MD Chantal Raherison-Semjen

Armine Izadifar

Maud Russier

Christine Rolland

Jean-Pierre Pierre Aubert

Chantal Touboul

Delphine Leynaud

Caroline Fabry-Vendrand

Alain Didier

Self-reported asthma prevalence and management in adults in France in 2018: ASTHMAPOP survey

Keywords: Adherence, asthma control, epidemiology, management, prevalence ASTHMAPOP Respiratory Medicine and Research

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Globally, approximately 339 million people have asthma, entailing a substantial economic and clinical burden [START_REF]The Global Asthma Report[END_REF]. Asthma is a major public health concern in France too [START_REF] Delmas | Asthma in France: a review of descriptive epidemiological data[END_REF][START_REF] Doz | The association between asthma control, health care costs, and quality of life in France and Spain[END_REF][START_REF] Afrite | Asthma in France in 2006: Prevalence and Control of Symptoms[END_REF].

However, current information on the prevalence and management of asthma in adults in France is unavailable. The most recent survey in the general population in France-the 2006 French Health, Health Care and Insurance Survey (ESPS, Enquête Santé et Protection Sociale) conducted by the Institute for Research and Information in Health Economics (IRDES, Institut de Recherche et Documentation en Économie de la Santé)-reported that 6.7% of the French population self-reported having asthma at the time of the survey and 10.2% at least once in their lifetime [START_REF] Irdes | L'asthme en France en 2006: prévalence, contrôle et déterminants[END_REF]. This survey also found, based on the Global Initiative for Asthma (GINA) 2006 criteria, that 39% had controlled asthma, 46% had partially controlled asthma, and 15% had uncontrolled asthma [START_REF] Irdes | L'asthme en France en 2006: prévalence, contrôle et déterminants[END_REF]. To date, only a few studies have generated data on asthma epidemiology based on its level of severity [START_REF] Siroux | Severe asthma in the general population: definition and prevalence[END_REF][START_REF] Nordon | Clinical and economic burden of severe asthma: a French cohort study[END_REF][START_REF] Raherison | Evolution of asthma severity in a cohort of young adults: is there any gender difference?[END_REF]. Indeed, results of a French literature review that estimated the prevalence of severe asthma as 1%-3% of the general population highlighted the need to conduct further studies to assess the epidemiology of asthma in France according to severity [START_REF] Siroux | Severe asthma in the general population: definition and prevalence[END_REF]. Furthermore, a study in Europe reported the distribution of asthma severity as 58% mild, 26% moderate, and 15% severe [START_REF] Raherison | Evolution of asthma severity in a cohort of young adults: is there any gender difference?[END_REF].

The current survey, ASTHMAPOP, was conducted to collect up-to-date epidemiological data on asthma prevalence in adults in France, including the severity and burden of disease according to GINA treatment steps, and assess the level of asthma control.

Methods

Study design and population

ASTHMAPOP was a cross-sectional study, conducted in France from January 10, 2018, to February 21, 2018. The study was funded by AstraZeneca, who participated in the conceptualization and design, development of the study protocol, data interpretation, and the manuscript review. A 4-page, self-administered questionnaire (included in supplementary material S1) was mailed to people aged ≥18 years belonging to the Kantar-TNS panel [START_REF] Charles | Monitoring the obesity epidemic in France: the Obepi surveys 1997-2006[END_REF], which comprised people representative of the French population in terms of age, gender, region, and socio-economic status; no exclusion criteria were applied. The Kantar-TNS panel is adapted to general population studies, covers 20 000 households, and generally has a good response rate of approximately 75%. The main population analyzed included all people with asthma, identified based on self-report in the self-administered questionnaire; asthma

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Confidential Page 4 of 31 diagnosis was not based on physicians' assessment. The characteristics of people with asthma were described in comparison to those without asthma. Asthma was classified by treatment steps per the GINA 2017 report [START_REF]Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention[END_REF], according to prescribed treatments as declared by respondents based on a pre-established list of medications. The study was not classified as research involving human subjects and therefore did not fall under the remit of the 'loi Jardé'.

However, as of 2018, the Kantar-TNS panel was included in the "register" of the Kantar data processing activities. In addition, Kantar-TNS performed a "Data Protection Impact

Assessment" in accordance with the French Data Protection Authority (Commission Nationale de l'Informatique et des Libertés) [CNIL]; CNIL number, 117856). Written informed consent was obtained from all subjects.

Outcome measures

Primary outcomes

The prevalence of lifetime asthma in France was defined as the percentage of people who had experienced asthma at least once in their lifetime, out of the total number of respondents. The prevalence of current asthma in France was defined as the percentage of people who reported having asthma and/or receiving treatment for asthma during the 12 months before the survey (same definition as in the European Community Respiratory Health Survey [START_REF] Burney | The European Community Respiratory Health Survey[END_REF]). For the current asthma population, prevalence according to treatment step was defined as the percentage of people in each of the GINA 2017 treatment steps 1-5 (supplementary material S2).

