Résumé Introduction

La rhinite allergique (RA) est une maladie fréquente qui altère la qualité de vie.

Le traitement de la RA est maintenant bien établi et la plupart des patients atteints par cette maladie y répondent.

Néanmoins, il existe un pourcentage de patients qui ne sont pas contrôlés, malgré un traitement maximal, amenant au concept de SCUAD (Severe Chronic Upper Airway Disease), acronyme anglais pour "atteinte sévère et chronique des voies aériennes supérieures". Les patients souffrant de SCUAD ont une qualité de vie altérée et cela participe à l'augmentation du fardeau de cette maladie, au niveau individuel et sociétal.

En Chine, les données concernant la RA non contrôlée et le SCUAD sont insuffisantes.

Le consensus d'experts ARIA (Allergic Rhinitis and its Impact on Asthma, acronyme anglais pour Rhinite Allergique et son Impact sur l'Asthme) a adopté une classification de la RA compte tenu de sa sévérité et durée et recommande une pharmacothérapie par paliers, guidée par la sévérité (initiale, et de plus en plus selon le niveau de contrôle). Le test de contrôle de la rhinite allergique (Allergic Rhinitis Control Test, ARCT) est un outil validé pour évaluer le contrôle de la RA et identifier la RA sévère. Néanmoins, l'ARIA n'offre pas de définition claire du contrôle de la RA et, du fait de l'absence de critères uniformes, le choix de la pharmacothérapie varie dans différentes régions et populations.

Objectif

La première étude a eu pour objectif d'évaluer la prévalence et les caractéristiques des patients avec RA non contrôlée et SCUAD à Wuhan. Elle montrait que les médecins utilisaient l'échelle visuelle analogique (EVA) et l'ARCT dans la prise en charge de la RA, pour évaluer la sévérité de la RA et la réponse au traitement. A partir de cette étude préliminaire, une autre étude a été mise en oeuvre, pour évaluer le rôle de l'ARCT en tant qu'outil pour guider une pharmacothérapie par paliers, dans le but d'atteindre le contrôle de la RA.

Méthode

Dans la première étude, tous les patients consultant pour une RA ont été évalues en prospectif par EVA et ARCT, et mis sous traitement selon le guide ARIA. Au bout de 15 jours (J15), une interview téléphonique a permis de ré-évaluer la RA au moyen d'une échelle numérique et de l'ARCT. La RA non contrôlée était définie par un score ARCT < 20. Les patients souffrant de SCUAD étaient définis par un score ≥ 5 à J15.

Dans la 2ème étude prospective, un traitement pharmacologique standard a été proposé aux patients souffrant de RA. Les paliers allaient du palier 1 (antihistaminique H1 à la demande) jusqu'au palier 5 (corticoïde oral). La RA était traitée et évaluée tous les 15 jours par ARCT.

Si le score ARCT était ≥20, maintenu pendant 15 jours, le patient terminait l'étude. Si l'ARCT était < 20 (RA non contrôlée), le patient recevait le prochain palier de traitement, selon une démarché prédéfinie, progressive, jusqu'au palier 5. Les différents sous-groupes de contrôle de la RA ont été comparés.

Résultats

Au total, 252 patients ont été inclus dans la 1ère étude. La RA modérée/sévère (EVA ≥ 5) était présente en 82,9% des patients, avec un impact sur le sommeil (86,9%), travail (84,9%), activités sociales (81%) et physiques (90,1%). Les patients avec RA non contrôlée à J15 (27,7%) étaient ceux avec un poids plus important (P=0,042), antécédents d'infections ORL ou de prise d'antibiotiques pour infections respiratoires dans les derniers 12 mois (62,3 vs. 45,6%, P=0,018), de tabagisme (15,9 vs. 6,7%, P=0,024) et de dysosmie (26,1 vs. 11,7%, P=0,005). Les patients avec SCUAD (24,5%) avaient plus fréquemment des antécédents d'infections ORL ou de prise d'antibiotiques pour infections respiratoires [START_REF] Nathan | Qualitative Development of the Rhinitis Control Assessment Test (RCAT), an Instrument for Evaluating Rhinitis Symptom Control[END_REF][START_REF] Schatz | A survey of the burden of allergic rhinitis in the USA[END_REF] vs. 45,7%, P=0,014) et de dysosmie [START_REF] Executive | Global strategy for asthma management and prevention[END_REF][START_REF] Schatz | A survey of the burden of allergic rhinitis in the USA[END_REF] vs. 11,7%, P=0,003) et moins fréquemment de dermatite atopique (13,1 vs. 28,2%, P=0,017).

Deux cents cinquante cinq patients ont été inclus dans la 2ème étude; 5 patients ont été perdus de vue. Deux patients (0,8%) étaient contrôlés à J0, 85 (34,0%) à J15, 177 (70,8%) à J30, 222 (88,8%) à J45, 241 (96,4%) à J60 et 242 (96,8%) à J75. Seulement 8 patients (3,2%) sont restés non contrôlés à la fin de l'étude. Les patients avec une RA modérée à sévère selon ARIA, RA persistante, impact modéré à sévère sur la qualité de vie, antécédents d'asthme, rhinorrhée et toux avaient toujours besoin d'un traitement associé (corticoïde nasal et antihistaminique H1), ainsi qu'un traitement prolongé pour atteindre le contrôle. Après ajustement sur chacune des variables, le seul facteur de risque restant significatif était la présence d'un asthme (il était moins probable que ces patients soient contrôlés par les premiers paliers de traitement).

Conclusion

Les patients ayant une RA non-contrôlée ou atteints de SCUAD sont nombreux. L'EVA et l'ARCT sont des outils simples qui peuvent être utilisés dans l'évaluation globale de la sévérité et du contrôle de la RA. La plupart des patients atteints de RA peuvent être contrôlés en utilisant un traitement par paliers. L'ARCT offre un critère objectif pour guider le traitement par paliers. L'analyse des facteurs de risque n'a pas relevé une association forte avec des caractéristiques cliniques qui permettrait un meilleur contrôle de la RA.

Mots clés Mots clés : rhinite allergique, épidémiologie, ARIA, auto-questionnaire, sévérité, contrôle, échelle visuelle analogique, test de contrôle de la rhinite allergique, SCUAD, traitement par paliers X Abstract Background Allergic rhinitis (AR) is a highly prevalent disease that affects the quality of life. The treatment of AR is now well established and most patients respond well to the treatment.

However, there are still some patients with uncontrolled AR despite optimal maximum treatment, leading to the concept of severe chronic upper airway disease (SCUAD). Patients with SCUAD often present impaired quality of life and they increase the health-economic burden of the individual and society. In China, there are insufficient epidemiological data regarding uncontrolled AR and SCUAD. Allergic Rhinitis and its Impact on Asthma (ARIA) has divided AR into different subgroups according to the symptom severity and duration and recommend different pharmacotherapy to step up or step down treatment according to disease severity (initially and more and more according to control) level. Allergic Rhinitis Control Test (ARCT) has been validated for assessing AR control and to identify severe AR. However, ARIA still has no clear definition of AR control, and due to the absence of uniformed criteria, pharmacotherapy adjustment regimens varies in different areas and populations.

Objective

The first study aimed to assess the prevalence and the characteristics of patients with uncontrolled AR and SCUAD in Wuhan. It also proposes that physicians in charge of AR patients use visual analogue scale (VAS) and/or ARCT as a simple and quantitative method for the global evalution of AR severity and response to treatment. On the basis of the preliminary study, a further study is designed to assess ARCT as a questionnaire driven stepwise pharmacological treatment to achieve AR control.

Methods

In the first epidemiology study, all patients consulting for AR were prospectively assessed using VAS and ARCT and put on standardized treatment based on ARIA guidelines. After 15 days, they were reevaluated by a telephone interview using a numerical scale and ARCT. A score of ARCT < 20 defined uncontrolled AR and a score ≥ 5 at day-15 defined SCUAD patients.

In the second study, a standard pharmacotherapy regimen from step 1 (oral second generation H1 antihistamine as needed) to step 5 (oral corticosteroid) was applied prospectively in a Chinese AR population. The AR patients were initiated with ARIA appropriate step treatment and assessed with ARCT every 15 days. If ARCT score was equal or above 20 (controlled AR) and maintained for 15 days, the patient would finish the study; if ARCT score was strictly less than 20 (uncontrolled AR), the patient would receive higher step treatment according to a predefined open design up to step 5. The different AR control subgroups were compared.

Results

A total of 252 patients were included in the first study. Moderate/severe AR (VAS ≥ 5) was diagnosed in 82.9% of the patients and they had an impact on sleep (86.9%), work life (84.9%), social activities (81%) and physical activities (90.1%). Patients with uncontrolled AR (27.7%) at day-15 more frequently presented a higher weight (P=0.042), past history of ENT infection or antibiotics intake for respiratory infection in the last 12 months (62.3 vs. [START_REF] Del Cuvillo | Validation of ARIA duration and severity classifications in Spanish allergic rhinitis patients -The ADRIAL cohort study[END_REF].6%, P=0.018), smoking (15.9 vs. 6.7%, P=0.024) and smell disturbance (26.1 vs. 11.7%, P=0.005).

Patients with SCUAD (24.5%) more frequently presented a past history of ENT infection or antibiotics intake for respiratory infection (63.9 vs. 45.7%, P=0.014) and smell disturbance (27.9 vs. 11.7%, P=0.003), while less commonly had atopic dermatitis (13.1 vs. 28.2%, P=0.017).

255 patients were enrolled in the second study, 5 patients dropped out. 2 (0.8%) were controlled at day 0, 85 (34.0%) at day 15, 177 (70.8%) at day 30, 222 (88.8%) at day 45, 241 (96.4%) at day 60 and 242 (96.8%) at day 75. Only 8 (3.2%) patients remained uncontrolled at the endpoint of the study. Patients with ARIA moderate/severe or persistent symptoms, moderate/severe impaired quality of life, asthma history, rhinorrhea and cough symptoms always needed up to step 4 (nasal corticosteroid plus antihistamine) and prolonged treatments to achieve disease control. After adjustment on each of the variables, the only factor that remained significant was asthma (less likely to be in a group controlled by the first steps' therapies).

Conclusion

Uncontrolled AR and SCUAD patients are numerous. VAS and ARCT are simple and quantitative methods and self-completion questionnaire that can be used for a global evaluation of the severity and control of AR. The majority of AR can be controlled with standard stepwise treatment. ARCT offers an objective criterion for the stepwise pharmacotherapy of AR. Risk factor analysis did not reveal strong clinical characteristics that would help the physician to control AR better.

Key words allergic rhinitis, epidemiology, ARIA, self-completion questionnaire, severity, control, visual analogue scale, allergic rhinitis control test, severe chronic upper airway disease, stepwise pharmacotherapy XIII

List of Tables

List of Figures

1-Introduction

Allergic rhinitis (AR) is a common disease worldwide affecting up to 40% of the population in young adults in Europe and its prevalence is increasing (1). The early studies have shown that the prevalence of AR in 13 to 14 year-old children in Chinese mainland (2) was about 10%. A cross-sectional population-based study in 11 major cities of China showed that the prevalence of AR ranges from 8.7% to 24.1% (3). Despite the fact that approximately 50% of AR patients visit their doctor for their symptoms present at least 4 months a year (4), over half of AR of sufferers do not seek medical advice from a physician in Europe, resulting in AR being usually under-recognized and ineffectively treated [START_REF] Canonica | A survey of the burden of allergic rhinitis in Europe[END_REF]. The direct and indirect health-care costs incurred by AR are substantial and can not be neglected by healthcare payers [START_REF] Malone | A cost of illness study of allergic rhinitis in the United States[END_REF].

The main typical symptoms of AR are nasal congestion, rhinorrhea, sneezing, and nasal itching as well as ocular redness, tearing, and itching [START_REF] Greiner | Allergic rhinitis[END_REF]. Although not life-threatening, the symptoms of AR are frequently bothersome, adversely affect school performances and/or work and quality of life and impose a significant burden on both the individual and society [START_REF] Canonica | A survey of the burden of allergic rhinitis in Europe[END_REF][START_REF] Schatz | A survey of the burden of allergic rhinitis in the USA[END_REF][START_REF] Schoenwetter | Economic impact and quality-of-life burden of allergic rhinitis[END_REF]. AR is also a strong risk factor for other chronic respiratory diseases such as asthma and chronic rhinosinusitis [START_REF] Shi | Epidemiology of chronic rhinosinusitis: results from a cross sectional survey in seven Chinese cities[END_REF]. Nearly 40% of AR patients combine or will develop asthma [START_REF] Simons | Allergic rhinobronchitis: the asthma-allergic rhinitis link[END_REF], whereas almost 85% of asthma patients have rhinitis [START_REF] Bousquet | Allergic rhinitis and its impact on asthma[END_REF]. A large epidemiological survey showed that sleep impairment is common in AR, particularly in more severe forms [START_REF] Colas | Disease severity impairs sleep quality in allergic rhinitis (The SOMNIAAR study)[END_REF]. Over 45% of adults and 41% of children with AR reported a serious impact on work or school in the previous years because of AR in Asia [START_REF] Pawankar | Allergic Rhinitis and Its Impact on Asthma in Asia Pacific and the ARIA Update 2008[END_REF][START_REF] Katelaris | Nasal allergies in the Asian-Pacific population: results from the Allergies in Asia-Pacific Survey[END_REF]. The majority of patients suffering from AR consult their general practitioner first [START_REF] Van Weel | General practitioners' central role in management of asthma and allergic rhinitis[END_REF][START_REF] Ryan | Primary care: the cornerstone of diagnosis of allergic rhinitis[END_REF]. In China, patients are allowed to consult directly the specialist. In order to enhance the effectiveness and quality of management for AR, a number of international guidelines and consensus statements have been developed [START_REF] Wallace | The diagnosis and management of rhinitis: an updated practice parameter[END_REF].

