSI). As a first step, we discuss in detail the results of our newly designed radio module (Inverted-F Antenna) for 2.4 GHz bandwidth wireless sensor networks. In the second step, we propose an intelligent antenna selection strategy to exploit antenna diversity. To evaluate, we consider TelosB motes and compare the performance of the built-in TelosB antenna with our proposed external antenna in both laboratory and realistic environments. Experimental results confirm the effectiveness of the proposed radio module over the built-in radio module of the TelosB motes.

I. INTRODUCTION

Wireless Sensor Networks (WSNs) can be seen everywhere and are now becoming the part of our daily life. The application of these WSNs ranges from environmental monitoring like wildlife tracking, habitat monitoring, forest fire detection, mine safety monitoring to military applications like target detection, and tracking [START_REF] Th | A Survey of Applications of Wireless Sensors and Wireless Sensor Networks[END_REF]. However, the performance of these WSNs depends upon the quality of the wireless link, the built-in antenna available on the sensor device, and the antenna diversity. In WSNs, there are several application scenarios where a clear line-of-sight (LOS) between the sender and receiver is not present [START_REF] Radenkovic | Wireless Mobile Ad-hoc Sensor Networks for Very Large Scale Cattle Monitoring[END_REF], [START_REF] Sasloglou | Antenna and Base-Station Diversity for WSN Livestock Monitoring[END_REF]. This results in fading of the signal and causes multipath propagation. Furthermore, the signal between transmitterreceiver pair is prone to attenuation and distortion, resulting in packet losses. The main reason of attenuation and This work is part of the project entitled "Wireless Sensor Networks for vehicle and pedestrian traffic assessment applications", funded by the University of Paris Est under the PPS program.

distortion is due to path loss, multipath fading, radiation characteristics, antenna orientation, and Doppler effects and are highly dependent upon the location and surrounding of the transmitter-receiver pair [START_REF] Rappaport | Wireless Communication Principles and Practice[END_REF]. Antenna diversity is a way in which two antennas are attached with the sensor node to improve the quality and reliability of the wireless link [START_REF] Sasloglou | Antenna and Base-Station Diversity for WSN Livestock Monitoring[END_REF].

In IEEE 802.15.4, the quality of the link is measured by two metrics: Link Quality Indicator (LQI) and Received Signal Strength Indicator (RSSI). These two metrics are offered by the IEEE 802.15.4 physical layer, which can then be used by the routing layer to select good quality routes. For instance, the impact of LQI-Based routing metrics on the performance of a One-to-One routing protocol for IEEE 802.15.4 Multihop Networks has been studied by the authors in [START_REF] Gomez | Impact of lqi-based routing metrics on the performance of a one-to-one routing protocol for IEEE 802.15.4 multihop networks[END_REF]. The authors in [START_REF] Srinivasan | RSSI is under appreciated[END_REF] provided a detailed study on the comparison of LQI and RSSI metrics. However, aforementioned works [START_REF] Gomez | Impact of lqi-based routing metrics on the performance of a one-to-one routing protocol for IEEE 802.15.4 multihop networks[END_REF], [START_REF] Srinivasan | RSSI is under appreciated[END_REF] did not consider the antenna diversity. Recently, the authors in [START_REF] Amiri Sani | Directional Antenna Diversity for Mobile Devices: Characterizations and Solutions[END_REF] showed that significant gain can be achieved through antenna diversity but their work mainly focus on directional antennas for smart-phone like mobile devices. In [START_REF] Han | Minimum-Energy Connected Coverage in Wireless Sensor Networks with Omni-Directional and Directional Features[END_REF], the authors focus on target coverage problem using directional sensor and antennas.

Based on link quality metric RSSI, our ultimate goal is to design and implement software defined intelligent antenna switching capability to wireless sensor nodes. More precisely, we want to attach an external antenna with the sensor nodes besides the built-in antenna to achieve antenna diversity. Then, based on wireless link condition, the sensor node switch to the appropriate antenna for communication.

Our Contributions: This paper makes the following contributions:

II. INVERTED-F ANTENNA (IFA) DESIGN

According to the TelosB datasheet [11], we have implemented an SubMiniature version A (SMA) connector in order to connect our small external antenna. This antenna is called as Inverted-F Antenna (IFA). Fig. 1 shows Inverted-F antenna attached with TelosB mote. The details regarding the design and connection procedure of our antenna with the TelosB mote can be found in [START_REF] Husain Rehmani | Towards Intelligent Antenna Selection in IEEE 802.15.4 Wireless Sensor Networks[END_REF].