Secondary outcomes

Secondary outcomes included a description of the profile of people with current asthma, including socio-demographic and clinical characteristics, asthma history, symptoms, and treatment, overall and by GINA treatment step. The level of asthma control was assessed via the 6-item Asthma Control Questionnaire (ACQ-6) [START_REF] Juniper | Development and validation of a questionnaire to measure asthma control[END_REF] and GINA 2017 [START_REF]Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention[END_REF] scores. The kappa coefficient was used to assess agreement between the two scores. Adherence to asthma treatment was assessed via the 4-item Morisky Medication Adherence Scale (MMAS-4) score [START_REF] Morisky | Improving the measurement of self-reported medication nonadherence: response to authors[END_REF]. Quality of life (QoL) was assessed via the 5-level version of the EuroQol 5dimensional questionnaire (EQ-5D-5L) score [START_REF]EQ-5D[END_REF]. A summary of these scales is described in supplementary material S3. Burden of disease (in terms of perception of asthma severity, registration with Affection de Longue Durée [ALD] for asthma, work/school absenteeism, and treatments used) was also described. ALD designates a long-term condition for which special medico-administrative arrangements (e.g., zero co-payment and increased reimbursement rates for drugs), based on the condition's severity, are provided in France when specific criteria are met. Asthma exacerbations were defined as episodes (several days [duration not specified in the questionnaire]) during which symptoms (cough, sputum, and dyspnea) were worse than usual.

Data collection and management

The 4-page questionnaire, a cover letter, and 2 lists of asthma medications (supplementary material S4) were sent via post to 19 676 people. Following completion, the questionnaires were returned to Kantar Health using a postage-paid envelope. All questionnaires were checked by reviewers specialized in medical studies. Data were checked for quality, per specific guidance, and then processed.

Patient and public involvement

Patients were not involved in any aspect of study design, recruitment, and conduct of the study.

Statistical analyses

To obtain a truly representative sample, the structure of the socio-demographic variables was compared with that of the French general population aged ≥18 years and weighted using raking-adjusted statistics [START_REF] Deville | Generalized raking procedures in survey sampling[END_REF] to adjust for any differences between the survey sample and the general population. Missing data were considered 'unavailable' and recorded separately as percentages. Data were analyzed using Daisie software (ADN Soft) version 2.4.82 (ADN SAS; Paris, France; http://adn-soft.com/daisie/) for descriptive and bivariate analyses. For validated scales, scoring methods were applied when questionnaires were fully answered.

The analyses were mostly descriptive. For continuous variables, means, standard deviation (SD), and median values were provided. For categorical variables, frequencies and percentages were provided. Analyses were performed globally and between subgroups (steps 1-5) using the χ 2 test [START_REF]Lesson 8: Chi-Square Test for Independence[END_REF] or the Z-test [START_REF]Z-test for independent proportions: Use & misuse[END_REF] to quantitatively compare mean data. A total of 8 tests were performed, and the Bonferroni correction was applied to take account of multiple comparisons. Therefore, the 95% significance threshold for each test was 0.00639115. The sample size was estimated based on the results of the IRDES 2006 survey that estimated the prevalence of asthma as 6.7% in France [START_REF] Irdes | L'asthme en France en 2006: prévalence, contrôle et déterminants[END_REF] and a return rate of 75%-78% observed in previous studies using this postal panel. This was considered adequate to identify and describe a sufficient number of people with asthma.

Results

Study population

Questionnaires were sent to 19 676 people, with an 81.7% return rate (n=16 083). Of the 16 083 returned questionnaires, 15 587 were analyzed after excluding incomplete or invalid questionnaires (refusal to answer, n=380; inconsistent answers related to health, n=73; less than 50% of questions answered, n=43; Fig. 1). Overall, 15 587 respondents completed the survey; 52% were female, 50% were aged 35-64 years, 37.8% were current or former smokers and 57.6% had never smoked. The sample was weighted to be representative of the French population.

Primary outcomes

In the French general adult population, the prevalence of lifetime asthma was 12.8% (95% confidence interval [CI]: 12.3%-13.3%; n=1 989) in 2018. The prevalence of current asthma in the French general adult population was 6.4% (95% CI: 6.0%-6.8%; n=993), the majority of whom (95.3%; n=946) were receiving ongoing asthma treatment (Fig. 1). The prevalence of current asthma among the various age groups and by gender is described in Fig. 2.

Among people with current asthma (n=993), 49.4% (n=491) were treated for mild asthma according to GINA step 1 or 2 (Fig. 2). The GINA treatment step was not evaluable (inhaled corticosteroids [ICS] dosage was missing) in 2.1% of people (n=21), and 4.8% of people (n=47) were receiving treatment inconsistent with a GINA step.

Secondary outcomes

Socio-demographic and clinical characteristics

The mean (SD) age of people with current asthma was 48.2 (18.1) years; the majority were women (60.5%) and never-smokers (57.6%). Among a predefined list, the most common comorbidity was allergic rhinitis (31.8%; Table 1). 3). The proportion of people with ≥1 asthma exacerbation increased from GINA steps 1 through 5 and was substantially higher in GINA steps 4 and 5. Similarly, the proportion of people with exacerbations leading to hospitalizations and/or emergency visits, was higher in GINA steps 4 and 5 compared with other steps (Table 3). GINA: Global Initiative for Asthma; N/A: not applicable; OCS: oral corticosteroids. Analyses were performed globally and between subgroups (steps 1-5) using the χ 2 test of homogeneity when the numbers were greater than or equal to 5 in every subgroup.