Allergic Rhinitis and its Impact on Asthma (ARIA) workshop (organized by the World Health Organization (WHO) was the first evidenced-based guidelines. It was published in 2001 and updated in 2008 and 2010 [START_REF] Bousquet | Allergic rhinitis and its impact on asthma[END_REF][START_REF] Brożek | Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision[END_REF][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]. ARIA focuses on the assessment and treatment of AR based on quality of life (QoL). ARIA guidelines introduced AR management including allergen avoidance, pharmacotherapy, patient education, allergen immunotherapy and surgical treatment. It divided AR into different subgroups according to the symptom severity (mild vs. moderate/severe) and duration (intermittent vs. persisitent). ARIA severity classification has been validated in primary care patients in many countries [START_REF] Bauchau | Epidemiological characterization of the intermittent and persistent types of allergic rhinitis[END_REF]. Several composite instruments have been developed to objectively assess the severity of AR, including Total Symptom Score 6 (TSS6) and Visual Analog Scale (VAS) [START_REF] Simola | Sensation of nasal airflow compared with nasal airway resistance in patients with rhinitis[END_REF][START_REF] Bousquet | Implementation of guidelines for seasonal allergic rhinitis: a randomized controlled trial[END_REF][START_REF] Simons | Efficacy and safety of desloratadine in the treatment of perennial allergic rhinitis[END_REF].

Although the treatment guidelines are now well established, treated patients may report poor levels of satisfaction, with a frequent search for a combination of medications to better reduce their nasal or ocular symptoms [START_REF] Marple | Keys to successful management of patients with allergic rhinitis: focus on patient confidence, compliance, and satisfaction[END_REF]. Many patients with AR continue to be undertreated and are at risk for acute exacerbations, resulting in reduced productivity at work, school performance and QoL, triggering increased health-care costs and the use of oral corticosteroids. As for the management of asthma following the introduction of the Global Initiative for Asthma (GINA) guidelines [START_REF] Executive | Global strategy for asthma management and prevention[END_REF], the generalization of the "control" is now being considered as a trend in the management of patients with AR, chronic rhinosinusitis, chronic urticaria and atopic dermatitis [START_REF] Bousquet | Severe chronic allergic (and related) diseases: a uniform approach-a MeDALL-GA2LEN-ARIA position paper[END_REF]. There is currently no single definition of AR control and the definition of AR control was a missing part in the original ARIA. The determination of AR control depends on the variables taken into account by the different available tools. Therefore, the concept of AR control was being only recently understood [START_REF] Demoly | Assessment of disease control in allergic rhinitis[END_REF]. Nevertheless, rhinitis control is essentially "absence of symptoms". The fact that the level of AR control is often overestimated by both patients and physicians indicates that AR treatment guidelines alone are not enough to determinethe assessment of AR control. The overestimation of AR control can result in failure to make the necessary adjustments to medication.

A measure of AR control should be used to evaluate treatment outcomes and simplify monitoring. Both severity and control can be measured in different ways, with both objective and subjective measurements and patient-reported vs. physician-reported outcomes. Till now, several questionnaires of AR control have been developed and validated in clinical practice [START_REF] Fonseca | Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma[END_REF][START_REF] Nathan | Qualitative development of the Rhinitis Control Assessment Test (RCAT), an instrument for evaluating rhinitis symptom control[END_REF][START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF]. Most of the control questionnaires focus on measurements of daily or nocturnal symptoms, symptom magnitude (i.e., the patients' perception of how bothersome their symptoms are) and impairment in every day activities. They include the Control of Allergic Rhinitis and Asthma Test (CARAT), the Rhinitis Control Assessment Test (RCAT) and the Allergic Rhinitis Control Test (ARCT). A simple VAS has also been validated to assess AR control.

In case of poor control of symptoms despite optimal maximum guideline-directed treatment, one needs to consider the presence of severe chronic upper airway disease (SCUAD) [START_REF] Bousquet | Unmet needs in severe chronic upper airway disease (SCUAD)[END_REF]. In the national French survey validating the ARCT instrument, 14.9% of the 902 AR patients were not controlled after 15 days of treatment [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF]. Poor disease control may be related to suboptimal treatment, poor treatment compliance [START_REF] Incorvaia | Patient's compliance with allergen immunotherapy[END_REF], a co-morbid condition not taken into account including psychosocial factors and treatment-resistant AR [START_REF] Van Oudenhove | The role of psychosocial factors and psychiatric disorders in functional dyspepsia[END_REF][START_REF] Petersen | Corticosteroids for Allergic Rhinitis[END_REF]. Patients with SCUAD often present uncontrolled nasal and/or ocular symptoms and impaired quality of life.

In a randomized European trial, it was found that 10% to 20% of patients with AR consulting a specialist have SCUAD [START_REF] Bousquet | Uncontrolled allergic rhinitis during treatment and its impact on quality of life: a cluster randomized trial[END_REF]. In China, there are insufficient epidemiological data regarding uncontrolled AR and SCUAD.

ARIA guidelines [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] have recommended different pharmacotherapy to step up according to disease severity. They have been widely accepted and implemented in many countries. ARIA guidelines also suggested step down treatment after the AR symptoms are controlled. An accessible and effective tool should be used to monitor the control level of AR and to determine the adjustment needed for a stepwise treatment, which was beneficial to the control of AR and improvement of patients' quality of life.

In this series of studies, the criteria utilized for the assessment of AR severity and control as well as the existing validated instruments were reviewed. Specifically, we provide insight into their use in clinical practice. More importantly, a prospective cohort study was designed to investigate the prevalence of uncontrolled AR and SCUAD in the allergy department of Tongji university hospital of Wuhan, China, and to describe their characteristics. This was done in partnership between the allergy unit of the University Hospital of Montpellier and that of the Tongji Hospital. Moreover, this study indicated that VAS and ARCT are simple and quantitative methods and self-completion questionnaire that can be used for a global evaluation of the severity and control of AR. Based on the first study, another prospective cohort study was designed and carried out in the allergy department of Tongji hospital, Wuhan, China to further assess ARCT as a questionnaire driven stepwise pharmacological treatment to achieve AR control and to describe the characteristics of the AR patients in different subgroups.

2-Assessment of the AR severity

ARIA recommendations written in collaboration with the WHO devised a new classification for AR (intermittent and persistent rhinitis) [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]. The ARIA guidelines also proposed a new grading of severity (mild and moderate/severe) and stepwise therapeutic recommendations based on this classification of severity.

ARIA classification of AR

In the early guidelines, AR was divided seasonal and perennial rhinitis [START_REF] Bousquet | Allergic rhinitis and its impact on asthma[END_REF]. However, this classification is not entirely perfect. Due to many patients are sensitized to different allergens, perennial symptoms of AR are often present and they have seasonal exacerbations when exposed to seasonal allergens (such as pollens and molds). Thus, a change in the classification of AR was proposed in the ARIA guidelines with the terms "intermittent" and "persisitent" [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].

ARIA paid close attention to the impact of AR on social life, school and work and emphasized the need to assess patients' symptoms. Therefore, it has been proposed to classify the severity as "mild" and "moderate/severe" and it is very easy to implement in clinic. Patients only need to answer yes/no to the following questions: "My symptoms disturb my sleep", "My symptoms restrict my daily activities (sports, leisure, etc.)", "My symptoms restrict my participation in schoolar work" and "My symptoms are troublesome".

Patients with no answers to all four questions are considered as having "mild" AR, whereas patients with a "yes" for one or more items are considered as having "moderate/severe" AR [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] Bousquet | Allergic rhinitis and its impact on asthma[END_REF][START_REF] Brozek | Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision[END_REF].

Objective measures of the severity of AR include symptom scores, measurements of nasal obstruction, measurements of inflammation and reactivity (such as nitric oxide measurements, provocation with histamine or allergens), measurements of the sense of smell and VAS. VAS is widely used in clinical practice as a simple and effective method to assess the severity of AR (21).

Instruments for assessing AR severity

Total Symptom Score 6 (TSS6) is a 4-point scale used to assess the severity of patients' 4 nasal symptoms (rhinorrhea, itching, sneezing and nasal congestion) and 2 nonnasal symptoms (gritty/red/itchy eyes and watery eyes) [START_REF] Maspero | An integrated analysis of the efficacy of fluticasone furoate nasal spray on individual nasal and ocular symptoms of seasonal allergic rhinitis[END_REF]. Each nasal and nonnasal symptoms are presented on a 0-3 scale: 0, no symptoms; 1, mild symptoms (obvious symptoms, but easily tolerated); 2, moderate symptoms (bothersome but tolerable symptoms) and 3, severe symptoms (symptoms hard to tolerate and/or impact the activities of daily living). [START_REF] Demoly | Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care[END_REF]. The TSS6 is the total scores of nasal and non-nasal symptoms ranging from 0-18. However, the cut-off level of the TSS6 discriminated the severity has not been suggested. In some studies the score of the 4 nasal symptoms is separated (Total Nasal Symptom Score) from that of the 2 ocular symptoms (Total Ocular Symptom Score).

Visual Analog Scale (VAS) is a simple and quantitative measure extensively used to assess the severity of AR in both intermittent and persistent rhinitis. Bousquet et al. [START_REF] Bousquet | Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines[END_REF] satated that a 0-10cm VAS soce and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) global score were significantly correlated and that a cut-off level of 5 cm was proposed to discriminate between mild and moderate/severe patients with AR. Many studies in different languages are being carried out to confirm the possible use of this scale in different countries.

Other study suggested that all symptoms of rhinitis could be assessed by VAS, but, a single scale with a simple simple question would be easier to use in primary care.

Severity assessment of AR in clinical practice

The ARIA severity classifications have been validated and implemented in primary care patients in many countries [START_REF] Bauchau | Epidemiological characterization of the intermittent and persistent types of allergic rhinitis[END_REF][START_REF] Demoly | Validation of the classification of ARIA (allergic rhinitis and its impact on asthma)[END_REF], and the majority of physicians and specialists are aware of this tool [START_REF] Demoly | Spreading and impact of the World Health Organization's Allergic Rhinitis and its impact on asthma guidelines in everyday medical practice in France. Ernani survey[END_REF]. A cohort study of AR patients in Spain found patients with "moderate/severe" AR have significantly higher symptom, RQLQ and VAS score than patients with "mild" AR [START_REF] Del Cuvillo | Validation of ARIA duration and severity classifications in Spanish allergic rhinitis patients -The ADRIAL cohort study[END_REF][START_REF] Jauregui | Validation of ARIA (Allergic Rhinitis and its Impact on Asthma) classification in a pediatric population: the PEDRIAL study[END_REF]. In China, among the subjects with self-reported AR in 11 major cities, 25.6% were diagnosed with persistent AR and 74.4% suffered from intermittent AR (3). Bousquet et al. [START_REF] Bousquet | Severity and impairment of allergic rhinitis in patients consulting in primary care[END_REF] reported that impairments were correlated more significantly with severity than duration. "Moderate-severe" AR usually includes patients with SCUAD (48), who may have severe symptoms and need allergen immunotherapy.

Low levels of awareness and application of the ARIA severity classification do not meet the clinical needs of patient care. Demoly et al. [START_REF] Demoly | Spreading and impact of the World Health Organization's Allergic Rhinitis and its impact on asthma guidelines in everyday medical practice in France. Ernani survey[END_REF] found that in France, only about 54% of the primary care physicians were aware of the ARIA classification, and over 90% of them had indeed applied the classification in clinical practice. Moreover, awareness of the ARIA classification could not influence the opinion of treatment according to the patient's symptoms severity [START_REF] Ramirez | Combining H1-antihistamines and nasal corticosteroids to treat allergic rhinitis in general practice[END_REF].

In most developed countries, a patient with "mild" AR is likely to consult a primary care physician rather than a specialist. However, in China, patients are more likely to consult the specialist directly, because general practioners are lacking. Thus, the "mild" vs.

"moderate/severe" distinction has more value for specialists. Van Hoecke et al. [START_REF] Valovirta | The voice of the patients: allergic rhinitis is not a trivial disease[END_REF][START_REF] Van Hoecke | Is the allergic rhinitis and its impact on asthma classification useful in daily primary care practice?[END_REF] observed that 89.3% of patients consulting physicians in Belgium were classified as "moderate-severe". In the telephone survey of self-reported AR in 11 major cities in China, 74.4% had intermittent AR, 25.6% had persistent AR, and only 39.3% had presented to a clinic (3). This reflected that severity of symptoms was an important factor to drive the patients to visit hospitals [START_REF] Wang | Prevalence of uncontrolled allergic rhinitis in Wuhan, China: A prospective cohort study[END_REF].

3-Assessment of AR control

Allergic rhinitis control

Currently, there is not a standardized definition of AR control. The concept of disease control is only applicable in treated patients [START_REF] Bousquet | Uncontrolled allergic rhinitis during treatment and its impact on quality of life: a cluster randomized trial[END_REF]. Based on an analogy with GINA [START_REF] Bateman | Global strategy for asthma management and prevention: GINA executive summary[END_REF], the concept of overall AR control may be considered as the degree of symptom reduction and of achievement of the treatment's goals. From this point of view, AR control can be measured in a multitude of ways, with both objective and subjective measurements and using patient-reported vs. physician-reported outcomes. Patient-reported metrics are growing in importance in clinical research and, increasingly, in patient care [START_REF] Braido | Specific recommendations for PROs and HRQoL assessment in allergic rhinitis and/or asthma: a GA(2)LEN taskforce position paper[END_REF], although there is debate as to whether it is the physician or the patient that is best placed to judge disease control [START_REF] Juniper | Measuring asthma control. Clinic questionnaire or daily diary?[END_REF].