In the next section, we analyze the performance of IFA antenna and the built-in antenna and study the behaviour of RSSI in different environments.

III. PERFORMANCE ANALYSIS OF BUILT-IN AND EXTERNAL ANTENNA

We first describe the methodology in this section and then proceed with the performance analysis. Methodology: Since our goal is to consider RSSI in making the antenna selection decision, we first perform extensive experiments to study the behaviour of RSSI in four different environments, namely, (1) Indoor Office Environment, (2) Outdoor Garden Environment, (3) Reverberation chamber, and (4) Anechoic chamber. Note that the reverberation chamber is used to simulate indoor environment with multipath and the anechoic chamber is used to simulate outdoor environment.

✁ ✂ ✄ ✁ ☎ ✆ ✝ ✄ ✁ ✞ ✝ ✟ ✠ ✡ ✠ ✝ ✂ ✟ ✞ ✝ ✟ ✠ ✡ ✠ ✝ ✂ ☛ ☞ ✞ ✝ ✟ ✠ ✡ ✠ ✝ ✂ ☛ ✌ ✞ ✝ ✟ ✠ ✡ ✠ ✝ ✂ ☛ ✍ ✞ ✝ ✟ ✠ ✡ ✠ ✝ ✂ ☛ ✎ ✞ ✝ ✟ ✠ ✡ ✠ ✝ ✂ ☛ ✏ ✑ ✁ ✒ ✁ ✠ ✓ ✠ ✂ ✔ ✆ ✝ ✄ ✁ ✞ ✝ ✟ ✠ ✡ ✠ ✝ ✂ ✕ ✖ ✗ ✕ ✖ ✗ ✕ ✖ ✗ ✕ ✖ ✗
Implementation Setup: We consider Telosb motes [12], which are equipped with Chipcon CC2420 radio module [START_REF]Chipcon cc2420 datasheet[END_REF]. The radio module CC2420 in its new versions is used in many radio devices. The transceiver of TelosB motes operate in 2.4 GHz band. We use RSSI as a link quality metric to study the performance of our newly designed antenna. The RSSI provides the signal strength at the receiver (in dBm) [START_REF] Srinivasan | RSSI is under appreciated[END_REF].

We consider two types of TelosB motes in our experiment: (1) sink node, which is connected with the serial port of the Laptop, and (2) the sending mote, which sends packet with a time delay of 500 ms. Total 100 packets were sent by the sending mote. As soon as the sink node receives packet by the sending mote, it saves the RSSI value of each corresponding packet. The sink node and the sender node is placed 1 feet and 1 meter apart. We carried out our experiment at 3 different power levels: 0 dBm, -10 dBm and -25 dBm. To change the transmission power, we change the default transmission power of CC2420 i.e., 0 dBm (CC2420 DEF RFPOWER = 31), to -10 dBm and -25 dBm, by changing the register values to 11 and 3, respectively. In order to study the impact of LOS and multipath on RSSI for both antennas, we place the sender node at five different locations, while the receiving node's position was fixed (cf. Fig. 2). We now describe the results for each environment.

A. Indoor Office Environment

We first consider indoor office environment in which we have walls, computers, tables, and other reflecting material. Moreover, we also have human activity and the experiments were conducted in the presence of a single person.

Fig. 3 compares the RSSI values of built-in antenna and external IFA antenna for each received packet with 0 dbm, -10 dBm and -25 dBm power levels. Results in Fig. 3(a), 3(b) and 3(c) were taken when the distance between the sender node and the receiving node was 1 feet. While Fig. 3(d) and 3(e) shows the results when the sender node and the receiving node were 1 meter apart. Note that in Fig. 3(d) and 3(e), the sender node is placed at five different locations (cf. Fig. 2).

