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Asthma burden according to treatment steps in the French population-based cohort CONSTANCES

Open AccessPublished:November 24, 2022DOI:https://doi.org/10.1016/j.rmed.2022.107057

      Highlights

      • Several studies worldwide assessed the prevalence of asthma, its associated comorbidities, but data on the economic burden of asthma in France are rare and old.
      • An actual and precise estimate of [
        • Soriano J.B.
        • Kendrick P.J.
        • Paulson K.R.
        • et al.
        Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the global burden of disease study 2017.
        ] the cost of asthma in France globally and per resource used and [
        • Masoli M.
        • Fabian D.
        • Holt S.
        • Beasley R.
        Global Initiative for Asthma (GINA) Program
        The global burden of asthma: executive summary of the GINA Dissemination Committee report.
        ] its burden in terms of symptoms and comorbidities, overall and by treatment step.
      • The results provide a basis for estimations of the impact of clinical care and health programs on costs, which can inform decision-makers and guidelines developers.

      Abstract

      Background

      Data on health care consumption and costs of asthma in the French population are scarce.

      Objectives

      The study objective was to describe the burden of asthma according to GINA treatment steps in the CONSTANCES cohort.

      Methods

      Data from 162,725 participants included between 2012-2019 were extracted. Participants were considered as current asthmatics if asthma was reported at inclusion and asthma symptoms and/or treatments were reported in 2019. Participants were classified in three categories according to GINA treatment steps. The results were compared to non-asthmatic participants matched with a propensity score calculated on age, sex, region of residence, precariousness score and year of inclusion.

      Results

      Among 162,725 participants aged 18–69 years, 6783 asthmatics (1566 not treated for asthma, 2444 + 251 GINA steps 1 + 2, 1054 + 1315 GINA steps 3 + 4, and 153 GINA step 5) were matched with 6783 controls. Average annual ambulatory cost and average annual hospitalization cost were respectively €1925 and €719 for asthmatics versus €1376 and €511 for participants without asthma (p < 0,0001). Cardiovascular risk factors, co-morbidities, visits and hospitalizations were higher for asthma participants as compared to controls and increased with GINA steps, as well as inpatient and outpatient costs. However, for cardiovascular risk factors and co-morbidities, differences were non-significant in multivariate analyses. Pharmacy costs were ten times higher for GINA step 5 participants than for GINA steps 1–2 participants: €3187 versus €393 (p < 0,0001).

      Conclusion

      mean cost of asthma was estimated at €757 per patient/year and increased with GINA treatment step.

      Keywords

      List of abbreviations

      ATS
      American Thoracic Society
      BMI
      Body Mass Index
      CNIL
      Commission Nationale de l’Informatique et des Libertes
      CNIS
      Conseil National de l’Information Statistique
      CNOM
      National Medical Council (Conseil National de l’Ordre des Médecin)
      COBRA
      Cohorte Obstruction Bronchique et Asthme
      EGB
      échantillon généraliste des bénéficiaires
      ERS
      European Respiratory Society
      FEV
      Force Expiratory Volume
      FEV1
      Forced expiratory volume in 1 second
      GINA
      Global Initiative for Asthma
      HPCS
      Health Prevention Centres
      ICS
      inhaled corticosteroids
      INSERM
      Institutional Review Board of the National Institute for Medical Research
      LABA
      long-acting beta agonist (LABA)
      LAMA
      long-acting muscarinic antagonist
      LTRA
      Leukotriene receptor antagonists
      OCS
      oral corticosteroids
      SABA
      short-acting beta-agonist
      SD
      Standard deviation
      SNDS
      French hospital and claims database
      USA:
      Unites States of America

