Severe asthma is related to high societal costs and decreased health related quality of life

Journal Pre-proof Severe asthma is related to high societal costs and decreased health related quality of life Sven-Arne Jansson, Helena Backman, Maria Andersson, Gunilla Telg, Anne Lindberg, Caroline Stridsman, Bo Lundbäck, Eva Rönmark PII:

S0954-6111(19)30374-9

DOI:

https://doi.org/10.1016/j.rmed.2019.105860

Reference:

YRMED 105860

To appear in:

Respiratory Medicine

Received Date: 30 March 2019 Accepted Date: 28 December 2019

Please cite this article as: Jansson S-A, Backman H, Andersson M, Telg G, Lindberg A, Stridsman C, Lundbäck B, Rönmark E, Severe asthma is related to high societal costs and decreased health related quality of life, Respiratory Medicine (2020), doi: https://doi.org/10.1016/j.rmed.2019.105860. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Ltd. All rights reserved.

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Severe asthma is related to high societal costs and decreased Health Related Quality Of Life Sven-Arne Jansson, PhDa; Helena Backman, PhDa; Maria Andersson, PhDb; Gunilla Telg, BScb; Anne Lindberg, MD, PhDc; Caroline Stridsman, PhDd; Bo Lundbäck, MD, PhDe; Eva Rönmark, PhDa

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d

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Department of Public Health and Clinical Medicine, Section of Sustainable Health, the OLIN unit, Umeå university, Umeå, Sweden AstraZeneca Nordic-Baltic, Södertälje, Sweden

Department of Public Health and Clinical Medicine, Division of Medicine, Umeå university, Umeå, Sweden Department of Health Sciences, Luleå University of Technology, Luleå, Sweden

Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

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[email protected]

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[email protected]

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[email protected]

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[email protected]

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[email protected]

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[email protected]

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[email protected]

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[email protected]

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Corresponding author:

Sven-Arne Jansson, PhD

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Department of Public Health and Clinical Medicine

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Section of Sustainable Health, The OLIN Unit

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Umeå University

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SE-901 87 Umeå, Sweden

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E-mail: [email protected]

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Abbreviations

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ACT: Asthma Control Test questionnaire; EQ-5D: EuroQoL Health Questionnaire 5 Dimensions;

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GERD: gastroesophageal reflux; HRQOL: Health Related Quality Of Life; ICS: Inhaled

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Corticosteroids; LABA: Long-Acting Beta-Agonists; MCS: Mental Component Summary; OCS:

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Oral Corticosteroids; OLIN: Obstructive Lung Disease in Northern Sweden; PCS: Physical

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Component Summary; SEK: Swedish Crowns; SF-36: Short Form Health Survey; SGRQ: St

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George’s Respiratory Questionnaire; SPSS: Statistical Package for the Social Sciences.

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ABSTRACT

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Background: The aim of the present study was to estimate the societal costs and the key cost

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drivers for patients with severe asthma in Sweden. In addition, health-related quality of life

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(HRQOL) and morbidity of patients with severe asthma is described.

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Methods: The study population comprised adults with severe asthma recruited from a large asthma

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cohort within the Obstructive Lung Disease in Northern Sweden (OLIN) studies. During 2017,

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patients were interviewed quarterly over telephone regarding their resource utilization and

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productivity losses.

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Results: Estimated mean annual asthma-related costs per patient with severe asthma amounted to

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€6,500, of which approximately €2,400 and €4,100 were direct and indirect costs, respectively. The

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main cost drivers for direct costs were hospitalizations followed by drugs: approximately €1,000

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and €800, respectively. Patients on treatment with regular oral corticosteroids (OCS) had greater

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direct costs compared with those without regular OCS treatment. Co-morbid conditions were

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common and the costs were substantial also for co-morbid conditions, with a total cost of

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approximately €4,200. The OCS group had significantly lower HRQOL compared to the non-OCS

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group.

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Conclusions: The societal costs due to severe asthma were substantial. Costs for co-morbid

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conditions contributed substantially to both direct and indirect costs. The direct costs were

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significantly higher in the maintenance OCS-group compared to the non-maintenance OCS-group.

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These results indicate a need for improved management and treatment regimens for patients with

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severe asthma.

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Keywords: Severe asthma, Costs, Health-related quality of life, Oral corticosteroids.