The IFA antenna provides higher power levels i.e., RSSI values at the receiver. More precisely, when power level is 0 dBm, the external IFA antenna provide -33.81 dBm power compared to -58.4 dBm power for the built-in antenna, i.e., the gain of 25 dB. When power level is -10 dBm, the external IFA antenna provide -44.41 dBm power compared to -74.0 dBm power for the built-in antenna, i.e., the gain of 30 dB. And when the power level is -25 dBm, the external IFA antenna provide -58.95 dBm power compared to -76.67 dBm power for the built-in antenna, i.e., the gain of around 17.75 dB. As mentioned earlier, to study the affect of LOS and multipath, we consider five different positions for the sender node. In addition, we also increase the distance between the sender node and receiving node to 1 meter. We now observe the RSSI values for the external and built-in antenna in Fig. 3(d) and 3(e). As can be seen in the figure, the RSSI value is different for every position (cf. Fig. 2). This is due to the multipath affect and due to the absence of clear line of sight between the sender and the receiver nodes. In summary, results in Fig. 3 We also conclude that when the sender and receiver nodes are at short distance, we observe the different RSSI values for the two antennas (cf. Fig. 3(a), 3(b) and 3(c)). On the other hand, when the sender and receiver nodes are at long distance, the RSSI values received at both the antennas fluctuates (cf. Fig. 3(d) and 3(e)). This is because of multipath fading and scattering effects, which ultimately changes the polarization of waves.

B. Reverberation Chamber

Reverberation chambers are used to study the effects of multi-path propagation environments [START_REF] Rosengren | Study of Distributions of Modes and Plane waves in Reverberation chambers for the characterizaiton fo antennas in a Multi-path environment[END_REF].

We compare the RSSI values of built-in antenna and external IFA antenna in Reverberation Chamber, for each received packet with -25 dBm power level, as shown in Fig. 4. More precisely, results in Fig. 4 were taken when the nodes were 1 meter apart and the sender node is placed at two different locations (cf. Fig. 2).

It can be clearly seen in Fig. 4 that RSSI values in Reverberation chamber highly fluctuates. This is due to the highly dynamic environment (Azimuth Stirrer rotation at 2 rpm). This results in multi-path and thus we have varying RSSI values for both antennas. Another important point that need to be noted over here is that the RSSI value for both antennas is time varying, means, for any time instant t, external antenna is performing good, while for time instant t+1, built-in antenna gives good performance. Thus, we plan to use this spatio-temporal variation in RSSI to select appropriate antenna (cf. Section IV for more details).

C. RF Anechoic Chamber

In Fig. 5, we compare the RSSI values of built-in antenna and external IFA antenna in Anechoic Chamber, for each received packet with 0 dbm, -10 dBm and -25 dBm power levels. Results in Fig. 5(a), 5(b) and 5(c) were taken when the nodes were placed 1 meter apart, while Fig. 5(d) and 5(e) shows the results when the nodes were 1 meter apart and the sender node is placed at five different locations (cf. Fig. 2).

Figure 5 witness that the external antenna outperforms the built-in antenna of TelosB mote. More precisely, with 0 dBm power (cf. Fig. 5(a)), the RSSI of external antenna is -45.51 dBm and the RSSI of built-in antenna is -53.94 dBm i.e., the gain of 8.5 dB. Similarly, with -10 dBm power (Fig. 5(b)), the RSSI of external antenna is -54.96 dBm and the RSSI of built-in antenna is -64.3 dBm i.e., the gain of 9.3 dB. The same behaviour can be observed in Fig. 5(c), when the power is -25 dBm.

D. Outdoor Garden Environment

In outdoor garden environment, we conduct experiments in the absence of any reflecting material except the ground of the garden.

We compare the RSSI values of built-in antenna and external IFA antenna in Outdoor Garden Environment, for each received packet, with 0 dbm, -10 dBm and -25 dBm power levels, as can be seen in Fig. 6(a), 6(b) and 6(c). More precisely, results in Fig. 6(a), 6(b) and 6(c) were taken when the nodes were places 1 meter apart. While Fig. 6(d) and6(e) shows the results when the nodes were 1 meter apart and the sender node is placed at five different locations (cf. Fig. 2).

In the outdoor garden environment, the IFA antenna provides higher power levels i.e., RSSI values at the receiver. More precisely, when power level is 0 dBm, the external IFA antenna provide -47 dBm power compared to -62 dBm power for the built-in antenna, i.e., the gain of 15 dB. When power level is -10 dBm, the external IFA antenna provide -57 dBm power compared to -73.0 dBm power for the built-in antenna, i.e., the gain of 16 dB. And when the power level is -25 dBm, the external IFA antenna provide -76 dBm power compared to -83 dBm power for the built-in antenna, i.e., the gain of around 7 dB.

E. Concluding Remarks

Results in section III-A, III-B, III-C and III-D shows that when dealing with different environments (office environment, outdoor garden environment, reverberation chamber, and anechoic chamber), we observed fluctuation on RSSI values for both antennas. This provide us the basis and motivate us to exploit antenna diversity. Results also confirm that if external antenna is used, the gain of RSSI is significant.