      1. Introduction

      Asthma is a serious global health problem that affects an estimated 273 million persons worldwide [
      • Soriano J.B.
      • Kendrick P.J.
      • Paulson K.R.
      • et al.
      Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the global burden of disease study 2017.
      ] and may raise by 2025 with an additional 100 million subjects [
      • Masoli M.
      • Fabian D.
      • Holt S.
      • Beasley R.
      Global Initiative for Asthma (GINA) Program
      The global burden of asthma: executive summary of the GINA Dissemination Committee report.
      ]. Reports on asthma prevalence and disease characterization have revealed wide variations within and between countries [
      • Rabe K.F.
      • Adachi M.
      • Lai C.K.
      • Soriano J.B.
      • Vermeire P.A.
      • Weiss K.B.
      • Weiss S.T.
      Worldwide severity and control asthma in children and adults. The global Asthma and Insights and Reality surveys.
      ,
      • Cisternas M.G.
      • Blanc P.D.
      • Yen I.H.
      • Katz P.P.
      • Earnest G.
      • Eisner M.D.
      • Shiboski S.
      • Yelin E.H.
      A comprehensive study of the direct and indirect costs of adult asthma.
      ]); thus, assessing the burden of asthma can be challenging. In France, the prevalence of current asthma in 2018 was estimated between 6.4 and 9.3% depending on the definition and the study ([
      • Raherison-Semjen C.
      • Izadifar A.
      • Russier M.
      • et al.
      Prévalence et prise en charge de l’asthme de l’adulte en France en 2018 : enquête ASTHMAPOP.
      ,
      • Tsiavia T.
      • Henny J.
      • Goldberg M.
      • Zins M.
      • Roche N.
      • Orsi L.
      • Nadif R.
      Blood inflammatory phenotypes were associated with distinct clinical expressions of asthma in adults from a large population-based cohort.
      ]).
      Notwithstanding that asthma-related hospitalizations and deaths have declined in some countries [
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ], the overall burden for patients from frequent exacerbations and day-to-day symptoms has augmented by almost 30% in the past 20 years [
      • Vos T.
      • Flaxman A.D.
      • Naghavi M.
      • et al.
      Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ]. The identification of comorbidities is essential to achieve an optimal control of asthma and is now an integral part of the management.
      Despite the stability of asthma prevalence in France since 2006 [
      • Delmas M.C.
      • Bénézet L.
      • Ribet C.
      • Iwatsubo Y.
      • Provost D.
      • Varraso R.
      • Zins M.
      • Leynaert B.
      • Nadif R.
      • Roche N.
      Prévalence de l’asthme chez l’adulte en France, données de la cohorte Constances [Prevalence of asthma among adults in France, data from the Constances cohort study].
      ], data on its economic burden are rare and old. The CONSTANCES cohort, which is a large sample of the general French adult population, offers the unique opportunity to better understand the economic and clinical burden of asthma in patients living with the disease.
      The objectives of this study were to describe the healthcare burden in patients with asthma in France, in terms of symptoms, comorbidities, healthcare consumptions and related costs globally and according to GINA treatment steps.

      2. Methods

      We used data from the CONSTANCES cohort to identify participants with current asthma and controls without ever-asthma. The CONSTANCES cohort is a randomly sample of 220,000 French adults aged 18–69 years at inception [
      • Zins M.
      • Goldberg M.
      CONSTANCES team
      The French CONSTANCES population-based cohort: design, inclusion and follow-up.
      ]. At inclusion, the selected participants were invited to fill out a self-administered questionnaire and undergo a comprehensive health examination at one of the participating Health Prevention Centres (HPCs). The follow-up includes an annual self-administered questionnaire, and a 4-year periodic visit to an HPC. Individual data is connected to the French hospital and claims database (SNDS) which provides additional information.

      2.1 This cohort study collects information from

      • Case report forms completed by the physicians at the date of the participants inclusion in the cohort and at each 4-year periodic visit thereafter.
      • Laboratory and other paraclinical tests including electrocardiogram and spirometry at inclusion and at 4-year periodic visits.
      • Self-questionnaires filled out by the participants at inclusion and every year thereafter.
      • Data collected from the French hospital and claims database (SNDS) that list all outpatient and inpatient healthcare consumptions.
      Two groups of participants from the CONSTANCES cohort were selected to perform the present study:
      • 1.
        Those diagnosed with asthma at inclusion who, in 2019 (when the respiratory questionnaire was filled in by all included participants), reported asthma symptoms or received a delivery of asthma drug in the past 12 months (current asthma).
      • 2.
        Those with never asthma at inclusion, selected from the never-asthmatic group by 1:1 matching using a propensity score based on the following variables: age, gender, year at inclusion in the cohort, region of residence and EPICES score (Evaluation of Deprivation and Inequalities in Health Examination Centers
        The EPICES score is directly available in the Constances database and is calculated with 11 questions related to social characteristics of the subjects.
        ).
        2The EPICES score is directly available in the Constances database and is calculated with 11 questions related to social characteristics of the subjects.
      The index date was when each participant completed the asthma symptoms questionnaire in 2019.
      For each eligible participant, information was extracted from the CONSTANCES cohort database on sociodemographic characteristics, cardiovascular risk factors, comorbidities documented by the physician at inclusion, paraclinical tests (eosinophil cells count, spirometry) performed at inclusion, health behavior (smoking and physical activities), healthcare consumptions in the year prior to the index date. Health resource consumptions and costs in the year prior to the index date were collected from the SNDS. For the calculation of the theoretical value of the FEV1, the Global Lung function Initiative equations [

      Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative. https://doi.org/10.1183/09031936.00080312.