Therefore, evaluation of AR control can be based on a number of criteria, including: nasal and ocular symptoms (congestion, rhinorrhea, sneezing, pruritus, post-nasal drip); a patient-reported metric of QoL and satisfaction (i.e., impairment in sleep or daily activities); objective measurements (e.g., peak nasal inspiratory flow, rhinomanometry); the necessity for increased use of rescue medication and how much. The last is also important as it has been suggested that a patient's degree of control could simply correspond to the "strength" of the medication necessary to suppress symptoms [START_REF] Demoly | Assessment of disease control in allergic rhinitis[END_REF]. Therefore, any increment in medication could indicate loss of control. Finally, presence of rhinitis comorbidities could also affect control, as 10% to 40% of rhinitis patients have comorbid asthma [START_REF] Cruz | Common characteristics of upper and lower airways in rhinitis and asthma: ARIA update, in collaboration with GA(2)[END_REF]. Practical tools are also needed for patients and physicians to determine whether optimal AR care is provided or whether treatment strategies needed to be adjusted.

Instruments for assessing AR control

Several composite instruments, mainly self-administered questionnaires, have been developed over the years. The time period of assessment ranges from 1-4 weeks prior to the consultation, long enough to assess changes and short enough to avoid recall bias.

The Control of Allergic Rhinitis and Asthma Test (CARAT

CARAT is a self-administered questionnaire (including 17 questions in a questionnaire with a Likert scale), initially developed by Nogueira-Silva et al. [START_REF] Nogueira-Silva | Control of allergic rhinitis and asthma test--a formal approach to the development of a measuring tool[END_REF] for assessing control of both AR and asthma in patients with comorbid diseases, as recommended by ARIA. Subsequently, a simply 10-item version of CARAT (CARAT10) was validated in a cross-sectional study of 193 adults with AR and asthma from 15 outpatient clinics in Portugal [START_REF] Fonseca | Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma[END_REF]. The range of possible scores for CARAT10 is 0 (absence of control) to 30 (complete control), and the reference/evaluation period is 4-6 weeks. Fonseca et al. [START_REF] Fonseca | Control of Allergic Rhinitis and Asthma Test (CARAT) can be used to assess individual patients over time[END_REF] observed good correlations between CARAT10 and Asthma Control Questionnaire (ACQ), symptoms' VAS and a simple binary yes/no physician's assessment of control. CARAT10 has adequate test-retest reliability and internal validity. It can be used in clinical practice to compare groups and to guide patient management.

Rhinitis Control Assessment Test (RCAT)

RCAT is a 26-item instrument developed by Nathan et al. [START_REF] Nathan | Qualitative Development of the Rhinitis Control Assessment Test (RCAT), an Instrument for Evaluating Rhinitis Symptom Control[END_REF] for the assessment of control of nasal and ocular symptoms the previous week. It was finally refined to a 6-item self-administered questionnaire (including frequency of nasal congestion, sneezing, watery eyes, sleep interference, activity avoidance and self-assessed control) after testing the RCAT in 410 AR patients [START_REF] Schatz | Psychometric validation of the rhinitis control assessment test: a brief patient-completed instrument for evaluating rhinitis symptom control[END_REF]. RCAT questions are measured on a 5-point scale with total score ranging from 6 (poor control) to 30 (complete control). A longitudinal study in 402 patients in 9 sites of allergists and otolaryngologists showed that RCAT demonstrated adequate reliability and validity, and confirmedthe items to be relevant and easy to answer. Moreover, RCAT provided an accurate picture of the severity of the symptoms of AR and non-AR [START_REF] Meltzer | Reliability, validity, and responsiveness of the Rhinitis Control Assessment Test in patients with rhinitis[END_REF]. Based on its sensitivity and specificity, a cut-point score of 21 or less was suggested to identify AR control [START_REF] Meltzer | Reliability, validity, and responsiveness of the Rhinitis Control Assessment Test in patients with rhinitis[END_REF]. It is planed to be included in an e-Health tool for AR patients (66).

Allergic Rhinitis Control Test (ARCT)

Demoly et al. [START_REF] Demoly | Validation of a self-questionnaire for assessing the control of allergic rhinitis[END_REF] developed the ARCT including 5 items by working with a multidisciplinary group associating allergists, pulmonologists, ENT physicians and methodologists. Similar to the Asthma Control Test (ACT) [START_REF] Nathan | Development of the asthma control test: a survey for assessing asthma control[END_REF], measuring AR control with the ARCT is multidimensional. The 5 items include the impact on professional/personal activities, sleep disturbance, medication and overall assessment of the disease. A 2-week recall is used in ARCT. The questionnaire was validated by testing it in 902 patients selected by 411 primary care physicians and allergists before the treatment and 2 weeks after the treatment. It appears to be correlated to the clinical status of the AR, as well as to the evolution after treatment. A score higher than or equal to 20, as a marker of well-controlled AR, is the most efficient (sensitivity: 67%, specificity: 82%). It is incorporated into a patient support programme (69).

Visual Analog Scale (VAS)

Initially developed as a simple tool to measure AR severity, VAS has turned out to be a possible tool to assess AR control, with a score of 50 mm or greater as the cut-off for uncontrolled AR during treatment [START_REF] Bousquet | Change in visual analog scale score in a pragmatic randomized cluster trial of allergic rhinitis[END_REF]. It was estimated that 20% of patients with AR are still uncontrolled despite adequate medical treatment of AR in a retrospective analysis [START_REF] Bousquet | Uncontrolled allergic rhinitis during treatment and its impact on quality of life: a cluster randomized trial[END_REF]. In a post-hoc analysis assessing VAS at inclusion and after 15 days of treatment, the change of VAS greater than 30 mm was considered significant in relation to the improvement of quality of life and of symptom score [START_REF] Bousquet | Change in visual analog scale score in a pragmatic randomized cluster trial of allergic rhinitis[END_REF]. The exact cut-off may still need to be worked out because it was shown to be of 23 mm based on a multi-centre prospective study [START_REF] Demoly | Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care: asthma and rhinitis[END_REF].

Allergy-Control-SCORE

The Allergy-Control-SCORE TM ( 72) is a symptom-medication scale. It was designed to assess the AR patients'allergy severity by recording nasal and non-nasal symptoms and rescue medication. The study showed that the Allergy-Control-SCORE was significantly correlated with the RQLQ score and the global assessment of allergy severity. The Allergy-Control-SCORE has been extensively used in clinical trials for many years as a "combined score" (a combination of a symptom score and a medication score) (73).

AR control instruments in clinical practice

Despite the availability of effective therapies, total control of AR is difficult to achieve for many patients. The ARIA guidelines stated that "treatment should be tailored according to the severity of the disease, comorbidities, treatment availability and affordability and patients' preference" [START_REF] Bousquet | Allergic rhinitis and its impact on asthma[END_REF]. The concept of achieving control can contribute to improve the doctor-patient relationship in the treatment and management of AR.

The CARAT, RCAT and ARCT are multi-item questionnaires that require the patient to provide a fair amount of informationon his/her recent condition. It should help treatment decisions. However, since control is largely a patient-led concept, remote measurements (by phone or over the Internet) could conceivably reduce the frequency of face-to-face consultations. Applications on cellular phones (i.e., e-health technology) could help [START_REF] Burnay | Challenges of a mobile application for asthma and allergic rhinitis patient enablement-interface and synchronization[END_REF].

Nevertheless, as noted by Glasziou et al. [START_REF] Glasziou | Monitoring in chronic disease: a rational approach[END_REF], the benefits of monitoring the response to treatment, detecting adverse effects and gauging the need to adjust treatment must be balanced against inconvenience, cost and the potential impact of false positives and false negatives of disease control. Measurements of control must therefore be reproducible, easy to perform, easy to interpret and should focus on the disease's impact in every-day life. For the patient, measures should be easily obtained and allowing patients to self-medicate. For the physician, tools must have a low burden in a busy clinical practice (i.e., should be auto-questionnaire) and should guide clinical action following the test result.

Relationship between severity and control of AR

Recent papers developed under the aegis of ARIA indicate that disease control is being considered for future initiatives and that, methods for measuring severity and control in respiratory allergic diseases must be uniformed [START_REF] Bousquet | Allergic Rhinitis and its Impact on Asthma (ARIA): achievements in 10 years and future needs[END_REF]. Severity, control and responsiveness to treatment are different concept, but they are not opposite to each other [START_REF] Calderon | Comparability of subcutaneous and sublingual immunotherapy outcomes in allergic rhinitis clinical trials[END_REF]. AR severity is not equivalent to the level of control. The severity is defined as the clinical grade experienced by each patient in the disease process. The control can be defined as significantly less disease syptoms or relapse. Some cases of severe disease might respond well to treatment (i.e., good control), whereas some cases of mild disease might not (i.e., poor control). Likewise, a totally controlled patient taking an H1 antihistamine (H1A) combined to a nasal corticosteroid (NCS) and relapsing every time will probably have a severe underlying disease [START_REF] Bousquet | Severe chronic allergic (and related) diseases: a uniform approach-a MeDALL-GA2LEN-ARIA position paper[END_REF]. Furthermore, poor disease control may also be related to poor treatment compliance and psychosocial factors rather than high disease severity [START_REF] Demoly | Assessment of disease control in allergic rhinitis[END_REF]. Mild disease may be a problem for some patients but not for others.

Conversely, severe disease may bother some patients far less than others.

Severity can be measured in treatment-naïve patients as proposed by ARIA guidelines [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], but, by definition, the concept of disease control is only applicable in treated patients [START_REF] Bousquet | Uncontrolled allergic rhinitis during treatment and its impact on quality of life: a cluster randomized trial[END_REF].

Therefore, measurements of severity will be indispensable in treatment-naïve patients consulting for the first time. Measuring tools (such as VAS, ARCT and CARAT) appear to be simple and convenient for assessments of disease severity or control. However, a one dimensional scale cannot replace or encompass the complex parameters of objective measurement involved in disease control (i.e., examination of nasal mucosa and structure, respiratory function tests and exacerbations quantification).

4-Uncontrolled allergic rhinitis 4.1 The definition of SCUAD

Constantly updated ARIA guidelines provide standard diagnostic procedures and personalized treatment programs according to the patient's symptoms and impact on quality of life. The traditional goal of treatment has been to reduce the symptoms of AR, and current opinion suggests that management should be aimed at achieving long-term, stable control, corresponding to minimal or even no symptoms, no limitations indaily activity, minimal use of rescue medications and infrequent exacerbations. Current drug therapy can be effective in relieving the symptoms of AR and improving the quality of life of patients. However, in real life, a significant percentage of patients still have very bothersome symptoms that are not readily controlled after adequate medical treatment based on established ARIA guidelines.

Bousquet et al. [START_REF] Bousquet | Unmet needs in severe chronic upper airway disease (SCUAD)[END_REF] defined this form of the disease as SCUAD.

The factor of SCUAD for AR

The proposed concept of SCUAD represents a therapeutic challenge for both patients and physicians. It is important to find the risk factors involved in SCUAD in clinical practice.

Disease-related factors of SCUAD

Allergic diseases show strong familial and intraindividual clustering and often occur with atopy [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]. Genetic factors are related to the inflammatory response and immune disorders [START_REF] Becker | Genetic variation determines mast cell functions in experimental asthma[END_REF] as well as the presence of nasal mucosa hyperreactivity [START_REF] Su | Altered epigenetic regulation and increasing severity of bronchial hyperresponsiveness in atopic asthmatic children[END_REF]. Environmental factors such as exposure to cigarette smoke, allergen load, indoor and outdoor pollutants and work-related factors may have an effect on the control of allergic airway symptoms in AR patients [START_REF] Greiner | Allergic rhinitis[END_REF]. For example, it is possible that the achievement of control in patients with AR induced by grass pollen is very different from that in patients with persistent AR induced by house dust mites. This is a complex area requiring and more research is required to clarify this complex process.

Hormonal factors have been related to the severe immune response [START_REF] Brozek | Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision[END_REF]. More severe allergic inflammation may occur during the pregnancy, puberty and the menstrual cycle [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]. Steroid resistance has been reported in asthma and may be the cause of lack of control. However, The existence and mechanisms of steroid resistance in AR need to be further explored [START_REF] Ishida | Overexpression of glucocorticoid receptor-beta in severe allergic rhinitis[END_REF][START_REF] Pujols | Importance of glucocorticoid receptors in upper and lower airways[END_REF][START_REF] Luo | Clinical Value of the High Expression of Corticosteroid Receptor-Beta mRNA in the Nasal Mucosa of Steroid-Resistant Patients with Allergic Rhinitis[END_REF].

Diagnosis-related factors of SCUAD

In recent years, the prevalence of AR continues to raise and more different phenotypes have been recognized while it remains an under-diagnosed conditions [START_REF] Hansen | Rhinitis: a complication to asthma[END_REF]. In patients with SCUAD, the physician needs to reconsider the diagnosis of AR according to the treatment algorithm recommended by ARIA guideline and attempt to find out other factors that may be overlooked or an incorrect diagnosis. A study found that only about 56% of the otolaryngologists preferred the management pathway of starting treatment and then discharging AR patients to general practitioners for further follow-up [START_REF] Ryan | Management of allergic rhinitis in UK primary care: baseline audit[END_REF]. Several subgroups of AR such as isolated nasal hyperreactivity and local AR present with mild symptoms that are often ignored and not adequately addressed [START_REF] Anto | Understanding the complexity of IgE-related phenotypes from childhood to young adulthood: a Mechanisms of the Development of Allergy (MeDALL) seminar[END_REF]. The diagnosis of AR needs to combine a typical history of symptoms and diagnostic tests. In vivo and in vitro test (e.g., positive skin prick testing or serum-specific IgE) are often used to diagnose allergic diseases. In patients with nasal hyperreactivity or occupational rhinitis, nasal or ocular challenge tests with allergens are important [START_REF] Kim | Usefulness of the subjective cold hyperresponsiveness scale as evaluated by cold dry air provocation[END_REF]. Nasal obstruction and increased nasal secretions can be observed in AR patients with nasal polyps, septal deviation and nasal valve dysfunction [START_REF] Eccles | Mechanisms of the symptoms of rhinosinusitis[END_REF]. ARIA recommends that all patients with persistent AR should undergo nasal examination and nasal endoscopy is the next step which is useful in patients with treatment failure [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].