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INTRODUCTION

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Asthma is a major health problem in society. The disease seriously affects both children and adults,

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and the prevalence worldwide has increased considerably during the second half of the past century,

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particularly in urban areas and high-income countries [1-5]. An increase in asthma prevalence has

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also been demonstrated in Sweden [6], although some studies also have indicated a stabilization

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[6,7]. For society, it is important to gain knowledge of the economic implications of common

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diseases such as asthma. Studies about costs of asthma have therefore been performed in many

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countries, mainly registry-based studies and studies of health statistics [8].

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The vast majority of asthmatics have a mild or moderate disease [9]. Severe asthma has been

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reported in 3-10% of all asthmatics [10-13], and is characterized by frequent symptoms, high co-

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morbid burden, increased bronchial hyper-responsiveness and airflow variability, accompanied with

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asthma exacerbations [13-17]. Furthermore, the majority of patients with severe asthma have poor

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asthma control [10,11,14,15,18], despite high doses of inhaled corticosteroids and other

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maintenance treatments.

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Severe asthma is associated with increased health-care utilization, lower health-related quality of

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life (HRQOL) and high costs for both the individual and the society [19-23]. However, data about

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the costs of severe asthma is scarce.

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The main aim of the present study was to estimate the societal costs and the key cost drivers for

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patients with severe asthma in Sweden. In addition, HRQOL and morbidity of patients with severe

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asthma is described.

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MATERIALS AND METHODS

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Study population

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The study population included adults (≥18 years) with severe asthma, identified by pre-defined

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inclusion and exclusion criteria detailed below, recruited from population-based cohorts within the

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Obstructive Lung Disease in Northern Sweden (OLIN) Studies [24-26]. Demographics and

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characteristics of the study population (n=32) are displayed in Table A.1.

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Severe asthma was defined as asthma requiring treatment with high dose inhaled corticosteroids

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(ICS), plus a second controller and/or oral corticosteroids to prevent it from becoming uncontrolled;

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or asthma that remained uncontrolled despite this therapy [14]. High doses of inhaled

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corticosteroids (ICS) and asthma control were defined according to the GINA 2014 [9]. Patients

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were excluded from participation if: age > 75 years with concomitant disease(s) which potentially

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could affect the asthma disease; or intermittent or chronic dyspnoea due to causes other than

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asthma, such as chronic heart failure. The study was approved by the Regional Ethical Review

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Board in Umeå, Sweden (2016/383-31) and all patients signed an informed consent.

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Study design

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At study entry, the patients were invited to a clinical examination and a structured interview

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performed by a senior consultant in respiratory medicine within the research team. The interview

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included questions on the clinical history, current medication, treatment adherence, respiratory

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symptoms, co-morbidities, smoking habits and occupation. Spirometry with reversibility testing,

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blood-sampling for eosinophil and neutrophil count measurements, and specific IgE to airborne

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allergens were performed. HRQOL questionnaires were completed and structured interviews

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regarding health care resource utilization during the previous year (Figure 1). The prospective study

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covered the 12 months following inclusion, during which the patients were interviewed over

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telephone every third month. Diary cards were used between the interviews.

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All structured interviews, both in the retrospective and prospective study, covered information on

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the asthma disease, co-morbidities and concomitant diseases, treatments (including detailed

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information about oral corticosteroid (OCS) use), all health care resource use, and productivity loss

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caused by disease. Health care resource use included both primary and specialist care, outpatient

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visits, emergency department visits, unscheduled primary care visits, hospitalizations and also

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telephone consultations. A total of 32 patients were included, whereof 31 participated in all four

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interviews in the prospective study.

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Costs

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Direct costs were estimated for resource utilization including costs for medication. Indirect costs

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included productivity loss due to early retirement and absence from work due to sick leave. Total

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societal costs were estimated by multiplying the unit costs with the resource use and productivity

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losses associated with asthma and co-morbid diseases, based on average annual exchange rates for

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2017 (1 euro = SEK 9.63; Swedish National Bank).

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Unit costs for health care resources were obtained from the Northern Sweden health care region’s

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price list of 2017 (www.norrlandstingen.se), which includes all costs for outpatient contacts and

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hospital admissions for the health care sector (Table 1). Costs of drugs were based on prices listed

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by the Dental and Pharmaceutical Benefits Agency, reflecting retail pharmacy prices (www.tlv.se).