      ] were used.
      Current asthmatics were classified according to GINA treatment steps (no treatment, Step 1–2, Step 3–4 and Step 5) based on drug treatments identified through the SNDS claims database.
      GLOBAL INITIATIVE FOR ASTHMA. Global Strategy for Asthma Management and Prevention. Update August 2017. http://ginasthma.org/download/317/.
      We considered drugs delivered in the past 3 months before the index date, except for short-acting beta agonists (SABA), for which we considered a delay of 18 months before the index date.
      All statistical analyses were performed using SAS© software Version 9.4 (Cary, USA). Bivariate analyses were performed using Chi2 tests to assess qualitative variables with Yates continuity correction or Fisher's exact test for sample sizes less than 5. For quantitative variables, a Student's t-test or analysis of variance was performed when distribution was close to normal; otherwise, non-parametric tests including Wilcoxon and Kruskal-Wallis were used.
      Within the asthmatic population, a logistic regression was performed to identify factors associated with comorbidities, risk factors and health behaviours across GINA step groups, adjusting for age, gender, socio-professional category, academic degree, marital status, income and the EPICES score.
      Costs were calculated from a societal perspective.
      The CONSTANCES Cohort project has obtained the authorization of the National Data Protection Authority on March 3, 2011 (Commission Nationale de l’Informatique et des Libertes—CNIL, authorisation no.910486). CONSTANCES was approved by the National Council for Statistical Information (Conseil National de l’Information Statistique—CNIS), the National Medical Council (Conseil National de l’Ordre des Médecins—CNOM), and the Institutional Review Board of the National Institute for Medical Research-INSERM (authorisation no. 01–011). All participants signed a written informed consent.

      3. Results

      Fig. 1 depicts the flowchart of patients with asthma and never asthma controls. Among the 162,725 cohort participants at the time of data extraction, 15,586 (9,6%) were diagnosed with asthma by a physician at inclusion. About half (45%, n = 7017) reported asthma symptoms and/or had a claim for a drug delivery for asthma in the past 12 months prior to inclusion. Finally, 6783 patients with asthma were included in the analysis and matched with 6783 never asthma controls. The GINA treatment steps could be determined for 5217 patients who had deliveries of asthma drugs (the treatment scheme did not correspond to any GINA step for 165 patients and 1566 patients did not have any delivery of asthma treatments in the past 12 months).
      Table I displays the proportions of patients with asthma who had an anti-asthma drug delivery in the past 3 months prior to the index date (18 months for SABA). As expected, higher proportions of asthmatics had a delivery of inhaled corticosteroids, long-acting beta-agonists, long-acting anti-muscarinic agents, oral corticosteroids, and leukotriene receptor antagonists in GINA steps 3–5.
      Table 1Asthma treatments deliveries in the past 3 months (3m) or 18 months (18m) prior to inclusion.
      Step 1 and 2

      N (%)
      Step 3 and 4

      N (%)
      Step 5

      N (%)
      p-value
      Population2695*2369*153*
      ICS (3m)69 (2.6)2369 (100.0)146 (95.4)<0.0001
      LAMA (3m)- -117 (4.9)111 (72.5)<0.0001
      LABA (3m)- -2084 (88.0)142 (92.8)<0.0001
      LTRA (3m)181 (6.7)370 (15.6)54 (35.3)<0.0001
      Anti-IGE mAb (3m)- -- -17 (11.1)<0.0001
      OCS (3m)292 (10.8)477 (20.1)75 (49.0)<0.0001
      Continuous OCS (3m)- -- -43 (28.1)<0.0001
      SABA (3m)565 (21.0)887 (37.4)77 (50.3)<0.0001
      SABA (18m)2604 (96.6)1590 (67.1)124 (81.0)<0.0001
      Theophylline (3m)1 (0.0)2 (0.1)5 (3.3)<0.0001
      Participant treated for asthma (3m) OR treated by SABA (18m)2695 (100.0)2369 (100.0)153 (100.0)<0.0001
      1566 participants had no treatment in the past 18 months and were not included in any treatment steps.
      ICS: inhaled corticosteroids, OCS: oral corticosteroids, LAMA: long-acting muscarinic antagonist, LABA: long-acting beta-agonist, LTRA: Leukotriene receptor antagonists, SABA: short-acting beta-agonist, Anti-IGE mAb: anti-IGE monoclonal antibody.
      Table III delineates the sociodemographic characteristics, results of paraclinical tests and health behaviors of patients with asthma and never asthma controls. The mean age of patients with asthma was 48.1 years, 55.4% were females, and 1096 (16.2%) had a full coverage for a severe chronic disease (asthma or another condition) in 2019 as compared to 794 never asthma controls (11.7%). A FEV1/FVC ratio <70% and a predicted FEV1 < 80% were respectively reported for 18.8% and 20.9% of patients with asthma compared to 4.5% and 4.5% for the never asthma group. A blood eosinophil count >300/mm3 was documented for 31.9% of patients with asthma and 12.2% of never asthma controls. More patients with asthma had a BMI >30 compared to never asthma controls. The proportions of current and ex-smokers were similar in both groups. Mean age at inclusion, proportions of participants with an altered pulmonary function and a blood eosinophil count >150/mm3 increased with GINA steps. The socioeconomic status of patients with asthma deteriorated with higher GINA steps as shown by increased EPICES score. In addition, the proportion of participants with a postgraduate degree decreased from step 1–2 to step 5. Finally, the proportion of patients with a BMI >30 increased from step 1–2 to step 5.
      Several comorbidities (hypertension, hypercholesterolemia, type 2 diabetes, ischemic coronary heart disease, chronic bronchitis/emphysema, depression, and suicide attempt) were significantly more frequent among patients with asthma (Table II). These frequencies significantly increased with GINA steps; however, the differences decreased and became non-significant after adjustment for potential confounding factors (age, gender, socio-professional category, academic degree, marital status, income, EPICES score) (Fig. 2).
      Table 2Sociodemographic characteristics, paraclinical tests and health behaviors.
      Never asthma controls