In this paper, we argued that antenna diversity can be used to achieve gain in RSSI. We also noticed that spatio-temporal fluctuations or interference may lead to the degradation of signal power (RSSI). We showed that this happens very frequently and if a proper strategy is designed to change the intelligent antenna selection decision adaptively, we can achieve higher gain.

In the next section, we discuss our proposed EWMA based adaptive intelligent antenna selection strategy.

IV. EWMA BASED INTELLIGENT ANTENNA SELECTION STRATEGY

EWMA is a one-step prediction technique [START_REF] Roberts | Control Chart Test Based on Geometric Moving Average[END_REF], which has been widely used in different applications, such as anomaly detection [START_REF] Ye | EWMA techniques for computer intrusion detection through anomalous changes in event intensity[END_REF], bandwidth prediction etc. In EWMA, higher importance is given to the more recent observations. Thus, EWMA is very suitable for predicting the RSSI value on a particular antenna. In fact, our goal is to detect any small variation in the RSSI value through EWMA prediction technique and then use the appropriate antenna.

In order to achieve this goal, we enable the wireless sensor nodes to keep the record of the RSSI values and this record will be served as an input to predict the RSSI value. Initially, no prediction will be done and each wireless sensor node just collect the historical data of RSSI values on different antennas. Once the nodes have some historical data, the receiving node will start predicting the RSSI values for both antennas. The antenna which provides strong predicted RSSI value at time instant t will then be selected for the next reception period, thus achieving the goal of antenna diversity. Fig. 7 shows the decision making by the sensor nodes to select the appropriate antenna according to the varying RSSI value. As can be seen in Fig. 7, first sensor nodes predict the values of RSSI for both built-in and external antenna. If the RSSI value of external antenna is greater than the built-in antenna, sensor node will switch to the external antenna, else vice versa. Then, sensor nodes keep these observed values of RSSI in the memory. Finally, these stored RSSI values will be then feedback to predict for the next time.

Let △RSSI (t) E be the mean of historical values of RSSI, △RSSI (t) be the observation at time t and γ is a smoothing factor (0 ≤ γ ≤ 1). The RSSI value at time (t+1) i.e., △RSSI(t + 1) can be calculated using the following formula:

△RSSI(t+1) E = (1-γ)△RSSI(t) E +γ△RSSI(t) (1)
In this manner, the wireless sensor node can predict the value of RSSI at time instanct t and make an intelligent antenna selection decision. This decision is achieved by implementing an adaptive electronic switch which reacts on the predicted value of RSSI. However, it may be possible that due to some abrupt fluctuation in the environment, the RSSI value vary a lot from the mean value of RSSI. This feature is exploited for intrusion detection [START_REF] Pius | Wireless Sensing Without Sensors -An Experimental Approach[END_REF] and for monitoring the human activity. In this paper, we focus on the consistent values of RSSI, instead of identifying the anomaly. In case, any anomaly is detected, the wireless sensor nodes will not take into account those anomalies. In order to identify any anomaly in △RSSI (t), we propose to use two control limits, Upper Control Limit (UCL) and Lower Control Limit (LCL), which can be calculated as:

✘ ✙ ✚ ✛ ✜ ✢ ✣ ✜ ✤ ✥ ✤ ✦ ✧ ★ ★ ✩ ✪ ✫ ✬ ✭ ✚ ✮ ✦ ✤ ✙ ✯ ✰ ✣ ✚ ✙ ✥ ✫ ✬ ✫ ✥ ✛ ✱ ✭ ✜ ✬ ✣ ✲ ✜ ✥ ✳ ✥ ✣ ✚ ✥ ✥ ✫ ✴ ✤ ✵ ✶ ✫ ✙ ✚ ✩ ✷ ✶ ✙ ✚ ✛ ✜ ✢ ✣ ✚ ✛ ✧ ★ ★ ✩ ✪ ✫ ✬ ✭ ✚ ✤ ✦ ✯ ✰ ✣ ✚ ✙ ✥ ✫ ✬ ✳ ✥ ✣ ✚ ✥ ✥ ✫ ✸ ✶ ✙ ✚ ✛ ✜ ✢ ✣ ✚ ✛ ✧ ★ ★ ✩ ✪ ✫ ✬ ✭ ✚ ✤ ✦ ✱ ✭ ✜ ✬ ✣ ✲ ✜ ✥ ✳ ✥ ✣ ✚ ✥ ✥ ✫ ★ ✚ ✬ ✚ ✢ ✣ ✯ ✰ ✣ ✚ ✙ ✥ ✫ ✬ ✳ ✥ ✣ ✚ ✥ ✥ ✫ ★ ✚ ✬ ✚ ✢ ✣ ✱ ✭ ✜ ✬ ✣ ✲ ✜ ✥ ✳ ✥ ✣ ✚ ✥ ✥ ✫ ✹ ✜ ✮ ✣ ✤ ✙ ✺ ✤ ✦ ✧ ★ ★ ✩ ✦ ✤ ✙ ✯ ✰ ✣ ✚ ✙ ✥ ✫ ✬ ✫ ✥ ✛ ✱ ✭ ✜ ✬ ✣ ✲ ✜ ✥ ✳ ✥ ✣ ✚ ✥ ✥ ✫ ✻ ✼ ✽ ✾ ✿
U CL △RSSI = △RSSI(t) + ks △RSSI