Patients in the category "not treated" did not report any treatments for their asthma. Therefore, "OCS courses" is listed as not applicable for this group of patients.

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Level of asthma control and adherence to treatment

Well-controlled asthma was more frequent in people in GINA step 1 than in other steps, as assessed by both ACQ-6 and GINA scores (Fig. 3). Based on GINA and ACQ-6 scores, 29.4% and 24.6% of people had partially controlled asthma, respectively, and 17.0% and 23.1% of people had uncontrolled asthma, respectively. Furthermore, when assessed using GINA and ACQ-6 scores, a high proportion of people in GINA step 4 (32.3% and 40.1%, respectively) and step 5 (23.9% and 40.4%, respectively) had uncontrolled asthma. Asthma in people in GINA step 5 was the least well-controlled per ACQ-6 scores. The kappa coefficient was 0.48, demonstrating a moderate concordance between ACQ-6 and GINA scores.

Of those taking continuous asthma controller medications and having answered all the MMAS-4 questions (n=501), 46.4% were adherent to their treatment regimen; a higher rate of adherence was observed in GINA step 4 (52.9%) and step 5 (54.6%) compared with GINA steps 1-3 (Fig. 4).

Asthma treatments and management

The majority reported having been prescribed asthma medications (mean=2.1 medications;

4.7% of people reported no treatment), with the most commonly prescribed being SABAs (70.9%) and ICS (60.5%; Table 4). Most people in GINA step 5 (76.8%) reported receiving long-term treatment with oral corticosteroids; biologics were used by 2 people (Table 4).

Overall, 28.3% of people self-reported using ≥3 SABA canisters/year. A significantly higher proportion of people using ≥3 SABA canisters/year reported asthma exacerbations, emergency visits, and hospitalizations (n=281; 65.6%, 25.0%, and 6.9%, respectively) compared with those using <3 SABA canisters/year (n=712; 40.5%, 10.0%, and 6.1%, respectively) (P<0.01 for all comparisons). Similarly, a significantly higher proportion of people using ≥3 SABA canisters/year had uncontrolled asthma (n=272) compared with those using <3 SABA canisters/year (n=697) (49.0% vs 12.0%; P<0.01) per ACQ-6 scores (supplementary material S6). However, no significant differences were observed in the proportions of people who self-reported using <3 and ≥3 SABA canisters/year in patients who were adherent or non-adherent to controller therapy (supplementary material S7). • All people reporting solely 'when needed/when symptoms' treatment (whatever the treatment) were classified in step 1;

• For people with 'daily use' of ICS, daily dose was used to classify them in the treatment steps 2-5;

• People receiving 'daily use' treatment with OCS were classified in step 5 whatever the other treatments.

During the previous 12 months, most people consulted a general practitioner for asthma (68.6%); pulmonologists and allergists were consulted less frequently (31.0% and 13.8%, respectively; supplementary material S8).

QoL and burden of disease

Overall, 57.7% and 48.9% of people with asthma reported ≥1 problem related to physical pain/discomfort and anxiety/depression, respectively. All aspects of QoL generally worsened as the GINA treatment step increased (supplementary material S9). Overall, 50.8% evaluated their general health condition as good; only 5.5% of people evaluated their asthma as severe, which was considerably lower than the severity based on combined GINA treatment steps 4 and 5 (24.4%). Of the 557 active people with asthma (i.e., those attending school or work), absenteeism of ≥1 day in the previous year was prevalent in 9.9% (supplementary material S10).

Discussion

With ASTHMAPOP, we report updated epidemiological data on adults with asthma in France in 2018. Furthermore, we describe the characteristics of people with asthma and the burden of the disease according to the GINA 2017 treatment steps, thereby providing a more comprehensive picture of the adult population with asthma in France than previous studies.

The prevalence of current asthma in our survey was 6.4%, a finding consistent with the 6.7%

prevalence rate reported by the ESPS conducted by the IRDES in 2006 [START_REF] Afrite | Asthma in France in 2006: Prevalence and Control of Symptoms[END_REF][START_REF] Irdes | L'asthme en France en 2006: prévalence, contrôle et déterminants[END_REF] and the 7.1%

prevalence rate in the IRDES 2012 study [START_REF]Enquête sur la santé et la protection sociale 2012[END_REF]. The prevalence of asthma has thus remained stable in France since 2006. Similar to the ESPS survey findings [START_REF] Afrite | Asthma in France in 2006: Prevalence and Control of Symptoms[END_REF][START_REF] Irdes | L'asthme en France en 2006: prévalence, contrôle et déterminants[END_REF], the prevalence of current asthma in our survey was numerically higher in women than in men. However, any further comparisons between the main socio-demographic and clinical characteristics We observed a difference between treatment steps described in GINA and real-world treatment patterns. However, this was not entirely unexpected since similar findings have been reported in other observational studies, highlighting poor implementation of GINA recommendations into routine clinical practice [START_REF] Baldacci | Prescriptive adherence to GINA guidelines and asthma control: An Italian cross sectional study in general practice[END_REF][START_REF] Nguyen | Implementation of GINA guidelines in asthma management by primary care physicians in Vietnam[END_REF]. Moreover, the use of GINA step stratification in observational studies poses a challenge since real-world prescriptions of asthma medications are not always in alignment with GINA recommendations which are updated on a yearly basis. After the first attempt to classify people with asthma, almost 50% of people (n=443) did not match a given GINA treatment step, necessitating a case-by-case reassignment based on the calculated daily dose of ICS and local medical practices.