      N (%)
      Asthma patients

      N (%)
      p-valueStep 1 and 2

      N (%)
      Step 3 and 4

      N (%)
      Step 5

      N (%)
      p-value
      Population678367832695
      1566 participants had no treatment in the past 18 months and were not included in any treatment steps; NA: no answer.
      2369
      1566 participants had no treatment in the past 18 months and were not included in any treatment steps; NA: no answer.
      153
      1566 participants had no treatment in the past 18 months and were not included in any treatment steps; NA: no answer.
      Age at inclusion in the cohort CONSTANCES44.6 (13.2)45.2 (13.4)0.0242.3 (12.8)49.0 (13.3)56.4 (11.0)<0.0001
      18–29 years609 (9.0%)574 (8.5%)0.07515 (19.1%)212 (8.9%)5 (3.3%)<0.0001
      30–39 years1625 (24.0%)1617 (23.8%)747 (27.7%)452 (19.1%)8 (5.2%)
      40–49 years1734 (25.6%)1639 (24.2%)664 (24.6%)530 (22.4%)23 (15.0%)
      50–59 years1275 (18.8%)1276 (18.8%)443 (16.4%)524 (22.1%)46 (30.1%)
      60–75 years1540 (22.7%)1677 (24.7%)326 (12.1%)651 (27.5%)71 (46.4%)
      Sex0.1678
      Male3001 (44.2)3023 (44.6)0.70381157 (42.9)1087 (45.9)71 (46.4)
      Female3782 (55.8)3760 (55.4)1538 (57.1)1282 (54.1)82 (53.6)
      EPICES score (mean, SD)15.3 (17.2)16.5 (17.4)<0.000116.2 (17.1)17.2 (18.1)25.6 (20.5)<0.0001
      Postgraduate degree4113 (60.6)4095 (60.4)0.80001677 (62.2)1293 (54.6)42 (27.5)<0.0001
      Full reimbursement coverage for a long-term disease in 2019794 (11.7%)1096 (16.2)<0.0001340 (12.6)495 (20.9)98 (64.1)<0.0001
      Full reimbursement coverage for a long-term disease in 2019 with diagnosis of Asthma J45200 (2.9)<0.000135 (1.3)121 (5.1)36 (23.5)<0.0001
      FEV1/FVC ratioNA = 1676NA = 1606NA = 601NA = 611NA = 57
      <70%230 (4.5)975 (18.8)<0.0001289 (13.8)469 (26.7)46 (47.9)<0.0001
      ≥70%4877 (95.5)4202 (81.2)1805 (86.2)1289 (73.3)50 (52.1)
      Predicted FEV1%NA = 1676NA = 1587NA = 594NA = 607NA = 55<0.0001
      <80%230 (4.5)1084 (20.9)<0.0001357 (17.0)490 (27.8)49 (50.0)
      ≥ 80%4877 (95.5)4112 (79.1)1744 (83.0)1272 (72.2)49 (50.0)
      Blood eosinophil countNA = 323NA = 264NA = 107NA = 76NA = 10<0.0001
      <150/mm33365 (52.1)1849 (28.4)738 (28.5)594 (25.9)27 (18.9)
      150-300/mm32307 (35.7)2589 (39.7)<0.00011047 (40.5)879 (38.3)70 (49.0)
      >300/mm3788 (12.2)2081 (31.9)803 (31.0)820 (35.8)46 (32.2)
      Body Mass Index (BMI)NA = 82NA = 75<0.0001NA = 29NA = 29NA = 2<0.0001
      <18.5200 (3.0)170 (2.5)72 (2.7)51 (2.2)2 (1.3)
      [18.5–25[3798 (56.7)3267 (48.7)1377 (51.7)1011 (43.2)41 (27.2)
      [25–30[1957 (29.2)2166 (32.3)806 (30.2)829 (35.4)65 (43.0)
      More than 30746 (11.1)1105 (16.5)411 (15.4)449 (19.2)43 (28.5)
      Smoker status<0.0001
      Current smoker1264 (18.6)1208 (17.8)519 (19.3)413 (17.4)22 (14.4)
      Ex-smoker2235 (33.0)2366 (34.9)0.053882 (32.7)908 (38.3)62 (40.5)
      Never smoker3.284 (48.4)3209 (47.3)1294 (48.0)1048 (44.2)69 (45.1)
      FEV (Forced Expiratory Volume) in 1 second and FVC (Forced Vital Capacity).
      a 1566 participants had no treatment in the past 18 months and were not included in any treatment steps; NA: no answer.
      Table 3Comorbidities identified at inclusion in the cohort.
      PopulationControls n (%)Asthmatics n (%)p-valueStep 1 and 2 n (%)Step 3 and 4 n (%)Step 5 n (%)p-value