Treatment and management-related factors of SCUAD

Many patients with AR do not recognize the signs and symptoms suggestive of moderate/severe rhinitis or do not consider doctors can do anything and do not timely consult a physician. Most of them commonly use over-the-counter (OTC) drugs or complementary medicines, seeking self-treatment for the relief of symptoms [START_REF] Brożek | Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision[END_REF]. It is therefore particularly important to improve the management of AR. In the longer treatment period, comprehensive and meticulous medical management is necessary for the long-term follow-up of AR.

However, in the majority of developing countries, abundant medical resources tend to be concentrated in large cities, thus the difficulty of follow-up is increased for patients with AR in the city with poor medical service. Uneven distribution of medical resources result in poor doctor-patient communication and treatment failure [START_REF] Marple | Keys to successful management of patients with allergic rhinitis: focus on patient confidence, compliance, and satisfaction[END_REF]. Efficient and optimal treatment of AR should take many factors into account, including safety, efficacy, patient's preference, cost-effectiveness of medications, severity and control of the disease and presence of co-morbidities. The expected efficacy of different treatment options may differ between patients. The route of administration (e.g., intranasal or oral) of medication has an impact on the efficacy [START_REF] Nair | Steroid sparing effects of intranasal corticosteroids in asthma and allergic rhinitis[END_REF]. Additionally, ocular and ear symptoms should not be neglected (89).

Patient-related factors of SCUAD

Noncompliance to the prescribed therapeutic regimen and incorrect medication use should be considered when treating uncontrolled AR. Low compliance to treatment is a problem of daily practice especially in long-term regimes, and the consequences are poor health outcomes. Mahesh et al. [START_REF] Mahesh | Factors associated with non-adherence to specific allergen immunotherapy in management of respiratory allergy[END_REF] found 60% of the patients with AR and/or asthma were compliant to subcutaneous immunotherapy (SCIT). Chang et al. [START_REF] Chang | Early compliance and efficacy of sublingual immunotherapy in patients with allergic rhinitis for house dust mites[END_REF] reported a discontinuation of sublingual immunotherapy (SLIT) in 30% of patients with AR for house dust mites within 6 months of treatment. A study of a novel antihistamine demonstrated high compliance rates of 90% and 83% after 6 and 12 months of treatment, respectively [START_REF] Valero | Safety of rupatadine administered over a period of 1 year in the treatment of persistent allergic rhinitis[END_REF]. Other studies on intranasal glucocorticosteroids stated compliance rates of 65% and 85% [START_REF] Loh | A clinical survey on compliance in the treatment of rhinitis using nasal steroids[END_REF]. Ideally, clinical efficacy, cost, fear for side effects are considered the major issues influencing patient's compliance [START_REF] Köberlein | Determinants of patient compliance in allergic rhinoconjunctivitis[END_REF]. The perceived knowledge, preferences, beliefs and expectations of the patient are perceived as important drivers in treatment outcome [START_REF] Phatak | Relationships between beliefs about medications and nonadherence to prescribed chronic medications[END_REF][START_REF] Dimatteo | Health beliefs, disease severity, and patient adherence: a meta-analysis[END_REF]. The most outstanding influences on under-treatment of AR in Europe are patients' perception about therapy [START_REF] Maurer | Undertreatment of rhinitis symptoms in Europe: findings from a cross sectional questionnaire survey[END_REF]. A survey found that patients consulting for AR have high expectations of anti-allergic treatment, prefer a nasal spray above oral treatment, prefer combined treatment rather than monotherapy, and fear adverse events of treatment [START_REF] Hellings | Explorative study on patient's perceived knowledge level, expectations, preferences and fear of side effects for treatment for allergic rhinitis[END_REF].

The use of the nasal route for drug delivery has had some new developments and strategies.

The correct use of nasal sprays is believed to be the key issue in the efficacy of treatment.

Optimal effect of treatment will not be obtained in case of inappropriate use of intranasal spray and bad positioning of the nasal spray at the time of nebulization of the molecule.

Therefore, an appropriate patient-physician relationship, family and community interactions are the major factors in improving compliance.

5-Prevalence of uncontrolled allergic rhinitis in Wuhan, China: A prospective cohort study

Objectives

The main aim of this prospective cohort study was to investigate the prevalence of uncontrolled AR and SCUAD consulting in the allergy department of Tongji Hospital, Wuhan, China (N.B. this is a partial prevalence, described in the sub-population of patients consulting in the allergy department of Tongji Hospital, Wuhan). The second aim was to describe the clinical characteristics of these patients. The results of this study can help doctors and patients understand the clinical features and control of AR in Wuhan City. We suggest that physicians in charge of AR patients use VAS and/or ARCT as a simple and quantitative method for the global evaluation of AR severity and response to treatment.

Materials and Methods

Patients

Patients consulting for AR were consecutively enrolled in the allergy department of Tongji Hospital, Wuhan, China during 1 year (August 2011 to July 2012).

The inclusion criteria were as follows:

(1) Patients aged 18-75 years, male or female;

(2) Patients presented at least 2 clinical symptoms of AR (rhinorrhea, nasal congestion, sneezing, nasal itching) at inclusion; The exclusion criteria were as follows:

(1) Aged < 18 years or > 75 years;

(2) Patients presented less than 2 clinical symptoms of AR (rhinorrhea, nasal congestion, sneezing, nasal itching) at inclusion;

(3) Patient had a negative skin prick tests to aeroallergens and/or serum specific IgE levels (sIgE ≥ 0.35KU/L, Phadia CAP System);

The general conditions of patients include: age, sex, education (postgraduate, undergraduate and bachelor), residential area (city, suburbs and mountainous area), height, weight and Body Mass Index (BMI).

(2) Diagnostic history and concomitant diagnosed pathologies Diagnostic history includes: duration of the rhinitis and smoking. Concomitant diagnosed pathologies include: history of atopic dermatitis, history of asthma, history of ENT infection or antibiotics intake for respiratory infection in the last 12 months, recurrent rhinosinusitis, nasal deformities, allergic conjunctivitis and smell disturbance. If AR patients had both history of atopic dermatitis and history of asthma, they were considered as having "multimorbidity". (4) Score of VAS at baseline VAS is a scale from 0-10 cm, with 0 cm representing no symptoms and 10 cm representing maximal imaginable symptoms [START_REF] Bousquet | Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines[END_REF]. Patients were asked to mark the line at that location that they found appropriate to best describe the severity of the symptoms they experienced at baseline. In this study, the severity of all combined symptoms (nasal and ocular symptom) and impact of AR (impact of sleep and work, social activities, physical activities and overall discomfort) was assessed using a VAS.

(5) NS at day 15 Patients were also asked to rate the severity of their symptoms by a telephone interview using a NS ranging from "0" (no symptoms) to "10" (maximum imaginable symptoms) after 15 days of treatment.

Initial Assessment

At the first visit (D0), patients were consecutively included in the study by physicians after written informed consent was obtained according to inclusion and exclusion criteria.

Physicians completed a general questionnaire. For each patient, symptoms of AR and their impacts were scored by VAS levels and AR control by treatment measured by ARCT [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF].

Patients with a baseline VAS level < 5 cm were considered as having "mild" AR, whereas a VAS level ≥ 5 cm were equated with "moderate to severe" AR [START_REF] Bousquet | Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines[END_REF]. Physicians followed a simple treatment based on the ARIA guidelines using a VAS score to assess severity. [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]. Oral or nasal H1A was used for the patients with "mild" AR (VAS < 5). Oral or nasal H1A plus NCS and/or LTRAs were used for the patients with "moderate to severe" AR (VAS ≥ 5).

Ocular H1A was used for the patients with ocular symptom.

Re-assessment

ARIA recommend the symptoms of patients with AR need to be re-assessed after 2-4 weeks treatment period (100). In this study, after 15 days, patients were reevaluated by a telephone interview using a NS and ARCT after 15±2 days (D15).

Data Entry

After the investigation was completed, all questionnaires were collected, reviewed, numbered and archived. The data was entered into the database and checked for accuracy.

Outcome measures

SCUAD

Currently, SCUAD does not have a precise definition. SCUAD defines those patients who have poor control of symptoms despite adequate guideline-directed pharmacotherapy [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].

For this study, patients presented a NS score at day 15 ≥ 5 were considered SCUAD patients.

Uncontrolled AR

Uncontrolled AR was defined by the score of ARCT after 15 days of treatment: patients with a score of ARCT < 20 were considered as having uncontrolled AR at day 15 [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF].

Significant improvement in symptoms

A change between VAS (day 0) and NS (day 15) ≥ 2.5 was considered as a significant improvement in symptoms [START_REF] Demoly | Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care: asthma and rhinitis[END_REF]. Patients whose initial VAS score was ≤ 2 were considered as having a significant improvement in symptoms if they had a NS score equal to 0 at day 15.

Statistical analysis

Qualitative variables such as demographic data and symptoms were expressed in percentages and frequencies. Quantitative data were expressed as means and standard deviations. Medians and 25th to 75th percentiles defined quantitative not normally distributed data. Comparisons for the qualitative data such as patient characteristics were carried out between groups by The analysis was performed with SPSS 11.5 software with the significance level set at 5% (0.05).

Ethics

This study was approved by Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China (N o 20110702). Informed consent was obtained from each participant after a full explanation of the study.

Results

Two hundred fifty-two patients were recruited by 8 allergists from the allergy department of

ARIA classification

According to ARIA, mild intermittent rhinitis was diagnosed in 6 patients (2.4%), mild persistent rhinitis in 7 (2.8%), moderate/severe intermittent rhinitis in 35 (13.9%) and moderate/severe persistent rhinitis in 204 (81%).

AR treatment

On the consultation day, all 249 patients were receiving H1A (87.6% of cases were oral administration, 1.6% nasal administration and 10.8% both routes of administration), 210 patients (84.3%) were receiving corticosteroids (97.6% nasal and 2.4% oral), 156 patients (62.7%) were being treated with ocular antihistamines, 74 patients (29.7%) with an anti-leucotrienes, and 28 patients (11.2%) with other treatments (Figure 5-1). Data are presented as number (percentage) or means ± SD, unless otherwise specified.

1 F2 and Wilcoxon-Mann-Whitney test were used for qualitative and quantitative variables. 2 The treatment was considered as "optimal" if mild AR (VAS D0 < 5) received treatment with oral antihistamines and moderate to severe AR (VAS D0 ≥ 5) received treatment with oral antihistamines and nasal corticosteroid. * Three patients were lost for follow-up and therefore 249 patients were analysed at D15.

Prevalence and characteristics of SCUAD patients

Prevalence and characteristics of SCUAD patients

The comparisons of the patients in different groups at day 15 (SCUAD vs non-SCUAD) are presented in Table 5-2. 24.5% of the patients had SCUAD (n = 61/249).

A past history of ENT infection or antibiotics intake for respiratory infection in the last 12 months, smell disturbance and impact of AR on sleep, work life, social activities and physical activities were more frequently present in patients with SCUAD, whereas history of atopic dermatitis was less common (P < 0.05; Table 5-2).

Patients with SCUAD were less frequently treated with anti-leucotrienes (4.9 vs. 37.8%, P < 0.001) and nasal antihistamines (4.9% vs 15.4%, P = 0.033), while nasal corticosteroid and other drugs were more frequently received (93.4 vs. 78.7%, P = 0.009). Almost all of them had uncontrolled AR according to ARCT at day-15. At inclusion, patients with SCUAD had slightly but significantly greater VAS scores and lower ARCT scores than non-SCUAD patients (P < 0.0001). The same result was found at day 15 (P < 0.0001) (Figure 567). Therefore, the assessment results of VAS and ARCT were consistent. had postgraduate degrees (12.8 vs. 5.54%, P = 0.045), whereas less of them had bachelor degrees (29.1 vs. 42.3%, P = 0.040). Moreover, they frequently presented a smell disturbance (22.1 vs. 12.3%, P = 0.043) and were more frequently treated with other drugs (20.9 vs. 6.1%, P < 0.001), while less of them received anti-leucotrienes (4.7 vs. 42.9%, P < 0.001). The number of controlled AR at day-15 was significantly less (32.6 vs. 93.3%, P < 0.001) (Table 5-4). At inclusion, the score of VAS in the two groups (significant improvement of symptoms vs.

insignificant improvement of symptoms) were respectively 6.0 ± 2.0 and 6.0 ± 2.0 (P = 0.129).

Patients with significant improvement of symptoms had significantly greater ARCT score than patients with insignificant improvement of symptoms (P < 0.0001).

Correlation between ARCT and VAS

Correlations between ARCT and VAS were poor on the consultation day (day 0) (r = -0.482, P < 0.001) but significantly stronger after 15 days of treatment (r = -0.884, P < 0.001).

Similar findings were observed for the change between consultation day and day-15 (r = 0.588, P < 0.001) (Table 5-8). Moreover, the prevalence of positive nasal symptoms was 29.4% after 5-year follow-up (104).

As a major industrial city of China with more than 8 million inhabitants, Wuhan has a high prevalence of AR and its impact on patient quality of life should be substantial but has never been evaluated. The results of prevalence of AR are different due to the different countries, regions, race, climate, environment and living habits and so on.

In recent years, the clinical research of AR is not only confined to the prevalence survey, but focus more on the severity of AR, the quality of life and treatment effect, so as to explore a simple, accurate and effective management or self-management method improved the quality of life of patients. As for the management of asthma, the control is now being considered as a goal of AR treatment. Therefore invertigating the prevalence of uncontrolled AR and proposing the simple and quantitative methods to evaluation the severity and control of AR are the aims of this study.