LCL △RSSI = △RSSI(t)ks △RSSI (3)

s 2 △RSSI = γ 2 -γ s 2 (4)
where s 2 is the variance of the generated and updated data base, which is used to calculate UCL and LCL, and k is set equal to 3 [START_REF] Lucas | Ewma Control Schemes: Properties and Enhancements[END_REF].

V. CONCLUSION AND FUTURE WORK

In this paper, we discussed our results of the newly deigned radio module (Inverted F Antenna) for 2.4 GHz wireless sensor networks. We first performed extensive experiments to understand the behaviour of RSSI values for the built-in and external antenna, in both lab and outdoor environments. We then proposed an EWMA based intelligent antenna selection strategy for wireless sensor nodes. Experimental results confirmed the effectiveness of our proposed radio module over the built-in TelosB radio module. In future, we plan to study different routing metrics with antenna diversity under multi-hop network configuration, and efficiency of IFA antenna. Finally, our goal is to integrate software defined switching capability to TelosB motes to change the antenna decision adaptively.

Figure 1 .

 1 Figure 1. Inverted-F antenna attached with TelosB mote.

Figure 2 .

 2 Figure 2. Sender and Receiving nodes positions.

  External Antenna (P0): 0 dBm, 1 m External Antenna (P1): 0 dBm, 1 m External Antenna (P2): 0 dBm, 1 m External Antenna (P3): 0 dBm, 1 m External Antenna (P4): 0 dBm, 1 m Antenna (P0): 0 dBm, 1 m Built-in Antenna (P1): 0 dBm, 1 m Built-in Antenna (P2): 0 dBm, 1 m Built-in Antenna (P3): 0 dBm, 1 m Built-in Antenna (P4): 0 dBm, 1 m (e) Figure 3. Number of Packets and RSSI in Indoor office environment. (a) 0 dBm Power. (b) -10 dBm Power. (c) -25 dBm Power. (d) External antenna placed at five different locations with 0 dBm Power. (e) Built-in antenna placed at five different locations with 0 dBm Power.

  (a), 3(b) and 3(c) confirm that the newly designed IFA antenna can provide good link reliability, suitable for wireless radio communication in IEEE 802.15.4 based WSNs.

Figure 4 .

 4 Figure 4. Number of Packets and RSSI in Reverberation chamber environment.

  Antenna (P0): -25 dBm, 1 m Built-in Antenna (P1): -25 dBm, 1 m Built-in Antenna (P2): -25 dBm, 1 m Built-in Antenna (P3): -25 dBm, 1 m Built-in Antenna (P4): -25 dBm, 1 m (e) Figure 5. Number of Packets and RSSI in Anechoic chamber environment. (a) 0 dBm Power. (b) -10 dBm Power. (c) -25 dBm Power. (d) External antenna placed at five different locations with -25 dBm Power. (e) Built-in antenna placed at five different locations with -25 dBm Power.

  Antenna (P0): -25 dBm, 1 m Built-in Antenna (P1): -25 dBm, 1 m Built-in Antenna (P2): -25 dBm, 1 m Built-in Antenna (P3): -25 dBm, 1 m Built-in Antenna (P4): -25 dBm, 1 m (e) Figure 6. Number of Packets and RSSI in Outdoor Garden environment. (a) 0 dBm Power. (b) -10 dBm Power. (c) -25 dBm Power. (d) External antenna placed at five different locations with -25 dBm Power. (e) Built-in antenna placed at five different locations with -25 dBm Power.

Figure 7 .

 7 Figure 7. Flow chart shows the decision making by the sensor nodes to select the antenna.