Although, these results are in alignment with a survey-based study of 117 GPs, in which asthma management in France was found to lack a homogeneous, guideline-informed structure [START_REF] Dima | Asthma management in French general practice: Physician-reported medical care and adherence support[END_REF], such findings highlight the need for educational initiatives and continuing medical education to ensure that clinical practices are aligned with the latest evidence-based treatment recommendations. This is particularly important at the primary care level since most currently available guidelines are complex and generally influenced by a secondary care perspective. Interestingly, despite not being mentioned in the GINA report [START_REF]Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention[END_REF], a high proportion of patients received chest physiotherapy, likely reflective of prescribing habits in France. Although preliminary evidence suggests that physiotherapy may improve QoL, cardiopulmonary fitness, and inspiratory pressure following an exacerbation, and reduce symptoms and medication use [START_REF] Bruurs | The effectiveness of physiotherapy in patients with asthma: A systematic review of the literature[END_REF], further studies are required to confirm these findings and physiotherapy should not be used as an alternative to medical treatments. A large proportion of people with asthma (74.1%) had undergone lung function tests, presumably for diagnostic purposes. This is a considerable improvement (approximately 19%) compared with the Asthma Insights and Reality in Europe (AIRE) 1999 study, in which 55% of adults in Europe underwent a lung function test [START_REF] Rabe | Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study[END_REF]. Furthermore, a study on asthma management practices across 7 European countries showed that lung function tests were significantly more likely to be carried out in France and Germany than in the other surveyed countries, a finding that was ASTHMAPOP Respiratory Medicine and Research Confidential Page 19 of 31 attributed to differences in perceptions of disease severity and better adherence to guidelines in terms of diagnosis [START_REF] Vermeire | Asthma control and differences in management practices across seven European countries[END_REF].

The age at asthma diagnosis was higher in people with severe asthma compared with those with mild asthma, likely because asthma severity increases with age [START_REF] Zein | Asthma is more severe in older adults[END_REF].

Many people (47.6%), including 41.8% of those with mild asthma (GINA steps 1-2), experienced ≥1 asthma exacerbation in the past 12 months, and approximately 14% had ≥1 emergency visit due to asthma. The relatively high proportion of patients with exacerbations reported in our survey may be due to the definition used, defined as episodes (several days;

duration not specified in the questionnaire) during which symptoms (cough, sputum, and dyspnea) were worse than usual. Although this varied from the 2017 GINA definition [START_REF]Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention[END_REF], it effectively captures exacerbations self-managed by patients, including mild exacerbations, and, therefore, provides an overall assessment of disease burden as reported by patients.

However, the mean number of asthma exacerbations in our study of 11.7/year was similar to the frequency of asthma worsening reported in the International Asthma Patient Insight

Research (INSPIRE) study (11.8/year) [START_REF] Partridge | Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study[END_REF]. The high variability in the number of exacerbations noted in our study is partly due to the fact that exacerbations were self-reported by patients and therefore may have been inadequately reported and/or over-estimated; such results are not unexpected in survey-based research which may be subject to recall bias [START_REF] Choi | A catalog of biases in questionnaires[END_REF].

Another potential factor could have been that patients did not fully comprehend the definition of exacerbations used in this study and therefore inaccurately recorded symptoms as asthma exacerbations. Nevertheless, these findings emphasize the current challenges in asthma treatment-the need to identify exacerbations in both clinical practice and research studies and ensure their effective management to improve treatment adherence in real-life clinical scenarios and the requirement for innovative therapies to improve asthma control and decrease future risk [START_REF] Chanez | Asthma: still a promising future?[END_REF].

Overall, the average age at asthma diagnosis in the surveyed population was 25.3 years. This may be attributable to underdiagnosis of asthma, which is a well-recognized phenomenon leading to delayed diagnosis. Indeed, one of the largest studies of its kind, involving 10 000 randomly selected subjects aged 14-44 years, revealed that 67% of patients with asthma had not been previously diagnosed [START_REF] Nolte | Unawareness and undertreatment of asthma and allergic rhinitis in a general population[END_REF]. Underdiagnosis of asthma has also been attributed to a failure to recognize symptoms, misattribution of symptoms to other causes such as obesity, and a lack of symptom reporting by patients [START_REF] Kavanagh | Over-and under-diagnosis in asthma[END_REF]. However, overdiagnosis of asthma is also

well recognized resulting in non-indicated and inappropriate treatment, overuse of rescue therapy, unnecessary adverse events and delays in initiating appropriate treatment [START_REF] Aaron | Underdiagnosis and overdiagnosis of asthma[END_REF]; this could potentially account for the poor levels of asthma control and high rates of SABA use observed in our study. Moreover, the presence of comorbid conditions complicates the management of asthma. Based on a pre-defined list of comorbidities, allergic rhinitis, hypertension, and sinusitis were the most commonly reported comorbidities in this study, and in line with previously published literature [START_REF] Rogliani | The impact of comorbidities on severe asthma[END_REF], were more prevalent in patients with moderate-to-severe asthma than those with mild asthma. Of note, food allergy was also commonly reported, particularly in people at GINA step 5. This is likely attributable to the fact that the coexistence of asthma and food allergies represents a distinct asthma phenotype and is associated with more severe asthma [START_REF] Foong | Asthma, food allergy, and how they relate to each other[END_REF]. In addition, food allergies and food intolerances are often confused by patients and healthcare professionals, with an estimated one-fifth of the general population believing that they have adverse reactions to food [START_REF] Turnbull | Review article: the diagnosis and management of food allergy and food intolerances[END_REF].