      678367832695
      Angina pectoris and/or history of myocardial infarction.
      2369
      Angina pectoris and/or history of myocardial infarction.
      153
      Angina pectoris and/or history of myocardial infarction.
      HypertensionNA = 8NA = 32<0.0001NA = 11NA = 12- -<0.0001
      Yes618 (9.1)805 (11.9)233 (8.7)383 (16.2)42 (27.5)
      No6157 (90.9)5946 (88.1)2451 (91.3)1974 (83.8)111 (72.5)
      HypercholesterolemiaNA = 44NA = 580.0219NA = 21NA = 20NA = 2<0.0001
      Yes455 (6.8)523 (7.8)156 (5.8)238 (10.1)34 (22.5)
      No6284 (93.2)6202 (92.2)2518 (94.2)2111 (89.9)117 (77.5)
      Type II diabetesNA = 46NA = 530.0013NA = 20NA = 19NA = 1<0.0001
      Yes98 (1.5)148 (2.2)46 (1.7)67 (2.9)12 (7.9)
      No6639 (98.5)6582 (97.8)2629 (98.3)2283 (97.1)140 (92.1)
      Coronary Heart Disease
      Angina pectoris and/or history of myocardial infarction.
      NA = 14NA = 520.0018NA = 17NA = 23NA = 10.0189
      Yes27 (0.4)55 (0.8)16 (0.6)28 (1.2)3 (2.0)
      No6742 (99.6)6676 (99.2)2662 (99.4)2318 (98.8)149 (98.0)
      Chronic bronchitisNA = 9NA = 314<0.0001NA = 124NA = 121NA = 11<0.0001
      Yes25 (0.4)161 (2.5)32 (1.2)85 (3.8)32 (22.5)
      No6749 (99.6)6308 (97.5)2539 (98.8)2163 (96.2)110 (77.5)
      EmphysemaNA = 1164NA = 14370.0349NA = 514NA = 550NA = 460.0023
      Yes16 (0.3)29 (0.5)11 (0.5)13 (0.7)3 (2.8)
      No5603 (99.7)5317 (99.5)2170 (99.5)1806 (99.3)104 (97.2)
      DepressionNA = 21NA = 26<0.0001NA = 6NA = 10- -0.0293
      Yes956 (14.1)1324 (19.6)496 (18.4)495 (21.0)39 (25.5)
      No5806 (85.9)5433 (80.4)2193 (81.6)1864 (79.0)114 (74.5)
      Past suicide attemptNA = 57NA = 84<0.0001NA = 33NA = 32NA = 10.8634
      Yes134 (2.0)226 (3.4)89 (3.3)83 (3.6)6 (3.9)
      No6592 (98.0)6473 (96.6)2573 (96.7)2254 (96.4)146 (96.1)
      Depression Score (CEDS Scale at inclusion)
      Mean (SD); * 1566 participants had no treatment in the past 18 months and were not included in any treatment steps; NA: no answer.
      10.8 (8.9)12.0 (9.7)<0.000111.9 (9.5)12.0 (9.8)14.8 (10.5)0.0076
      Depression status (CEDS scale)NA = 292NA = 313<0.0001NA = 113NA = 118NA = 190.0010
      Not Depressive5036 (77.6)4699 (72.6)1906 (73.8)1635 (72.6)78 (58.2)
      Depressive1455 (22.4)1771 (27.4)676 (26.2)616 (27.4)56 (41.8)
      a Angina pectoris and/or history of myocardial infarction.
      b Mean (SD); * 1566 participants had no treatment in the past 18 months and were not included in any treatment steps; NA: no answer.
      Fig. 2
      Fig. 2Multivariate analysis on comorbidities, risk factors, and health behaviors in patients with asthma vs never asthma controls; odds ratio adjusted for age, gender, socio-professional category, academic degree, marital status income, and EPICES score.
      Table IV delineates healthcare consumptions in the year prior to inclusion. Asthmatics were more often hospitalized (23.0% vs 18.1%) and had at least one consultation with a lung specialist (20.4% vs 3.1%), a general practitioner or a nurse compared to controls. Among asthmatics, 22.0% had at least one spirometry testing. Importantly, healthcare consumptions increased gradually with the GINA steps (Table IV).
      Table 4Healthcare consumptions in the year prior to inclusion.
      Never asthma controls