Assessment of the severity of AR

ARIA introducted a classification based on the symptom duration ("intermittent" vs.

"persistent") and symptom severity impacting daily quality of life ("mild" vs.

"moderate/severe") [START_REF] Bousquet | Allergic rhinitis and its impact on asthma[END_REF]. VAS has long allowed the assessment of subjective symptoms such as pain VAS (105), and it is considered to be a sensitive, robust and reproducible method of expressing severity in AR [START_REF] Demoly | Assessment of disease control in allergic rhinitis[END_REF]. Bousquet et al. [START_REF] Bousquet | Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines[END_REF] found that a 0 to 10 cm VAS score and the RQLQ score were significantly correlated. VAS can also be used to assess the symptom severity of AR and the impact of quality of life (106, 107), but total VAS score is often used in practice due to its simple implement. VAS ≥ 5 is an easy way to distinguish mild and moderate/severe AR at inclusion of patients, and our study showed that 82.9% of the patients with moderate/severe AR had allergic conjunctivitis, moderate/severe persistent AR according to ARIA classification and symptoms usually with an impact on sleep, work life social activities and physical activities. In the telephone survey of Zhang et al. ( 3) including patients with self-reported AR in 11 major cities in China, 74.4% had intermittent AR, 25.6% had persistent AR and only 39.3% had presented to a clinic. This reflected that the impairments were correlated more strongly with severity than duration, and severity of symptoms was an important factor to drive the patients to the hospital allergy clinic.

Prevalence and characteristics of SCUAD patients

For different types of AR, ARIA recommends different treatment regiments, which makes it easy to apply in clinical practice [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, some patients still have very severe symptoms after adequate treatment according to ARIA guidelines. Bousquet et al [START_REF] Bousquet | Uncontrolled allergic rhinitis during treatment and its impact on quality of life: a cluster randomized trial[END_REF] defined this form of the disease as SCUAD, and addressed attention to the control of AR patients using simple clinical tools. In this study, patients were reevaluated by a telephone interview using NS, thereby obtaining the prevalence of SCUAD.

The prevalence of SCUAD in our cohort was 24.5%, which was higher than that in France:

18.9% (54) and 22% [START_REF] Demoly | Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care: asthma and rhinitis[END_REF]. However, our cohort has very few mild intermittent/persistent AR patients (5.2%) compared to that of Bousquet et al. (20.2%), which implied that the prevalence of SCUAD might be overestimated in our cohort or reflect the reality in Wuhan.

Both studies being run with different methodologies in different countries, it is not possible to draw any conclusion.

There are many risk factors associated with SCUAD, such as environment (allergen exposure, direct or indirect smoking, air pollution, etc.) (108), genetic factors [START_REF] Becker | Genetic variation determines mast cell functions in experimental asthma[END_REF][START_REF] Su | Altered epigenetic regulation and increasing severity of bronchial hyperresponsiveness in atopic asthmatic children[END_REF], glucocorticoid-resistance ( 80), diagnosis and treatment-related factors and patient's own factor (psychological factor) (109). In this study, compared with non-SCUAD patients, SCUAD patients had less history of atopic dermatitis but more smell disturbance problem, more history of ENT infection or antibiotics administration in the last 12 months and more significant impact on quality of life. This may reflect either a higher susceptibility of these patients with upper respiratory infections or some participation of non-allergic components.

Thus, bacterial infection of the upper airways may play an important role in SCUAD. The history of asthma and recurrent sinusitis were not significantly more prevalent in SCUAD compared to non-SCUAD patients, and more data is needed to better understand SCUAD pathophysiology.

Clinical response of patient with AR to drug treatment

Currently, there are many methods to assess the therapeutic effect in AR, but most have not yet been confirmed or implemented in real 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]. RQLQ and TSS6 are two methods commonly used, but their sensitivity are poor (110). VAS combines AR symptoms and the impact on quality of life of patients to assess the effect of treatment, and has been used in several clinical trials (106, 110, 111, 112). In a randomized cluster trial assessing VAS at baseline and after 15 days of treatment, the optimal cut-off in VAS was 30 mm [START_REF] Bousquet | Change in visual analog scale score in a pragmatic randomized cluster trial of allergic rhinitis[END_REF]. Other study reported changes in VAS greater than 23 mm may reflect the responsiveness to treatment [START_REF] Demoly | Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care: asthma and rhinitis[END_REF]. The patients in the first study were included to receive treatment according to the ARIA or to the free-choice treatment. The cut-off in the latter study was calculated on the basis of RQLQ and TSS score and the patients at baseline included a majority of severe AR.

In this study, we chose the latter as the reference standard, but for easy implementation, a change in VAS ≥ 2.5 was considered as a significant improvement in symptoms.

The result showed that the percentage of patients with insignificant improvement was 34.5%.

It was slightly higher than in the study of Zhang et al.

(3) reporting that 27.2% of the patients received treatment in clinic, and amongst them, 71.1% were satisfied. To obtain the control of AR, it is probably necessary to better phenotype severe AR patients and patients with no response to current treatment and treat according to phenotype and not according to severity only, as it is the case nowadays.

The control of AR

Demoly et al. [START_REF] Demoly | Validation of a self-questionnaire for assessing the control of allergic rhinitis[END_REF] demonstrated that similar to the asthma control questionnaire (113), ARCT is a sensitive self-questionnaire to distinguish poor and well-controlled rhinitis and is correlated to VAS for symptoms and symptom impacts. According to WHO recommendations [START_REF] Brozek | Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision[END_REF], the general course of treatment for patients with AR is 2-4 weeks. In our study, patients were assessed after 2 weeks after the start of treatment. We found that 27.7% of our patients had uncontrolled AR. This study validates the Chinese translation of ARCT. We also found weight, smoking, past history of ENT infection or antibiotics administration in the last 12 months and smell disturbance had impacts on AR control, and especially on work life (OR = 9.4), however, we do not know through which exact mechanisms. 27.7% of the patients with uncontrolled AR (ARCT < 20) presented higher prevalence of SCUAD, which also suggested that ARCT had a strong correlation with VAS and could be used as a surrogate indicator in future AR survey.

Clinical significance of study results

Based on our results, we propose a simple and effective practical method for the management of AR. First, a careful history, a nasal examination (using a nasal speculum/otoscope) and allergy tests (skin tests, in vitro tests or even nasal challenge) to confirm or exclude an allergic etiology are recommended to confirm the diagnosis of AR [START_REF] Bousquet | Allergic rhinitis and its impact on asthma[END_REF]. Second, a VAS is used to evaluate the severity of AR and the threshold of 5 is satisfied to distinguish mild (VAS < 5)

and moderate/severe (VAS ≥ 5) AR. The first-line treatment based on the ARIA guidelines is followed according to the assessment of severity using VAS score. Third, a reevaluation (possibly self-assessment) should be practiced after 15 days of treatment using a NS or ARCT.

When dealing with SCUAD or uncontrolled AR, the first question one should ask is about patient's compliance in correct medication use and adherence to the prescribed therapy.

Correct utilization of the prescribed medication is a key factor for obtaining control by medical treatment beyond several weeks (114). Second, a co-morbidity should be looked for.

For the AR patients with polyp, nasal valve dysfunction and/or malformations (e.g., septal deviation), a consensus has to be made by allergist and otolaryngologist. Li et al. (115) reported 68.9% of patients with AR had skin-prick tests positivity to more than one allergen in China. Therefore, allergen avoidance is important for the patients with positive skin prick testing and/or serum-specific IgE with symptoms when exposed to the positive allergens. It is likely that allergen immunotherapy can improve severe symptoms that are uncontrolled by medications, but more studies are required. Novel treatments are also needed.

Deficiencies and prospects

There are some limitations in this trial. First, patients were selected from one hospital consultation, but because we included response to treatment, there is no real other way in China to include and follow treated patients, private medicine being very limited. Second, the reevaluated data of rhinitis severity was acquired by telephone interview but not by a rescheduled follow-up visit to assure patients' compliance; however, the scores filled out by patient in a print scale directly under the doctors' guide were considered to be reliable. Third, similar to other trials, few patients may have had poor compliance, which may have had an influence on the final outcome.

Conclusions

Our study provides the prevalence and demographic characteristics of uncontrolled AR and SCUAD in Wuhan allergy clinic. We suggest that physicians in charge of AR patients use VAS and/or ARCT as a simple and quantitative method for the global evaluation of AR severity and response to treatment.

Patients were classified as intermittent, persistent, mild, or moderate-to-severe AR according to ARIA classification (21).

Sudy Design

The data were obtained from a prospective cohort study carried out in the allergy department of Tongji hospital, Wuhan, China, with the aim to further assess ARCT as a questionnaire driven stepwise pharmacological treatment for obtaining AR control and to describe the characteristics of the AR patients in different subgroups. (3) Impact of AR on quality of life (0-3 scale)

Patients were asked to rate the severity of impact of AR on quality of life using a scale including "0" (no impact), "1" (mild ), "2" (moderate) and "3" (severe).

(4) Concomitant diagnosed pathologies Diagnostic history include: history of asthma, history of sinus surgery and history of deviated septum surgery.

(5) Nasal examinations Nasal examinations include: nasal mucosa, nasal structure and nasal secretions.

(6) Symptoms of AR

The symptoms of AR include: rhinorrhea, sneezing, nasal congestion, nasal itching, itchy eyes, watery eyes, cough and dysosmia. ARCT every 15 days until study completed.

Outcome measures

Allergic rhinitis control test

Allergic rhinitis control test (ARCT):

ARCT is a self-completion questionnaire assessing the control of AR [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF]. It is made up of five questions scored from 1 to 5, and these individual scores are then added up to obtain a score ranging from 5 (worse score) to 25 (best score).

ARCT ≥ 20 was regarded as controlled AR [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF]. The Chinese version has been validated (53).

Grading of AR control

Grading of AR control (ARC) level: we defined several steps of AR control. ARC1: when AR was controlled without medication or with H1A as needed (Step 1); ARC2: when AR was controlled by one of the following medications taken on an every day basis: local or oral H1A

or NCS (Steps 2 and 3); ARC3: when AR was controlled by daily NCS plus H1A (combined therapy, Step 4); ARC4: when AR was controlled by oral CS (Step 5); ARC5: when AR was not controlled by any treatment at the end of the study.

Statistical analysis

Taking into account the fact that about 10% of the patients suffering from AR in Wuhan would be uncontrolled [START_REF] Wang | Prevalence of uncontrolled allergic rhinitis in Wuhan, China: A prospective cohort study[END_REF], we estimated a prevalence of controlled AR at the end of the study of 90%. We calculated a sampling error of 4% with a confidence level of 95%. A sample of at least 216 patients was required.

Qualitative variables such as demographic data and symptoms were expressed in percentages and frequencies. Quantitative data were expressed as means and standard deviations. Medians and 25th to 75th percentiles defined quantitative not normally distributed data. Comparisons for the qualitative data such as patient characteristics were carried out between groups using χ2 or Fisher's exact test for small samples. Comparisons of quantitative variables were made using the Wilcoxon-Mann-Whitney or Kruskal Wallis tests.

Following descriptive analysis, certain explanatory variables were regrouped (low number in certain groups, no statistical difference between groups). Thus, the ARC levels were redefined a posteriori in 3 groups that were: group 1 (AR controlled with no treatment or single-drug treatment daily or as needed, i.e., ARC1 and ARC2), group 2 (AR controlled by means of combined therapy, ARC3) and group 3 (AR control achieved by oral CS or uncontrolled AR, i.e., ARC4 and ARC5). A risk factor analysis was undertaken by using ordered logistic regression. However, the proportional odds assumption did not hold and therefore, a multinomial logistic model (generalized logit) was chosen. Variables with P < 0.20 in univariate analysis were introduced in the multivariate model. ) with a final level of statistical significance of P<0.05.

Ethics

The study was approved by the Independent Ethics Committee (IEC) of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China ((N o 20130907). All the participators or his/her statutory guardians had signed the informed consent to participate in the study.

Results

Patient characteristics

A total of 255 patients were recruited from the allergy department of Tongji Hospital, Wuhan, were in the subgroup ARC3; 78.6% of the patients with mild intermittent AR were in subgroup ARC1 and ARC2, which indicated that patients with severe AR needed significantly higher step treatment (P < 0.001). Similar findings were observed in other factors such as the impact of AR on quality of life (P < 0.001), the duration of AR, history of concomitant asthma, increased nasal secretions and cough (P < 0.01). Variables in bold and italics were introduced in the multivariate analysis (P < 0.20).

* Sensitization to both Dp and Df was considered as monosensitization

Risk factor analysis

Ten variables (P < 0.20, Table 6-2) were kept in the multivariate model. After adjustment on each of the variables, the only factor that remained significant was asthma. Thus, compared to non-asthmatics, asthmatics were less likely to be in a group controlled by "softer" therapy (group 3 vs. group 1: OR = 0.08, 95% CI : 0.01-0.69; group 3 vs. group 2: OR = 0.20, 95%CI :0.05-0.74). None of the other variables were significant (P > 0.05).

Predictors of achieving control

Twenty five per cent of the patients achieved control by D30 and three quarters by two months (D60) (Figure 2). After adjustment on all the potential predictors of achieving control, intermittent allergic rhinitis and low impact on QoL turned out to significantly increase the probability to achieve control at D75 from baseline (Table 3). Two other possible predictors were identified, although the proportional hazard assumption could not be confirmed for these covariables. Thus, the absence of two nasal symptoms (rhinorrhea and sneezing) was

Discussion

AR control status

Allergic rhinitis affects at least 600 million people worldwide and some studies suggest that its incidence is increasing (116). AR not only substantially affects patients' health-related quality of life but also causes reduced productivity at work and alters school performances (117). ARIA guidelines classify AR into 4 subgroups according to symptom severity and duration. However, this classification cannot meet the whole needs of AR management.