This may have further contributed to the high prevalence of food allergies observed in this survey. Crucially, despite a range of available therapies, asthma control remains suboptimal, as demonstrated by the AIRE study and the Recognise Asthma and Link to Symptoms and Experience (REALISE) survey in Europe [START_REF] Rabe | Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study[END_REF][START_REF] Price | Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience ASTHMAPOP Respiratory Medicine and Research Confidential Page 28 of 31 (REALISE) survey[END_REF]. Lack of asthma control is associated with poor health and QoL [START_REF] Braido | Determinants and impact of suboptimal asthma control in Europe: the International Cross-Sectional and Longitudinal Assessment on Asthma Control (LIAISON) Study[END_REF][START_REF] Demoly | Prevalence of asthma control among adults in France, Germany, Italy, Spain and the UK[END_REF] and increased asthma-related costs [START_REF] Doz | The association between asthma control, health care costs, and quality of life in France and Spain[END_REF]. Well-controlled asthma was reported in 53.6% of people in ASTHMAPOP and uncontrolled asthma in 17.0% (based on the GINA 2017 criteria). Overall, asthma control in our survey was better compared with that reported by the European Cost of Asthma Treatment (EUCOAST) study, in which wellcontrolled asthma was observed in 40.6% of people and uncontrolled asthma in 21.4% (based on GINA 2009 criteria) [START_REF] Doz | The association between asthma control, health care costs, and quality of life in France and Spain[END_REF]. Furthermore, a post hoc analysis in people with severe asthma in France reported that uncontrolled asthma (ACQ score ≥1.5) was observed in 67% of people [START_REF] Taillé | Patients in the IDEAL cohort: a snapshot of severe asthma in France[END_REF]. This is considerably higher than that reported in our survey, in which uncontrolled asthma (based on ACQ-6 scores) was observed in approximately 40% of people in GINA step 4 or 5. However, comparisons between our survey and these studies should be interpreted with caution, given the differences in study methodology and design. The suboptimal asthma control observed in our study could also be possibly related to the preponderance of the female gender (60%) in the surveyed population. It has been previously

shown that women are more likely to volunteer information on disease symptoms and seek medical care [START_REF] Osborne | Characteristics of patients with asthma within a large HMO: a comparison by age and gender[END_REF][START_REF] Tovt-Korshynska | Gender differences in psychological distress in adults with asthma[END_REF]. Physiologically, non-specific bronchial hyperresponsiveness is found more commonly among women than men [START_REF] Manfreda | Geographic and gender variability in the prevalence of bronchial responsiveness in Canada[END_REF]. In terms of asthma control, only 69% of patients in our survey were categorized consistently across the ACQ-6 and the GINA 2017 ASTHMAPOP Respiratory Medicine and Research Confidential Page 21 of 31 assessment of asthma control. However, this is not entirely surprising given that the ACQ-6 is an ordinal scale, primarily based on symptom intensity or impact, while the GINA 2017 assessment of asthma control is a categorical scale, mainly based on symptom frequency [START_REF] O'byrne | Measuring asthma control: a comparison of three classification systems[END_REF].

In GINA step 1, approximately one-quarter reported asthma symptoms and/or using SABAs more than twice a month. This is noteworthy since GINA currently recommends the use of a controller medication in such patients [START_REF]Global Initiative for Asthma. Global Strategy for Asthma Prevention and Management[END_REF]. Our results also highlighted poor adherence (46.4%) to asthma treatment regimens. Although not observed in our survey, poor adherence to controller medication is historically related to an over-reliance on short-acting reliever medications for symptom control often at the potential expense of appropriate ICS use to reduce the underlying inflammation [START_REF] Partridge | Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study[END_REF], a finding that has been associated with poor treatment outcomes, including hospitalization and asthma-related deaths [START_REF] O'byrne | The paradoxes of asthma management: time for a new approach?[END_REF]. Moreover, patients may inappropriately adjust their medications during asthma worsening, potentially resulting in poor asthma control [START_REF] Partridge | Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study[END_REF]. This underscores the need for asthma awareness and education programs [START_REF] Cabrera | SABINA: global programme to evaluate prescriptions and clinical outcomes related to short-acting β2-agonist use in asthma[END_REF]. Furthermore, 28.3% of people in ASTHMAPOP reported using ≥3 SABA canisters/year; this is consistent with poor asthma control and is associated with a ≥2fold increase in the risk of severe asthma exacerbations [START_REF] Stanford | Short-acting β-agonist use and its ability to predict future asthma-related outcomes[END_REF]. Indeed, in line with this finding, a significantly higher proportion of people using ≥3 SABA canisters/year in ASTHMAPOP had emergency visits and hospitalizations compared with those using <3 SABA canisters/year. Overall, the underuse of ICS-containing controller medications and overuse of SABA reliever medications demonstrated in our study highlights the continued inadequate and inappropriate use of asthma medications in France, which remains a public health concern. Therefore, changes in treatment practices at all levels of healthcare systems in France should urgently align asthma management with not just the latest global evidencebased treatment recommendations, but also local treatment strategies, such as those from the Société de Pneumologie de Langue Française [START_REF] Raherison | Updated guidelines (2015) for management and monitoring of adult and adolescent asthmatic patients (from 12 years and older) of the Société de Pneumologie de Langue Française (SPLF) (Full length text)[END_REF], which also take into consideration marketing authorizations and reimbursement status of medicines in France.