      N (%)
      Asthma patients

      N (%)
      p-valueStep 1 and 2

      N (%)
      Step 3 and 4

      N (%)
      Step 5

      N (%)
      p-value
      Population67836783<0.00012695
      *1566 participants had no treatment in the past 18 months and were not included in any treatment steps.
      2369
      *1566 participants had no treatment in the past 18 months and were not included in any treatment steps.
      153
      *1566 participants had no treatment in the past 18 months and were not included in any treatment steps.
      <0.0001
      Hospitalization1229 (18.1)1557 (23.0)<0.0001577 (21.4)608 (25.7)70 (45.8)<0.0001
      ≥1 consultation with a general practitioner
      **Outpatient consultations with physicians in public hospitals were not collected.
      5722 (84.4)6306 (93.0)<0.00012556 (94.8)2295 (96.9)151 (98.7)<0.0001
      ≥1 consultation with a specialist
      **Outpatient consultations with physicians in public hospitals were not collected.
      4328 (63.8)4946 (72.9)<0.00011899 (70.5)1877 (79.2)143 (93.5)<0.0001
      ≥1 consultation with a lung specialist
      **Outpatient consultations with physicians in public hospitals were not collected.
      212 (3.1)1383 (20.4)<0.0001352 (13.1)768 (32.4)108 (70.6)<0.0001
      ≥1 outpatient consultation1039 (15.3)1338 (19.7)<0.0001510 (18.9)507 (21.4)63 (41.2)<0.0001
      ≥1 consultation with a nurse2263 (33.4)2668 (39.3)<0.0001965 (35.8)1061 (44.8)109 (71.2)<0.0001
      ≥1 spirometry1493 (22.0)<0.0001413 (15.3)819 (34.6)103 (67.3)<0.0001
      All differences between subgroups were statistically significant (p < 0.0001).
      a *1566 participants had no treatment in the past 18 months and were not included in any treatment steps.
      b **Outpatient consultations with physicians in public hospitals were not collected.
      Table V illustrates the costs of healthcare consumptions from a societal perspective. The overall cost of healthcare consumptions for asthmatics was estimated at €2,644, versus €1886 for the control group, which corresponds to an incremental cost of €758 including €208 for hospital and €550 for ambulatory costs. For ambulatory consumptions, the incremental cost was higher for pharmacy (€272), medical consultations and visits (€139), and medical devices (€50). Cost of healthcare consumptions increased with the GINA steps from €2279 for step 1–2 to €3106 for steps 3–4 and €8593 for step 5. This increase was related to both hospitalizations (respectively €633, €810 and €2340) and ambulatory care (€1,646, €2296 and €6252).
      Table 5Costs of Healthcare consumptions.
      PopulationNever asthma controls

      N (%)
      Asthma patients

      N (%)
      p-valueStep 1 and 2Step 3 and 4Step 5p-value
      678367832695
      1566 particpants had no treatment in the past 18 months and were not included in any treatment steps, SD: Standard Deviation.
      2369
      1566 particpants had no treatment in the past 18 months and were not included in any treatment steps, SD: Standard Deviation.
      153
      1566 particpants had no treatment in the past 18 months and were not included in any treatment steps, SD: Standard Deviation.
      Costs, € (mean, SD)
       Medical fees470.2 (646.6)609.1 (744.0)<0.0001574.2 (720.3)685.3 (735.8)1237.6 (1315.3)<0.0001
       Dentist140.1 (416.6)150.7 (446.0)0.0020137.6 (415.8)171.8 (474.1)249.7 (785.4)<0.0001
       Pharmacy296.0 (1270.3)567.9 (1448.6)<0.0001393.5 (1116.3)763.8 (1427.9)3187.1 (4686.8)<0.0001
       Laboratory81.6 (157.2)96.4 (158.1)<0.000192.3 (156.1)98.8 (146.9)227.6 (270.2)<0.0001
       Paramedics100.6 (275.6)139.6 (342.8)<0.0001128.1 (313.4)153.8 (361.9)383.6 (710.4)<0.0001
       Medical devices223.8 (503.4)273.7 (584.1)<0.0001240.8 (502.6)323.4 (644.0)673.8 (1211.0)<0.0001
       Transports16.5 (164.8)26.8 (237.4)<0.000120.8 (197.5)33.2 (275.0)133.2 (499.5)<0.0001
       Other costs46.8 (459.8)61.2 (408.0)<0.000159.4 (478.8)66.3 (375.3)159.8 (429.2)<0.0001
      Total cost of ambulatory care1375.6 (2107.6)1925.3 (2475.3)<0.00011646.7 (2196.4)2296.3 (2418.5)6252.4 (5916.9)<0.0001
      Total cost of hospitalisations511.0 (2425.0)719.4 (3115.3)<0.0001633.1 (2860.4)810.4 (3354.3)2340.8 (5457.9)<0.0001
      Total cost1886.6 (3777.8)2644.7 (4736.8)<0.00012279.8 (4430.6)3106.7 (4861.2)8593.2 (8962.4)<0.0001
      a 1566 particpants had no treatment in the past 18 months and were not included in any treatment steps, SD: Standard Deviation.