Generally very few mild AR patients will visit a doctor, which is not beneficial to the prevention of AR progression and might lead to the worsening of disease process (118).

Moreover, this classification does not take the patients' previous medication into consideration and most patients already receive medications before they see a doctor or go to hospital, which makes the standard treatment recommended by ARIA not applicable.

Accurate assessment of AR control status is critical for determining whether care is optimized and for adjusting treatment strategies to achieve control. When we designed the study, ARIA still had no clear definition of AR control, and due to the absence of uniformed criteria, pharmacotherapy adjustment regimens varies in different areas and populations (119). Despite advances in knowledge about the pathophysiology of AR and the availability of effective therapy, well controlled AR remains an elusive goal for many patients (120). Our preliminary study [START_REF] Wang | Prevalence of uncontrolled allergic rhinitis in Wuhan, China: A prospective cohort study[END_REF] indicated that more than one quarter of patients have uncontrolled AR. Thus, a simple tool to assess AR control was urgently needed in clinical practice. ARCT questionnaire has been validated in different populations [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF][START_REF] Wang | Prevalence of uncontrolled allergic rhinitis in Wuhan, China: A prospective cohort study[END_REF]. In this study, we further assessed ARCT as a questionnaire driven stepwise pharmacotherapy for AR.

ARCT driven treatmentcould achieve AR well control

Our study showed a slightly higher control rate of AR compared to the treatment regimen determined by AR severity classification in ARIA [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF][START_REF] Demoly | Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care[END_REF]. Previous published data showed that, using ARCT [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF] or a visual analog scale (41), 85% of the patients were controlled at day 15. According to the present study, only 34% of the patients could be controlled after 15 days of treatment. In published real life studies [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF][START_REF] Demoly | Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care[END_REF], the choice of treatment was left to the physician. With our prolonged and pre-defined stepped up treatment, the AR control rate elevated gradually up to 96.8% at day 75. This demonstrates that ARCT driven treatment could achieve AR well control in the majority of the patients in a step-wise manner. ARCT offers for the first time a reliable objective indicator for AR stepwise treatment. We defined a follow up period of 2 weeks, while ARIA guidelines recommend 2-4 weeks interval. Two weeks is the duration chosen to validate the sensitivity to change of patient related outcomes in AR [START_REF] Demoly | Validation of a self questionnaire for assessing the control of allergic rhinitis[END_REF][START_REF] Demoly | Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care[END_REF]. Only two patients' symptoms relapsed when controlled after only 2 weeks in conditions of high level allergen exposure (house dust mite), concomitant respiratory infection, non-compliance and other cofactors, which probably led to the overestimation of long term AR control level in our study (data not shown).

The demographic and clinical characteristics impacted AR treatment.

Our study showed several demographic and clinical characteristics that had impacts on AR treatment. Uncontrolled patients often needed more powerful medications (i.e., higher steps)

or prolonged treatment period to achieve AR control. Persistent AR patients were more difficult to achieve AR control. Patients whose qualities of life were moderately/severely impacted at inclusion needed prolonged treatment, which was similar to the study conducted in Europe (121). Patients with moderate/severe persistent AR have a greater bronchial hyperreactivity and may be more likely to suffer from asthma than those with mild intermittent AR (122). ARIA recommend oral H1A and NCS to be used to control the symptoms of moderate/severe AR [START_REF] Brożek | Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision[END_REF]. We also observed that AR associated with asthma needed more medications, confirming previous studies in which comorbidities may affect the control level of AR (123)

We evaluated the role of rhinorrhea as a possible predictor of control in the Cox model, despite some inconsistency regarding the proportional hazard assumption, mostly because of its clinical importance as a sign of rhinitis impacting the quality of life. However, as for sneezing, the results must be regarded with caution and the value of these predictors should be better assessed in studies with a different design (namely, continuous survey time, in order to avoid aggregation of data in fixed time points, as in our study, where time points were chosen in advance at D15, D30, D45, D60, D75). Patients with cough were also more difficult to get AR controlled, and we supposed that cough might be a manifestation of asthma or airway hyperreactivity (124). However, after adjustment on other variables, cough as a symptom in itself become non-significant, probably owing to the multiple mechanisms eliciting cough in AR patients (association of asthma, presence of posterior nasal drip…).

Deficiencies and prospects

According to the present study, we showed for the first time that an AR control questionnaire (namely ARCT) offers an objective criterion for the stepwise pharmacotherapy of AR. A few limitations may hamper the results. First, although opened, this study was prospective with clear predefined step-ups in case of no AR control and an imposed labelled design. We based the steps on clinical experience and published medication relative clinical impacts (125). For practicality, we did not define a step with NCS alone in our study; indeed, once a patient could not be controlled with H1A, NCS would be added but not be replaced, which could be inconsistent with ARIA. Moreover, we also found it was difficult to enrol mild intermittent AR patients, but these patients most likely do not seek for medical help. Thus, the sample size was not large enough so that the subjects in ARC1 and ARC5 were less numerous, which might lead to some other biases. Finally, we could only obtain the AR control rate according to the stepwise treatment guided by ARCT without comparison to other measurements such as VAS or RCAT. None of the available AR control tools has been used to be a criterion in AR stepwise pharmacotherapy, the first step of our study was to confirm if ARCT is qualified for AR stepwise treatment; the next step would certainly be to focus on head-to-head comparisons of others control-based tools and ARCT.

Similarly, we did not set a placebo control group in our study, because our aim was to validate the ARCT longitudinally and each patient was his/her own control. Moreover, considering the study period of our AR patients which lasted from 15 to 75 days, it would have been difficult

to add a placebo group and ascertain the compliance of patients in the placebo group. It is well known that the placebo effect has a potential influence on AR studies (126). However, the placebo effects were less than 60% in majority studies (127). While in our study, 96.8% of the patients with AR were controlled with standard stepwise treatment, which was far exceeded the effect of placebo. Therefore, we can conclude that the high efficacy was derived from the ARCT driven stepwise pharmacotherapy but not to a placebo effect.

Conclusion

The Chinese version of the ARCT questionnaire is able to evaluate the AR control level and to guide the stepwise approach for AR treatment in a large Chinese cohort. Our study suggested that the majority of AR patients can be controlled with ARCT driven stepwise standard treatment. ARCT was an accessible and effective tool to monitor the condition and control level of AR and to determine the adjustment needed for a stepwise treatment, which was beneficial to the control of AR and improvement of patients' quality of life. It prevented from under and over treatments. Independently of the usefulness of ARCT, the use of a Cox model allowed us to identify at least 2 predictors of achieving control, namely intermittent AR and low impact on QoL. With this in mind, practitioners dealing with patients with persistent AR and AR with moderate/severe impact on QoL could decide to adapt the stepwise treatment and in some cases skip one step when stepping up.

7-General discussion

New information brought

The prevalence of AR has increased in recent years worldwide. However, little epidemiological data have been published for AR in China. In this series of studies, the prevalence and demographic characteristics of uncontrolled AR and SCUAD in the Wuhan Allergy Clinic were provided. Specifically, this study indicated that VAS and ARCT are simple and quantitative methods and self-completion questionnaire that can be used for a global evaluation of the severity and control of AR. Moreover, the criteria utilized for the assessment of AR severity and control as well as the existing validated instruments were reviewed and we provide insight into their use in clinical practice. Our further study showed the Chinese version of the ARCT questionnaire is able to evaluate the AR control level and to guide the stepwise approach for AR treatment in a large Chinese cohort. The study result suggested that the majority of AR patients can be controlled with ARCT driven stepwise standard treatment.

Strength and limitations

This series of studies were prospective cohort studies. Patients consulting for AR were consecutively enrolled in the allergy department of Tongji Hospital, Wuhan, China during 1 year. All patients were prospectively assessed using questionnaire (VAS and ARCT).

Standardized treatment based on ARIA guidelines was put on. Patients were reevaluated by a telephone interview using a numerical scale and ARCT. The second study is on the basis of the preliminary study and was designed to assess ARCT as a questionnaire driven stepwise pharmacological treatment to achieve AR control. Therefore, in methodology and operability, they are reliable, objective and easy to draw practical conclusions from.

There are some limitations in the first trial. First, patients were selected from one hospital consultation, but because we included response to treatment, there is no real other way in China to include and follow treated patients, private medicine being very limited. Second, the reevaluated data of rhinitis severity was acquired by telephone interview but not by a rescheduled follow-up visit to assure patients' compliance; however, the scores filled out by patient in a print scale directly under the doctors' guide were considered to be reliable. Third, similar to other trials, few patients may have had poor compliance, which may have had an influence on the final outcome.

A few limitations may hamper the results of the second study. First, although opened, this study was prospective with clear predefined step-ups in case of no AR control and an imposed labelled design. We based the steps on clinical experience and published medication relative clinical impacts. For practicality, we did not define a step with NCS alone in our study; indeed, once a patient could not be controlled with H1A, NCS would be added but not be replaced, which could be inconsistent with ARIA. Moreover, it was difficult to enrol mild intermittent AR patients, but these patients most likely do not seek for medical help. Thus, the sample size was not large enough so that the subjects in ARC1 and ARC5 were less numerous, which might lead to some other biases. Finally, we could only obtain the AR control rate according to the stepwise treatment guided by ARCT without comparison to other measurements such as VAS or RCAT. Similarly, we did not set a placebo control group in our study, because our aim was to validate the ARCT longitudinally and each patient was his/her own control and the high efficacy was derived from the ARCT driven stepwise pharmacotherapy but not to a placebo effect.

Perspectives

According to our results, we suggest that physicians in charge of AR patients use VAS and/or ARCT as a simple and quantitative method for the global evaluation of AR severity and response to treatment. It should help the physician to control AR better. As shown in recent years, remote measurements (by phone or over the Internet) could conceivably reduce the frequency of face-to-face consultations. Applications on cellular phones (i.e., e-health technology) could help patients to manage their AR. Our study also suggested that the majority of AR patients can be controlled with ARCT driven stepwise standard treatment.

ARCT was an accessible and effective tool to monitor the condition and control level of AR and to determine the adjustment needed for a stepwise treatment, which was beneficial to the control of AR and improvement of patients' quality of life. Another study would need to be designed to assess ARCT as a questionnaire driven step-down (and not up) pharmacological treatment to achieve AR control. The results of this study can help doctors and patients understand the clinical features and control of AR in Wuhan City. A simple and quantitative method will be proposed for physicians to assess AR severity and response to treatment.

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Figure 5 - 1 Figure 5 - 2 Figure 5 - 3 Figure 5 - 4 Figure 5 - 5 Figure 5 - 6 22 Figure 5 - 7 28 Figure 5 - 8 29 Figure 5 - 9 32 Figure 5 - 10

 51525354555622572858295932510 Figure 5-1 The initial treatment20 Figure 5-2 Improvement of nasal and ocular symptoms20 Figure 5-3 Improvement of impact of allergic rhinitis on sleep, work life, and social and physical activities21 Figure 5-4 Improvement of impact of allergic rhinitis on overall discomfort21 Figure 5-5 Improvement of overall score of VAS and ARCT22 Figure 5-6 Improvement of nasal and ocular symptoms (mean ± SD)22 Figure 5-7 Comparison of score of VAS and ARCT (SCUAD vs. non-SCUAD)28 Figure 5-8 Change of the score of VAS and ARCT (SCUAD vs. non-SCUAD)29 Figure 5-9 Comparison of score of VAS and ARCT (significant improvement of symptoms vs. insignificant improvement of symptoms) 32 Figure 5-10 Change of the score of ARCT (significant improvement of symptoms vs. insignificant improvement of symptoms) 32

Figure 6 - 1 Figure 6 - 2

 6162 Figure 6-1 The control status of AR47 Figure 6-2 Graph of the survival analysis for the event "controlled AR" (probability to be uncontrolled at different time points)54

( 3 )

 3 Patients had a history of AR for at least the past 2 years; (4) Patients had a positive skin prick tests to aeroallergens and/or serum specific IgE level (sIgE ≥ 0.35KU/L, Phadia CAP System); (5) Patients had a history of AR symptoms when exposed to allergens; (6) Patients volunteer to participate in the study, and have the ability to read, understand and sign an informed consent form.

( 3 )

 3 ARIA classification Intermittent: < 4 days per week, or < 4 weeks per year; Persistent: ≥ 4 days per week, and ≥ 4 weeks per year; Mild: normal sleep, no impairment of daily activities, sport and leisure, normal work and school, no troublesome symptom; Moderate-severe (one or more items): abnormal sleep, impairment of daily activities, sport and leisure, abnormal work and school, troublesome symptom.

( 6 )

 6 ARCTARCT is a self-completion questionnaire on the control of AR validated by Demoly et al.[START_REF] Demoly | Validation of a self-questionnaire for assessing the control of allergic rhinitis[END_REF], It is made up of five questions ranging from 1 to 5, and these scores were then added up to obtain a score ranging from 5 to 25 (best score). A Chinese version of ARCT was obtained after a translation-back translation process (99).(7) AR treatmentThe standardized treatment based on ARIA guidelines was put on: oral H1A, nasal H1A, ocular H1A, oral or nasal corticosteroid (CS), Leukotriene Receptor Antagonists, (LTRAs) and other treatment.

using 2 .

 2 Comparisons of quantitative variables were made by using nonparametric Mann-Whitney U test and Wilcoxon test. Correlations between ARCT and VAS were examined using Spearman's rank test. A binary logistic regression was performed to evaluate possible risk factors for SCUAD, uncontrolled AR and insignificant improvement in symptoms. Only factors associated (P < 0.15) with the outcome were included in this model.