Only 5.5% of participants in our survey evaluated their asthma as severe, despite 24.4% having been prescribed GINA step 4 or 5 treatment. This finding is not unexpected as several studies have reported a similar trend, with people tending to overestimate their level of asthma control and underestimate the severity of their symptoms [START_REF] Rabe | Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study[END_REF][START_REF] Price | Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience ASTHMAPOP Respiratory Medicine and Research Confidential Page 28 of 31 (REALISE) survey[END_REF][START_REF] Menzies-Gow | Perceptions of asthma control in the United Kingdom: a crosssectional study comparing patient and healthcare professionals' perceptions of asthma control with validated ACT scores[END_REF]. Indeed, results from the REALISE survey reported that more than 80% of respondents who had experienced

an acute exacerbation in the past year (oral steroid use, emergency department visits or hospitalizations) considered their asthma as well controlled, highlighting a disconnection between patients' perceptions of their asthma and guideline-defined levels of control. Indeed, evidence suggests that patients perceive asthma control as management of exacerbations, reflective of crisis-oriented disease management [START_REF] Price | Time for a new language for asthma control: results from REALISE Asia[END_REF].

Certain limitations of the ASTHMAPOP survey should be acknowledged. Well-known limitations of questionnaire data, such as recall bias, could have affected the overall results.

Although the definition of asthma was based on the definition used in epidemiological studies with a validated questionnaire, people were identified as having asthma according to selfreport and not based on a physician's diagnosis with confirmation in medical records.

However, over 97% of people with asthma reported that their asthma was confirmed by a physician. Lung function test results were not recorded, and therefore some people might not have met the GINA criteria for asthma diagnosis due to lack of objective evidence of variable expiratory airflow limitation. In addition, results may have been confounded by the fact that approximately 15% of patients were smokers which could have influenced outcomes since it has been well established that smokers with asthma have worse asthma control than nonsmokers with asthma [START_REF] Polosa | Smoking and asthma: dangerous liaisons[END_REF]. Furthermore, approximately 15% of patients also had selfreported COPD, suggesting that a small proportion of patients may have had asthma-COPD overlap syndrome; this may have influenced results because such patients are known to experience greater impairment to their health status and higher exacerbation burden than those with asthma alone [51]. Furthermore, although based on pre-established treatment lists, therapeutic management was declarative, the perception of disease and symptoms is generally biased in a declarative survey as patients tend to incorrectly perceive their asthma control levels in real life [START_REF] Menzies-Gow | Perceptions of asthma control in the United Kingdom: a crosssectional study comparing patient and healthcare professionals' perceptions of asthma control with validated ACT scores[END_REF]. The definition of exacerbations reported in our survey does not match severe exacerbations defined in clinical studies, but perhaps more closely reflects the burden of asthma among patients. Additionally, information on comorbidities was not checked against medical records.

Despite these limitations, ASTHMAPOP is the most recent survey in France since 2006 to collect epidemiological data on asthma, using a nationally representative sample.

Additionally, this study provides a comprehensive overview of the adult population with asthma in France because it also includes findings for health-related QoL and treatment adherence. Based on our findings, future directions for research include assessing the effect

of body mass index, comorbidities (and factors that may influence the impact of comorbidities, such as age and smoking), allergen immunotherapy usage, access to specialist care, frequent spirometry evaluations, MMAS score, and access to ALD on disease severity, control, and outcomes.

Conclusions

The prevalence of asthma in France has remained stable since 2006 and was 6.4% in 2018. A large proportion of people reported having undergone lung function tests, presumably for diagnostic purposes. However, the levels of asthma control and treatment adherence were relatively poor. Many people, including those with mild asthma, reported having experienced asthma exacerbations. These findings underscore the fact that asthma management in France requires improvement. ). After the first classification, 443 people could not be categorized as belonging to a specific GINA treatment step. After a second reassignment, based on the calculated daily dose of ICS, 174 people could not be categorized as belonging to a specific GINA treatment step. Finally, a case-by-case assessment based on medical practice allowed for classification of most of the people; the GINA treatment step was not evaluable (i.e., ICS dosage was missing or inconsistent with a GINA treatment step) in 2.1% of people (n=21), and 4.8% of people (n=47) reported receiving a treatment inconsistent with a GINA step (i.e., the treatment combination could not be classified per a GINA treatment step).

GINA: Global Initiative for Asthma; ICS: inhaled corticosteroids.