      4. Discussion

      In this observational study conducted in France using the CONSTANCES general population cohort, we investigated the healthcare burden in 6783 asthmatics matched with controls in a 1:1 ratio. Most of the asthmatics were managed using GINA step 1–2 (2695) and step 3–4 (2369) treatments, only very few (153) receiving GINA step 5 treatment. Except for chronic bronchitis, comorbid conditions were not more frequent in asthmatics compared to controls after adjusting for confounding factors such as age, gender, socio-professional category, academic degree, income, and EPICES score. The overall cost of healthcare consumptions for asthmatics was estimated at €2,644, versus €1886 for the control group, which corresponds to an incremental cost of €758.
      Constances is the largest French population-based epidemiological study in adults. Constances is however not fully representative of the French adult population as 1) participants were randomly selected from the beneficiaries of the National Health Insurance Fund (“Caisse nationale d'assurance maladie”, CNAM) that covered around 85% of the French population, and 2) some geographical areas of France were not included. Nevertheless, the prevalence of asthma in our study is consistent with what was previously reported. As all consumptions for asthma were captured in the claims database, we were able to extensively characterize our studied patient population. Some limitations of the study should also be acknowledged. We used GINA treatment steps to approach asthma severity. Although GINA step is a well-established criterion, it is an indirect proxy for asthma severity. Limited conclusions can be drawn from the GINA step 5 given the low number of patients in that step. Furthermore, the treatment steps were missing for some patients and could not be reconstituted. Since we investigated only direct costs, no data on indirect costs could be reported including work-related losses and early mortality. Finally, the use of a propensity score to select the control population without asthma does not completely eliminate the risk of imbalance between studied population.
      Although comorbid conditions have been increasingly reported as contributors to poor asthma control, their role in the clinical expression of the disease has yet to be fully elucidated [
      Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.
      ]. In our study, we observed a higher proportion of asthma patients who received ICS in GINA step 3–4 (100%) and GINA step 5 (95.4%) compared to patients with a delivery of SABA for GINA step 3–4 (37.4%) and GINA step 5 (81%) in the past 3 months. We found higher prevalences of comorbid conditions among patients with asthma, however, the differences decreased and became non-significant after adjustment. It is important to note that asthmatics from the CONSTANCES cohort are identified in a sample of the general population accepting to undergo a complete health check-up. As such it may be hypothesized that they are “less sick” than asthmatics from asthma cohorts, which could impact the rate of comorbidities. Unfortunately, we have no way of exploring this hypothesis. Several studies have reported an increased prevalence of comorbidities due to systemic corticosteroid use in patients with asthma, ranging from psychological effects to serious and life-threatening conditions including type 2 diabetes, cardiovascular diseases, obesity, sleep disturbance, fractures, cataracts, and adrenal suppression ([
      • Bårnes C.B.
      • Ulrik C.S.
      Asthma and adherence to inhaled corticosteroids: current status and future perspectives.
      ,
      • Sweeney J.
      • Patterson C.C.
      • Menzies-Gow A.
      • Niven R.M.
      • Mansur A.H.
      • Bucknall C.
      • Chaudhuri R.
      • Price D.
      • Brightling C.E.
      • Heaney L.G.
      British thoracic society difficult asthma network. Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the optimum patient care research database and the British thoracic difficult asthma registry.
      ]).
      Since 2020, the GINA document recommends low-dose ICS–formoterol as the preferred symptom reliever at any treatment step or SABA as an alternative (GINA), which is based on two concerns: first, SABA-only treatment (as a treatment option for step 1) increases urgent asthma-related healthcare [
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.P.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      ]. Second, although low daily dose of ICS (as a treatment option for step 2) is highly effective in reducing asthma symptoms, adherence to ICS remains challenging for most patients which expose them to the risk of SABA-only treatment [
      • Boulet L.P.
      Influence of comorbid conditions on asthma.
      ]. In our population, we found that most asthmatics (96.6%) received a SABA to manage their symptoms in GINA step 1 and 2 compared to only 2.6% who had a delivery of ICS. This result is in line with the absence of indication of low-dose ICS–formoterol for GINA step 1 and 2 in Europe. Beyond the description of delivered treatments it would be of interest to analyse patients' adherence to these medications, to better understand the burden of disease and the possible determinants associated with poor adherence. This could be further explored in future studies in the Constances cohort. It would also be of interest to explore whether patients’ care differ according to the type of geographic area such as urban versus rural or other indicators for socioeconomic disadvantaged regions.
      Not surprisingly, we found that healthcare consumption was higher in asthmatics compared to controls and significantly increased with the GINA steps, which is consistent with previous studies [
      • Suissa S.
      • Ernst P.
      • Kezouh A.
      Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma.
      ,
      • Viinanen A.
      • Lassenius M.I.
      • Toppila I.
      • Karlsson A.
      • Veijalainen L.
      • Idänpään- Heikkilä J.J.
      • Laitinen T.
      The burden of adult asthma in Finland: impact of disease severity and eosinophil count on health care resource utilization.
      ]. ‘We estimated the incremental cost to be €758 for healthcare consumption in patients with asthma, largely driven by pharmacy costs and medical fees, but also hospitalizations.All healthcare consumption costs increased with the GINA steps. It is possible that a part of these costs are related to comorbidities associated with asthma as we did not adjust the cost estimates on comorbidities, in line with thestudy objective to capture crude healthcare costs, considering that costs related to asthma comorbidities are part of the global burden of asthma. Other cohorts and registries were actually designed in the same manner [
      • Bourdin A.
      • Fabry-Vendrand C.
      • Ostinelli J.
      • Ait-Yahia M.
      • Darnal E.
      • Bouee S.
      • Laurendeau C.
      • Bureau I.
      • Gourmelen J.
      • Chouaid C.
      The burden of severe asthma in France: a case-control study using a medical claims database.
      ] or even without any control group [
      • Nordon C.
      • Grimaldi-Bensouda L.
      • Pribil C.
      • Nachbaur G.
      • Amzal B.
      • Thabut G.
      • Marthan R.
      • Aubier M.
      COBRA Study Group
      Clinical and economic burden of severe asthma: a French cohort study.
      ]. Our findings are consistent with that of Jacob et al. [
      • Jacob C.
      • Bechtel B.
      • Engel S.
      • Kardos P.
      • Linder R.
      • Braun S.
      • Greiner W.
      Healthcare costs and resource utilization of asthma in Germany: a claims data analysis.
      ] in Germany who reported a €753 higher total cost per patient with asthma compared to the control group. In a review on the costs and social impact of asthma in several European countries, Nunes et al. [
      • Nunes C.
      • Pereira A.M.
      • Morais-Almeida M.
      Asthma costs and social impact.
      ] estimated the annual direct and indirect per capita costs to reach $2000 ($2496 in 2012) in France, Italy, and Norway. We observed the highest cost in GINA step 5, accounting for €8593 which is similar to previous studies conducted in France [
      • Bourdin A.
      • Fabry-Vendrand C.
      • Ostinelli J.
      • Ait-Yahia M.
      • Darnal E.
      • Bouee S.
      • Laurendeau C.
      • Bureau I.
      • Gourmelen J.
      • Chouaid C.
      The burden of severe asthma in France: a case-control study using a medical claims database.
      ,
      • Nordon C.
      • Grimaldi-Bensouda L.
      • Pribil C.
      • Nachbaur G.
      • Amzal B.
      • Thabut G.
      • Marthan R.
      • Aubier M.
      COBRA Study Group
      Clinical and economic burden of severe asthma: a French cohort study.
      ]. More specifically, Bourdin et al. [
      • Bourdin A.
      • Fabry-Vendrand C.
      • Ostinelli J.
      • Ait-Yahia M.
      • Darnal E.
      • Bouee S.
      • Laurendeau C.
      • Bureau I.
      • Gourmelen J.
      • Chouaid C.
      The burden of severe asthma in France: a case-control study using a medical claims database.
      ] used the permanent beneficiaries sample database (EGB) in France and reported an absolute cost of severe asthma at $9227.
      Finally, it is important to note that we observed a relatively low use of spirometry and specialist visits in patients with GINA steps 3–4 (30–35% of patients with spirometry and/or pulmonologist visit) and GINA step 5 (approximately 70% for each) therapy. Improving care pathways for these patients could improve outcomes.
      In conclusion, the findings of this study shed light on the substantial burden of asthma in terms of comorbidities and healthcare consumptions in France. This burden increases notably with GINA treatment steps. This highlights the need for a broader paradigm of asthma management including larger access to asthma education and more elaborated care pathways (spirometry and/or pulmonologist visits) that could help control symptoms, reduce OCS use and costs.