Figure 5 - 1 5 . 4 . 4 Figure 5 - 2

 5154452 Figure 5-1 The initial treatment (%)

Figure 5 - 3 Figure 5 - 4 Figure 5 - 5

 535455 Figure 5-3 Improvement of impact of allergic rhinitis on sleep, work life, and social and physical activities

Figure 5 - 6

 56 Figure 5-6 Improvement of nasal and ocular symptoms (mean ± SD)

Figure 5 - 7

 57 Figure 5-7 Comparison of score of VAS and ARCT (SCUAD vs. non-SCUAD)

Figure 5 - 8

 58 Figure 5-8 Change of the score of VAS and ARCT (SCUAD vs. non-SCUAD)

Figure 5 - 9 Figure 5 - 5 . 4 . 9 (ARCT ≥ 20 5. 4 . 9 . 1

 59554920491 Figure 5-9 Comparison of score of VAS and ARCT (significant improvement of symptoms vs. insignificant improvement of symptoms)

6. 2 . 2 . 1 ( 2 )

 2212 Questionnaire of ARCT-driven stepwise strategy included (1) Social, demographic and environmental data The social, demographic and environmental information include: age, sex, occupation, residential area, smoking, living condition, contact with animal allergens and duration of the rhinitis. Rhinitis graded according to ARIA Intermittent: < 4 days per week, or < 4 weeks per year; Persistent: ≥ 4 days per week, and ≥ 4 weeks per year; Mild: normal sleep , no impairment of daily activities, sport and leisure, normal work and school, no troublesome symptom; Moderate-severe(one or more items): abnormal sleep, impairment of daily activities, sport and leisure, abnormal work and school, troublesome symptom.

( 7 )

 7 Test of allergens 16 common aeroallergen sources were skin tested for all the patients and they included house dust mites (Dermatophagoides pteronyssinus, Dermatophagoides. farina), dog and cat danders, cockroach, mulberry silk, pollen (Populus, Cypress, Platanus, Artemisia, Ambrosia and Humulus) and moulds (Alternaria, Cladosporium, Aspergillus, Paecilomyces). (8) Stepwise treatment The study was designed as an open-labelled stepwise pragmatic approach for AR pharmacologic treatment derived from ARIA. Patients were evaluated and initiated with appropriate ARIA step treatment and assessed with ARCT every 15 days. Patients with a score of ARCT < 20 were considered as having uncontrolled AR (32). Patients with uncontrolled AR received step up treatment and were then evaluated 15 days later. Steps were adapted according to ARIA as follows: Step 1: local or oral non sedative H1A as needed for 15 days; Step 2: oral H1A one tablet every day, for 15 days; Step 3: oral H1A (one tablet) plus local H1A (1 puff twice) every day, for 15 days; Step 4: oral H1A (one tablet) plus nasal corticosteroid (NCS, one puff per nostril) every day, for 15 days, repeated another 15 days if control was not achieved (30 days in total); Step 5: oral CS (0.5 mg/kg once daily), for 15 days. The endpoint of the patient was ARCT ≥ 20 and maintained for 15 days or received step 5 treatment for 15 days.Once the treatment was initiated, the patients were assessed with

  Survival analysis was used to model factors that influenced achievement of control. The control state was defined as ARCT score 20. Patients who were uncontrolled by any treatment at the end of the study (day 75, D75) were right-censored. Non-parametric estimation of the survival function was performed using the Kaplan Meier estimator. The equality of survival function over strata was estimated by the log-rank test. Variables that showed differences between strata in univariate analysis (P < 0.20) and held the proportional hazard assumption were introduced into the multivariate Cox regression model. The proportional hazard hypothesis was verified using log(-log (survival)) and Schoenfeld residuals. Numerical variables were introduced in classes. Data were analysed using SPSS version 11.5 (SPSS, Inc., Chicago, IL) software and SAS (SAS ® Studio, SAS ® University edition, SAS Institute Inc.

  H1A plus NCS [and 22 (95.7%) were controlled]; 4 (1.6%) patients were prescribed oral CS (and were controlled); 216 (86.4%) patients finished the follow-up, 7 (2.8%) patients were not controlled by any treatment and finished the follow-up passively (right-censored patients) (Table6-1).

Figure 6 - 1 6 . 4 . 4

 61644 Figure 6-1 The control status of AR

  predictive (HR = 99.42, 95% CI : 5.75-1717.34, P = 0.001 and HR = 4.23, 95% CI : 1.02-17.43, P = 0.045, respectively).

Figure 6 - 2

 62 Figure 6-2 Graph of the survival analysis for the event "controlled AR" (probability to be uncontrolled at different time points)

  cursor at the position that best defines the severity of impact of AR on quality of life and mark the score in the followlling table.

1 . 2 . 3 . 4 .

 1234 Impact of AR on sleep └──┴── ┘ mpact of AR on work life └──┴── ┘ Impact of AR on social activities └──┴── ┘ Impact of AR on physical activities └──┴── ┘ Please place the cursor at the position that best defines the severity of impact of AR on overall discomfort and mark the score in the followlling table.

Please tell me the the number that best defines the severity of impact of AR on quality of life. 0 correspond to no symptoms and 10 to maximal imaginable symptoms. 1 . 2 . 3 . 4 .

 1234 according to NS Telephone interview Please tell me the the number that best defines the severity of your AR symptoms. 0 correspond to no symptoms and 10 to maximal imaginable symptoms. └──┴──┘ Please tell me the the number that best defines the severity of your AR symptoms. 0 correspond to no symptoms and 10 to maximal imaginable symptoms. Impact of AR on sleep └──┴──┘ Impact of AR on work life └──┴──┘ Impact of AR on social activities └──┴──┘ Impact of AR on physical activities └──┴──┘ Please tell me the the number that best defines the severity of impact of AR on overall

Table 5 - 1

 51 Characteristics of patients with mild and moderate/severe AR (as defined by VAS)

	at inclusion23

Table 5 - 2

 52 Characteristics of the patients in the different group at day 15 (SCUAD vs.

	non-SCUAD)26

Table 5 - 3

 53 Risk factors for SCUAD at day 1528

Table 5 - 4

 54 Characteristics of the patients in the different group at day 15 (significant improvement in symptoms vs. insignificant improvement in symptoms)[START_REF] Demoly | Assessment of disease control in allergic rhinitis[END_REF]

Table 5 - 5

 55 Risk factors for insignificant improvement of symptoms at day 1532

Table 5 - 6

 56 Comparison of characteristics of the patients with uncontrolled AR and controlled AR at day 1534

Table 5 - 7

 57 Risk factors for uncontrolled AR at day 1535

Table 5 - 8

 58 Correlations between symptoms, impact of AR, VAS and ARCT36

Table 6 - 1

 61 Distribution of patients and control according to the treatment (N) 48

Table 6 - 2

 62 Comparison of characteristics of different AR subgroups52

Table 6 - 3

 63 Predictors of achieving control at D75 from baseline55XIV

  Of 249 patients, the mean (SD) age was 32 ± (18) years, 103 (41%) were men and the mean (SD) age was 30 ± (10.9) years. Mean weight, height and BMI were respectively 58 ± (13) kg, 164 ± (10) cm and 21.3 ± (3.1) kg/m 2 . 20 patients (7.9%) were postgraduate, 95 patients (37.7%) were bachelor and 137 patients (54.4%) were under bachelor. Among them, 191 (75.8%) lived in the city, 47 (18.7%) in suburbs and 14 (5.6%) in a mountainous area.Twenty-four patients (9.5%) were smokers. All patients had a diagnosis of sensitization to aeroallergens determined by skin-prick tests (96% of patients with a documented diagnosis) and/or serum allergen-specific IgE (53.6% of patients with a documented diagnosis). The first symptoms of their rhinitis appeared at a mean of 17 years before the consultation. 38.1% presented a family history of atopy, rhinitis for 27.8%, asthma for 11.5%, atopic dermatitis for 5.2%. Similarly, 43.7% had personal history of atopic dermatitis (24.6%) and asthma (24.2%).

	Tongji Hospital during 1 year (August 2011 -June 2012). 80 patients were included during
	August 1, 2011 to October 15, 93 patients were included during October 30, 2011 -February
	28, 2012 and 79 patients were included during March 1, 2012 -June 1, 2012. Three patients

could not be contacted by telephone after 15 days and therefore 249 patients were analysed at day-15.

5.4.1 Patient characteristics

Half of them (50%) had a past history of ENT infection or antibiotics intake for respiratory infection in the last 12 months. Sneezing (99.2%), rhinorrhea (98.9%), nasal itching (96.8%), nasal congestion (92.9%), itchy eyes (88.9%) were commonly presented. Ocular symptoms were also commonly presented by most patients (65.9%), followed by nasal deformity (31.7%), rhinosinusitis (21.4%), smell disturbance (15.9%).

Table 5

 5

	-1.
	5.4.6.1 General information
	209 patients (82.9%) had moderate/severe rhinitis and 43 patients (17.1%) had mild rhinitis.
	No difference was found for age, gender, height, weight, education, residential area or
	smoking (P > 0.05). Patients with moderate/severe AR more frequently presented allergic
	conjunctivitis (70.8% vs 41.9%, P < 0.001).
	5.4.6.2 ARIA classification and the impact of AR
	There were more moderate/severe persistent AR according to ARIA in the moderate/severe

(VAS ≥ 5) group (87.6% vs. 48.8%, P < 0.001) and, in this group, there were more impacts of AR, such as sleep, work life, social activities and physical activities were significantly more common (P < 0.001).

5.4.6.3 Treatment and AR control

Treatment with NS was more frequent and the number of SCUAD was significantly greater in patients with moderate/severe AR at inclusion (P < 0.001). Patients receiving nasal antihistamines were more common in mild (VAS < 5) group (46.3 vs. 5.8%, P < 0.001). At inclusion, there were more AR patients with the score ARCT ≥ 20 in mild (VAS<5) AR group (90.2% vs. 68.8%, P < 0.05).

Table 5 -

 5 1 Characteristics of patients with mild and moderate/severe AR (as defined by VAS)

	at inclusion

Table 5 -

 5 2 Characteristics of the patients in the different group at day 15 Only factors associated (P < 0.15) with the outcome were included in this model. The variables with significance level less than 0.05 (P < 0.05) were presented in Table 5-3. Treatment with oral corticosteroid, treatment with "others" and smell disturbance were positively associated with SCUAD (OR=32.167, 6.264, 2.922, P < 0.05).

	(SCUAD vs. non-SCUAD)
		SCUAD	Non-SCUAD P value 1
	Number	61 (24.5)	188 (75.5)	-
	Age (year)	32±19.0	32±18.0	0.664
	Duration of the rhinitis (years)	16±10.5	16±10.0	0.778
	Height (cm)	165.4±7.9	163.5±10.0	0.813
	Weight (kg)	60±19.0	57.8±14.0	0.248
	BMI (kg/m 2 )	21.6±3.4	21.4±2.7	0.435
	Male gender	25 (41.0)	77 (41.0)	0.997
	Education:
	Postgraduate	8 (13.1)	12 (6.4)	0.159
	Bachelor	20 (32.8)	74 (39.4)	0.357
	Under bachelor	33 (54.1)	102 (54.3)	0.983
	Residential area:
	City	44 (72.1)	145 (77.1)	0.428
	Suburbs	14 (23.0)	32 (17.0)	0.300
	Mountainous area	3 (4.9)	11 (5.9)	1.000
	Smoking	7 (11.5)	16 (8.5)	0.487
	History of atopic dermatitis	8 (13.1)	53 (28.2)	0.017
	Family history of allergic diseases	28 (45.9)	67 (35.6)	0.152
	History of asthma	14 (23.0)	45 (23.9)	0.875
	Multimorbidity (asthma&atopic dermatitis)	2 (3.2)	16 (8.5)	0.170
	Past history of ENT infection or
	antibiotics intake for respiratory	39 (63.9)	86 (45.7)	0.014
	infection in the last 12 months
	Recurrent rhinosinusitis	15 (24.6)	38 (20.2)	0.468

Data are presented as number (percentage) or means SD, unless otherwise specified. 1 F2 and Wilcoxon-Mann-Whitney tests were used for qualitative and quantitative variables. 5.4.7.2 The risk factors for SCUAD at day 15 A binary logistic regression was performed to evaluate possible risk factors for SCUAD.

Table 5

 5

	-4 Characteristics of the patients in the different group at day 15 (significant
	improvement in symptoms vs. insignificant improvement in symptoms)
		Significant	Insignificant
		improvement in	improvement in	P value 1
	Number	symptoms	symptoms
		163 (65.5)	86 (34.5)	-
	Age (year)	32.0±17.0	32.0±17.0	0.660
	Duration of the rhinitis (years)	16.0±9.0	15.5±10.0	0.842
	Height (cm)	164±10.0	164.5±12.0	0.443

Data are presented as number (percentage) or means ± SD, unless otherwise specified 1 F2 and Wilcoxon-Mann-Whitney tests were used for qualitative and quantitative variables.

5.4.8.2 The risk factors for insignificant improvement of symptoms at day 15

A binary logistic regression was performed to evaluate possible risk factors for insignificant improvement of symptoms. Only factors associated (P < 0.15) with the outcome were included in this model. The variables with significance level less than 0.05 (P < 0.05) were presented in

Table 5

 5

	number of SCUAD was significantly greater in patients with uncontrolled AR (84.1 vs. 1.7%,
	P < 0.001) (Table 5-6).
	5.4.9.2 Risk factors for uncontrolled AR at day 15
	A binary logistic regression was performed to evaluate possible risk factors for uncontrolled
	AR. Only factors associated (P < 0.15) with the outcome were included in this model. The
	variables with significance level less than 0.05 (P < 0.05) are presented in Table 5-6.
	Impact of AR on work life (OR = 9.409), treatment with oral corticosteroid (OR = 15.772)
	and treatment with "others" (OR = 6.826) were significant risk factors for uncontrolled AR
	(Table 5-7).