Figure 1 Figure 2

 12 Figure 1 Prevalence of asthma in France in 2018

Figure 3

 3 Figure 3 Assessment of asthma symptom control according to ACQ-6 and GINA scores. a) Distribution of people according to ACQ-6 score, stratified by 2017 GINA treatment step (n=969). b) Distribution of people according to GINA scores, stratified by 2017 GINA treatment step (n=811). c) Distribution of people according to ACQ-6 and GINA scores among people who responded to both questionnaires (n=799)

Figure 4

 4 Figure 4 Adherence to treatment regimen. a) Distribution of people taking continuous asthma medications who answered all MMAS-4 questions (n=501). b) Distribution of fully adherent people stratified by 2017 GINA treatment step

Table 1

 1 Socio-demographic and clinical characteristics of people with and without asthma

Socio-demographic or clinical characteristic People with current asthma, % (n=993) People without asthma, % (n=14 594) Gender

  Comorbidities, such as hypertension, chronic obstructive pulmonary disease, cardiac diseases, gastro-esophageal reflux disease, and osteoporosis, were considerably higher in people in GINA steps 4-5 than in other GINA steps (Table2). Overall, 23.7% of all people

	ASTHMAPOP
	Respiratory Medicine and Research		Confidential	Page 10 of 31
	Normal (18.5-24.9) Mean number without	40.5	47.0
	Overweight (25.0-29.9) allergic comorbidities (SD);	28.2 2.0 (1.2); 1.0	30.9 1.6 (0.9); 0.8
	Obese (30.0-39.9) median	24.4	16.0
	Mean (SD); median	26.7 (5.9); 25.7	25.6 (6.1); 24.8
	Women Frequency of physical	60.5	51.6
	Men activity	39.5	48.4
	Age, years Twice a week or more	39.5	40.9
	18-24 Once a week	11.3 18.4	9.8 20.7
	25-34 Less than once a week	16.8 18.6	15.2 17.5
	35-49 Never	24.7 21.5	25.1 19.4
	50-64 Comorbidities	25.7	24.9
	≥65 Allergic rhinitis	21.5 31.8	25.0 6.4
	Mean (SD); median Hypertension	48.2 (18.1); 46.9 19.2	49.6 (18.1); 48.9 15.7
	Long-lasting condition (ALD) a Chronic bronchitis/ COPD/emphysema	14.1	1.3
	Yes Eczema/other skin allergies	30.8 13.7	18.1 4.2
	Yes, for asthma Yes, for another disease Gastro-esophageal reflux disease	13.6 24.4 12.7	0.2 18.1 5.7
	No Anxiety/depression	67.7 12.1	80.6 6.7
	SPC Sinusitis	11.0	2.1
	SPS+ Diabetes	25.7 8.7	28.2 6.4
	SPS-Hypercholesterolemia	30.4 7.8	28.7 6.6
	Inactive Food allergies	43.9 7.3	43.2 1.3
	Monthly income, € Cardiac diseases	7.3	4.8
	≤1 500 Obstructive sleep apnea	25.5 6.1	16.3 2.7
	1 501-3 000 Osteoporosis	44.8 4.4	45.9 3.0
	>3 000 Glaucoma	29.7 3.5	37.6 2.3
	Tobacco status Cataract	3.3	2.4
	Former smoker Nasal polyposis	23.1 2.1	23.6 0.3
	Current smoker Never-smoker Mean number of comorbidities (SD); median	15.5 57.6 2.4 (1.6); 1.5	14.1 59.6 1.7 (1.0); 0.9
	BMI, kg•m -2
	Underweight (<18.5)	3.7	3.7

with asthma received chest physiotherapy and vaccinations against influenza and pneumococcus were more frequent in people in GINA steps 4-5 (supplementary material S5).

ALD: An Affection de Longue Durée; BMI: body mass index; COPD: chronic pulmonary disease; SD: standard deviation; SPC. Socio-professional category; SPS+: Farmer/Trader, Craftsman/Entrepreneur, Senior manager, liberal profession/Intermediate profession, Foreman; SPS-: Employee, Services/Worker.

Table 2

 2 Prevalence of comorbidities in people with current asthma, according to 2017 GINA treatment step Asthma history and symptoms Most people (97.1%) reported receiving an asthma diagnosis from a physician, with lung function tests performed in approximately 74% of people. The mean age at asthma diagnosis was 25.3 years and was higher for people in GINA steps 4-5 (supplementary material S5).

		Not	Step 1	Step 2	Step 3	Step 4	Step 5
		treated % (n=47)	% (n=435)	% (n=56)	% (n=145)	% (n=209)	% (n=33)	P value
	Comorbidities
	Allergic rhinitis	28.1	33.1	41.6	27.8	31.0	43.2	0.267
	Hypertension	13.4	12.0	12.8	24.2	28.2	30.3	<0.00001
	Chronic bronchitis/ COPD/emphysema	0	6.3	7.0	12.6	27.4	28.3	N/A
	Eczema/other skin allergies	6.6	15.0	16.4	6.8	18.7	11.8	N/A
	Gastro-esophageal reflux disease	8.2	10.5	12.3	15.2	15.1	27.4	0.0469
	Anxiety/depression	6.9	11.2	12.6	8.6	13.5	28.4	0.043142
	Sinusitis	11.6	8.5	6.9	8.7	14.6	21.2	N/A
	Diabetes	12.5	4.7	5.5	12.8	11.6	9.8	N/A
	Hypercholesterolemia	6.7	5.6	1.0	13.3	10.0	7.4	N/A
	Cardiac diseases	7.5	3.0	1.2	9.1	13.0	10.3	N/A
	Food allergies	0	7.3	13.1	5.0	6.9	22.3	0.016895
	Obstructive sleep apnea	1.2	3.0	5.0	6.4	9.9	19.8	N/A
	Osteoporosis	0	2.1	10.2	4.9	4.0	16.1	0.000217