      Funding

      The study was sponsored by AstraZeneca, Courbevoie, France .

      Uncited references

      [
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      CRediT authorship contribution statement

      Nicolas Roche: Writing – original draft, participated in the study design and the interpretation of the study results, participated in the writing of the manuscript. Rachel Nadif: Writing – original draft, participated in the study design and the interpretation of the study results, participated in the writing of the manuscript. Caroline Fabry-Vendrand: Writing – original draft, participated in the study design and the interpretation of the study results, participated in the writing of the manuscript. Laura Pillot: Writing – original draft, participated in the writing of the manuscript. Gabriel Thabut: Writing – original draft, participated in the writing of the manuscript. C. Teissier: Formal analysis, performed the statistical analysis. Stéphane Bouée: Writing – original draft, Formal analysis, participated in the study design and the interpretation of the study results, performed the statistical analysis, participated in the writing of the manuscript. Marcel Goldberg: Writing – original draft, participated in the study design and the interpretation of the study results, participated in the writing of the manuscript. Marie Zins: Writing – original draft, participated in the study design and the interpretation of the study results, participated in the writing of the manuscript. .

      Declaration of competing interest

      NR received research funds and fees from Boehringer Ingelheim , Novartis , Pfizer , GSK , and fees (advisory boards, consultation, education, presentations) from MSD, AstraZeneca, Chiesi, Sanofi, Zambon. Rachel Nadif received fees from CEMKA for consulting activities, between April 2019 to April 2020. Caroline Fabry-Vendrand, Laura Pillot and Gabriel Thabut are employees of AstraZeneca, which support this study. Stephane Bouee and Clément Tessier are employees of CEMKA, which received grants from AstraZeneca to conduct this analysis. Marcel Goldberg and Marie Zins have no links of interest.

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