-6)

. Patients with uncontrolled AR more frequently received other drugs (27.5 vs. 5.0%, P < 0.001), but less of them were being treated with anti-leucotrienes than patients with controlled AR (7.2 vs. 38.3%, P < 0.001). The

Table 5 -

 5 [START_REF] Malone | A cost of illness study of allergic rhinitis in the United States[END_REF] Comparison of characteristics of the patients with uncontrolled AR and controlled

	AR at day 15
		Controlled AR (ARCT ≥ 20)	Uncontrolled AR (ARCT < 20)	P Value 1
	Number	180 (72.3)	69 (27.7)	-
	Age (year)	32±17.0	32±18.0	0.799
	Duration of the rhinitis (years)	16±10.0	16±10.5	0.863
	Height (cm)	163±10.0	165±11.5	0.403
	Weight (kg)	57±13.8	60±17.0	0.042
	BMI (kg/m 2 )	21.3±2.7	21.7±3.4	0.093
	Male gender	71 (39.4)	31 (44.9)	0.431
	Education:
	Postgraduate	11(6.1)	9 (13.0)	0.072
	Bachelor	70 (38.9)	24 (34.8)	0.550
	Under bachelor	99 (55.0)	36 (52.2)	0.689
	Residential area:
	City	141 (78.3)	48 (69.6)	0.148
	Suburbs	28 (15.6)	18 (26.1)	0.055
	Mountainous area	11 (6.1)	3 (4.3)	0.816
	Smoking	12 (6.7)	11 (15.9)	0.024

Table 5 -

 5

	8 Correlations between symptoms, impact of AR, VAS and ARCT
			VAS (total)			ARCT
		D0	D15	Change (D15-D0)	D0	D15	Change (D15-D0)
	Nasal symptoms	0.749	0.817	0.634	-0.512	-0.816	0.428
		P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001
	Ocular symtoms	0.415	0.551	0.279	-0.496	-0.557	0.393
		P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001
	Impact of sleep	0.504	0.698	0.395	-0.734	-0.708	0.630
		P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001
	Impact of work	0.559	0.661	0.343	-0.698	-0.668	0.560
		P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001
	Social activities	0.482	0.597	0.350	-0.642	-0.628	0.522
		P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001	P<0.0001

The prevalence of AR has increased in recent years worldwide. There are many epidemiological studies of the prevalence of AR in other countries.

Bauchau

et al. (101) reported that among 9646 subjects, 19% self-identified as having AR numbered 19%, and of this group, 70% reported having a doctor diagnosis of AR. Klossek et al. (102) found that the overall prevalence of AR was 31%. China is vast in territory, it is relatively difficult to implement a large-scale epidemiological survey. Therefore, there are not enough epidemiological data of AR in China. Zhang et al. (3) reported the self-reported prevalence of AR (16-65 year old general population) in 11 major cities in China was 8.7%-24.1%, among of them, prevalence of AR in Wuhan was 19.3%. Kong et al. (103) reported the prevalence of AR in 3-6 year old children in Wuhan was 24.1%, and 10.8% were confirmed by skin tests.

Table 6

 6

	-.

Table 6

 6

	-2. Comparison of characteristics of different AR subgroups
	Number	ARC1	ARC2	ARC3	ARC4	ARC5	P
	(%)	2 (0.8)	29 (11.6)	205 (82)	6 (2.4)	8 (3.2)

History of asthma 56 (22.4) 1 (1.8) 2 (3.6) 45 (80.4) 2 (3.6) 6 (10.7) 0.001

	Nasal examinations Number of positive SPT (>2)*	56 (22.4)	-	2 (3.6)	50 (89.3)	1 (1.8)	3 (5.4)	0.138
	Abnormal nasal mucosa Df	245 (98.0) 225(90.0)	2 (0.8) 2(0.9)	28 (11.4) 24(10.7)	201 (82.0) 190(84.4)	6 (2.4) 6(2.7)	(3.3) 5(2.2)	0.633 0.109
	Abnormal structure Dp	43 (17.2) 227(90.8)	-2(0.9)	4 (9.3) 25(11.0)	37 (86.0) 187(82.4)	1 (2.3) 6(2.6)	(2.3) 5(2.2)	0.979 0.118
	Increased nasal secretions Cockroach	239 (95.6) 39(15.6)	1 (0.4) -	25 (10.5) 1(2.6)	199 (83.3) 35(89.7)	6 (2.5) -	(3.3) 3(7.7)	0.018 0.198
	Symptoms of AR Platanus acerifolia	20(8.0)	-	3(15.0)	16(80.0)	0	1(5.0)	0.766
	Rhinorrhea Artemisia sieversiana	249 (99.6) 20(8.0)	1 (0.4) 3(15.0)	29 (11.6) 15(75.0)	205 (82.3) -	6 (2.4) 2(10.0)	-	(3.2)	0.008 0.340
	Sneezing Alternaria alternate	248 (99.2) 8(3.2)	2 (0.8) -	29 (11.7) -	203 (81.9) 8(100%)	6 (2.4) -	-	(3.2)	1.000 0.766
	Nasal congestion Cat	248 (99.2) 4(1.6)	2 (0.8) -	28 (11.3) -	204 (82.3) 3(75.0)	6 (2.4) 1(25.0)	-	(3.2)	0.328 0.221
	Nasal itching Dog	242 (96.8) 3(1.2)	2 (0.8) -	29 (12.0) -	197 (81.4) 2(66.7)	6 (2.5) 1(33.3)	-	(3.3)	0.766 0.196
	Itchy eyes ARC = Allergic Rhinitis Control;	158 (63.2)	1 (0.6)	18 (11.4)	132 (83.5)	3 (1.9)		(2.5)	0.765
	Dp = Dermatophagoides pteronyssinus; Df = Dermatophagoides farinae.
	Duration of asthma (year) Watery eyes	5.2±5.1 133 (53.2)	-1 (0.8)	6.5±5.0 17 (12.8)	5.0±5.1 107 (80.5)	3.0±1.4 3 (2.3)	7.1±7.0 (3.8)	0.583 0.942
	Qualitative data: 2test; Quantitative variables: Kruskal-Wallis H test;
	History of sinus surgery Cough	9 (3.6) 94 (37.6)	-1 (1.1)	1 (11.1) 4 (4.3)	7 (77.8) 82 (87.2)	-2 (2.1)	1 (11.1) (5.3)	0.501 0.017
	History of deviated septum surgery Dysosmia	7 (2.8) 28 (11.2)	--	1 (14.3) 2 (7.1)	5 (71.4) 23 (82.1)	-2 (7.1)	1 (14.3) (3.6)	0.332 0.384
			53

Table 6 -

 6 3 Predictors of achieving control at D75 from baseline

	Variable	P-value	Hazard Ratio (95%CI)
	ARIA AR classification (intermittent vs. persistent)	<0.001	1.57 (1.17-2.11)
	Impact on QoL (low vs. moderate/severe)	<0.001	1.80 (1.24-2.61)
	Nasal secretion (absent vs. present)	0.14	1.59 (0.85-2.99)
	Sensitization to DP (absent vs. present)	0.76	0.83 (0.33-2.26)
	Sensitization to DF (absent vs. present)	0.67	0.80 (0.29-2.21)
	AR = allergic rhinitis; ARIA = allergic rhinitis and its impact on asthma;
	QoL = quality of life;
	DP = Dermatophagoides pteronyssinus; DF = Dermatophagoides farina

Acknowledgements ............................................................................ VI Acknowledgements Finally I could have a delighted time after 3 years PH.D study. I write this final part with excited, cheerful and complicated mood I have taken an interesting and unforgettable experience in Montpellier. It is a really nice city with nice people. First of all, I would like to express my gratitude to my supervisor, Professor Jean-Pierre Daurès, for his instructive suggestions and valuable comments on the writing of this thesis. I am deeply grateful of his help in the completion of this thesis. I would like to extend my sincere gratitude to my co-supervisor, Professor Pascal Demoly, for his constant encouragement and guidance. Without his invaluable help, this thesis could not have reached its present form. I have nice experience under his advising and I learn a lot of stuff from him, including how to start a scientific project, write papers as well as interact with people. I want to thank Professor Jean Bousquet, Professeur Jocelyne JUST et Docteur Isabella Annesi-Maesano, who have offered me valuable suggestions and expert guidance on my thesis. At the same time, I would like to express my heartfelt gratitude to Professor Guanghui Liu and Professor Rongfei Zhu for providing me chances to study in France. They not only have spent much time reading through each draft and provided me with inspiring advice but also took care of my daily life. Special thanks should go to my best friends in Montpellier, Anca Mirela CHIRIAC, who gave me her help and time in listening to me and helping me work out my problems during the difficult course of the thesis. Her encouragement and unwavering support has sustained me through frustration and depression. Besides, I wish to thank the Professors, teachers and my colleagues at the Department of Allergy, Hôpital Arnaud de Villeneuve: Madame Marie pascal Demoly, Dr. Jean Luc, Bourrain, Dr. Marie Lagreula, Dr. Maria Chiara Leoni, Dr. Rik Schrijvers, who have instructed and helped me a lot in the past 3 years. I also want to thank all the members in the

Abbreviations List

ACT Asthma Control Test ACQ (4) Patients had received allergen immunotherapy,or been treated with antihistamines during the last week;

(5) Patients had an infection of the upper airway and have finished necessary antibiotics intake in more than 14 days or a viral infection more than 7 day;

(6) Patients had chronic sinusitis and purulent discharge; [START_REF] Greiner | Allergic rhinitis[END_REF] Patients had a history of drug allergy;

(8) Patients had drug-induced rhinitis;

(9) Pregnant or breast-feeding women;

(10) Patients suffering from neurological or psychiatric diseases; [START_REF] Shi | Epidemiology of chronic rhinosinusitis: results from a cross sectional survey in seven Chinese cities[END_REF] Patients can not provide contact information.

Sudy Design

Sample Size Estimation

Based on published data (3), we expected a prevalence of AR in Wuhan of around 20%.

Considering a sampling error of 5% and a confidence interval of 95%, a sample of at least 246 participants was required.

Study period

The subjects were included during the following three periods:

(1) August 1, 2011 -October 15, 2011, Pollen concentration of Artemisia, Ambrosia and Humulus is higher during this period;

(2) October 30, 2011 -February 28, 2012, dust mites and mold are bleeding due to the temperature, humidity and other climatic factors change more apparent. Although patients allergic to dust mites may have symptoms throughout the year, this period is a peak.

season;

(3) March 1, 2012 -June 1, 2012, Pollen concentration of Cypress and Platanusis higher during this period.

Questionnaire of AR

The main contents of the questionnaire include: general information ( patient number, the time included and contact information); inclusion and exclusion criteria (see the section of patients); history; ARIA severity classification; AR symptom severity assessed by the score of VAS at inclusion and a Numeric Scale (NS) after 15 days; score of ARCT; AR treatment.

(1) General conditions of patients 6-Allergic Rhinitis Control Test questionnaire-driven stepwise strategy to improve allergic rhinitis control

Objectives

ARCT has been validated for assessing AR control and to identify severe AR. The present study was designed to further assess ARCT as a questionnaire driven stepwise pharmacological treatment to achieve AR control. ARCT offers an objective criterion for the stepwise pharmacotherapy of AR.

Materials and Methods

Patients

Patients consulting for AR were consecutively seen at the allergy department of Tongji Hospital, Wuhan, China during 1 year (September 2013 to August 2014).

The inclusion criteria were as follows:

(1) Over 5 years of age, male or female;

(2) With the diagnosis of AR according to ARIA and presenting clinical symptoms;

(3) Over one year history of AR;

(4) With positive skin prick tests result and serum specific IgE (sIgE ≥ 0.35KU/L, Phadia

ImmunoCAP) to at least one relevant common aeroallergen;

(5) All patients or their guardians had signed a written informed consent for anonymous data collection.

The exclusion criteria were as follows:

(1) Receiving allergen immunotherapy;

(2) With upper respiratory infection or chronic rhinosinusitis;

(3) With a history of drug allergy;

(4) Pregnancy or breast-feeding;

(5) Who have had neurological or psychiatric system diseases. Anti-leucotrienes

Research purposes

Allergic rhinitis (AR) is a common disease worldwide. The main aim of this study is to investigate the prevalence of uncontrolled AR and severe chronic upper airway disease (SCUAD) consulting in the allergy department of Tongji Hospital, Wuhan, and to describe the clinical characteristics of these patients.

Research process and methods

You will be asked to complete a questionnaire include: general information, inclusion and exclusion criteria, history; severity classification; score of symptoms and AR treatment with the help of doctors. You will follow a standardized treatment of AR. After 15 days,your symptoms will be reevaluated by a telephone interview of doctors.

Research significance

ARCT was an accessible and effective tool to monitor the condition and control level of AR and to determine the adjustment needed for a stepwise treatment, which was beneficial to the control of AR and improvement of patients' quality of life.

Privacy policy

Your privacy will be protected during the study.

Statement

Taking part in this study is completely voluntary.

Research purposes

Allergic Rhinitis Control Test (ARCT) has been validated for assessing allergic rhinitis (AR) control and to identify severe AR. The present study was designed to further assess ARCT as a questionnaire driven stepwise pharmacological treatment to achieve AR control.

Research process and methods

You will be asked to complete a simple questionnaire include: contact information, social demographic data, allergen screening, nasal cavity signs, rhinitis symptoms, history, impact on quality of life (as assessed by a 0-3 scale, 0 for none, 1 for mild, 2 for moderate and 3 for severe), concomitant diagnosed comorbidities (such as asthma) and previous AR treatments

Research significance

Department of Allergy, Tongji Hospital for their direct and indirect help to me and providing an enjoyable work environment.

Finally, I greatly appreciate my parents and husband's support and endless love. They always been helping me out of difficulties and supporting without a word of complaint.

It is interesting life in France for these 3 years. It will affect me for the whole life. It is time to say goodbye to friends and people in Montpellier. I will miss you all.