COPD: chronic obstructive pulmonary disease; GINA: Global Initiative for Asthma; N/A: not applicable; SD: standard deviation.

Analyses were performed globally and between subgroups (steps 1-5) using the χ 2 test of homogeneity when the numbers were greater than or equal to 5 in every subgroup.

Overall, 47.6% of people reported ≥1 asthma exacerbation in the past 12 months (including 41.8% with mild asthma), with a mean (SD) of 11.7 (43.8) exacerbations/year (median=2.0); 14.3% of people had ≥1 emergency visit and 3.1% had ≥1 hospitalization due to asthma (Table

Table 3

 3 Asthma exacerbations, emergency consultations, and OCS use during the previous 12 months, according to 2017 GINA treatment

	step
		People	Not treated	Step 1	Step 2	Step 3	Step 4	Step 5
		with
		current (n=993) asthma %	% (n=47)	(n=435) %	% (n=56)	% (n=145)	% (n=209)	% (n=33)	P value
	≥1 asthma exacerbation	47.6	30.6	41.6	43.4	46.2	61.6	65.4	0.000017
	No asthma exacerbation	51.7	66.7	57.5	56.6	53.8	38.0	34.6
	People with ≥1 asthma exacerbation	n=472	n=14	n=181	n=24	n=67	n=129	n=22
	1 asthma exacerbation	26.1	15.6	32.7	37.8	30.2	20.8	7.6	N/A
	2 asthma exacerbations	21.5	23.6	21.7	22.1	26.2	18.1	19.7	N/A
	3-6 asthma exacerbations	28.4	22.3	26.8	16.5	26.1	29.1	48.4	N/A
	≥7 asthma exacerbations	19.2	34.6	16.7	17.2	10.8	23.8	24.2	N/A
	≥1 emergency visit	14.3	5.2	7.8	10.9	12.7	25.5	39.0	N/A
	≥1 hospitalization	3.1	0	1.4	0	3.4	4.4	12.4	N/A
	OCS courses	14.5	N/A	15.0	11.4	10.2	21.9	20.3	N/A

Table 4

 4 Profile of asthma therapy, according to 2017 GINA treatment step

		People with	Step 1	Step 2	Step 3	Step 4	Step 5
		current
		asthma % (n=993)	% (n=435)	% (n=56)	% (n=145)	% (n=209)	% (n=33)
	ICS-based therapy	60.5	35.9	67.3	100	100	84.1
	ICS alone (no	12.8	14.1	60.1	12.9	2.4	14.6
	LABA)
	ICS + LABA	3.1	1.0	2.8	6.9	6.5	1.7
	(separate inhalers)
	ICS + LABA	44.6	20.8	4.4	80.2	91.1	67.8
	(fixed combination)
	LABA	51.4	23.0	7.3	87.1	97.6	73.2
	LTRA	14.9	2.6	50.3	18.4	30.0	21.9
	LAMA	10.0	1.4	1.4	7.6	18.9	24.8
	LABA/LAMA	4.1	0.6	1.4	2.9	5.3	14.1
	SABA	70.9	86.1	72.7	59.3	66.0	74.3
	OCS	16.9	15.0	11.4	10.2	21.9	84.7
	Long-term therapy	2.7	N/A	N/A	N/A	N/A	76.8
	≥1 burst	14.5	15.0	11.4	10.2	21.9	20.3
	Number of treatments
	Mean (SD)	2.1 (1.2) 1.6 (0.9) 2.1 (0.9) 2.1 (0.9) 2.6 (1.2) 4.0 (2.2)
	Median	1.3	0.8	1.5	1.6	2.0	3.0
	GINA: Global Initiative for Asthma; ICS: inhaled corticosteroids; LABA: long-acting
	β2-agonist; LAMA: long-acting muscarinic antagonist; LTRA: leukotriene receptor
	antagonist; N/A: not applicable; OCS: oral corticosteroids; SABA: short-acting β2-agonist;
	SD: standard deviation.

Note: A treatment list was provided. Patients were asked to report each treatment prescribed and if it was for 'daily use' or 'when needed/when symptoms'; daily dosage was also reported.

Acknowledgments

Medical writing support was provided by Sudha Korwar, PhD, Steven Tresker, and Saurabh Gagangras, all of Cactus Life Sciences (part of Cactus Communications), which was funded by AstraZeneca in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

Funding

AstraZeneca funded the ASTHMAPOP survey and was involved in the survey concept and design, developing the study protocol and data interpretation. AstraZeneca reviewed the manuscript prior to submission and funded the medical writing support.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Contributors