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The indirect costs were estimated according to the human capital approach [27], as follows. Each

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patient’s average monthly salary including payroll tax and social security contributions was used to

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calculate the cost of each day’s absence from work due to sick-leave or early retirement. Costs of

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early retirement were estimated as the costs of absence from work every working day before the age 6

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of 65 years (the most common retirement age in Sweden), based on the percentage of the disability

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pension (100%, 75%, etc.). Costs for the patient who did not complete all interviews were imputed

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equal to the average annual costs in the available interviews, according to the patient-year approach

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method [27].

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HRQOL questionnaires and asthma control

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Generic and disease-specific questionnaires were used both at study entry and at study end. The

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generic Short Form Health Survey (SF-36) measures eight domains of health, which can be

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transformed into two summary measures: the Physical Component Summary (PCS) and the Mental

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Component Score (MCS) [28]. The generic EuroQoL Health Questionnaire, 5 Dimensions (EQ-5D)

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includes five domains: Mobility, Self-care, Usual activities, Pain/Discomfort and

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Anxiety/Depression [29]. The disease-specific St George’s Respiratory Questionnaire (SGRQ)

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consists of three domains, Symptoms, Activity and Impacts, which are summarized to a total score

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[30]. Asthma control was based on the Asthma Control Test questionnaire (ACT), and categorized

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as uncontrolled (<20), partly controlled (20-24) and controlled (25) [31].

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Analyses

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Statistical analyses were performed with the IBM Statistical Package for the Social Sciences (SPSS)

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Statistics 24. Mean annual direct and indirect asthma-related costs as well as costs due to co-morbid

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conditions were analyzed. The costs were analyzed for all patients in the study, and in order to

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investigate differences between disease severity, comparisons were performed between those who

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used OCS as maintenance treatment and those not using OCS as maintenance treatment, based on

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the assumption that only the most severe patients have OCS as maintenance treatment. As the

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distribution of the costs was skewed, the non-parametric Mann-Whitney U-test was used to test 7

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differences between the groups. Furthermore, HRQOL was analyzed for all patients and separately

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for those with and without OCS maintenance treatment.

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RESULTS

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Demography and clinical characteristics at study entry

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Mean age of the 32 patients was 59.6 years (23-82 years) and 75% were women (Table A.1). None

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of the patients was currently smoking, 59% were non-smokers, and 41% were ex-smokers. Two

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patients (10% of the working-age patients) were early retired due to asthma. Co-morbid diseases

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were common, with osteoporosis and/or past diagnoses of fracture and gastroesophageal reflux

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disease (GERD) being the most frequent (Table A.1). Four patients had no co-morbid diseases, six

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had one, eight had two, seven had three, and seven had four or more co-morbid diseases. Most of

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the patients had uncontrolled or partly controlled asthma (Table 2). Asthma medication at study

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entry is described by daily doses of ICS, long-acting beta-agonists (LABA) and other treatments

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(Table A.2). Out of the 32 patients, eight used OCS as maintenance treatment or had used OCS

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periodically.

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Resource use and mean annual costs due to asthma

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During the 12 months study period, 72% of the patients had at least one exacerbation and 44% had

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experienced three or more exacerbations (Table 3).The mean annual total cost per patient due to

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severe asthma was approximately €6,500. Indirect costs were significantly greater than direct costs,

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approximately €4,100 versus €2,400, p=0.038 (Table 3). The main cost drivers in direct costs were

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hospitalizations and drugs: approximately €1,000 and €800, respectively. The main cost driver of

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indirect costs was productivity loss due to early retirement (€3,499). When estimating the costs for

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patients in working age, the direct costs decreased to €1,640 per patient per year, while the indirect

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costs increased to €7,280. The direct costs were significantly higher in the maintenance OCS-group

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compared to the non-maintenance OCS-group, €3,900 versus €1,900, p=0.033, (Table 4).

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Mean annual costs due to both asthma and co-morbid conditions

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The costs for co-morbid conditions were substantial, with a total cost of €4,200. The total cost for

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both asthma and co-morbid conditions in this severe asthma population amounted to €10,700 per

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patient per year. The distribution of all direct and indirect costs is shown in Figures 2 and 3.

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Health-related quality of life

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When estimating HRQOL with the disease-specific SGRQ-questionnaire, the least affected domain

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was “Impacts”, while the domains “Activity” and “Symptoms” were the most affected. When using

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the generic SF-36 questionnaire, the physical score (PCS) was the most affected whereas the mental

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score (MCS) was the least affected. The HRQOL tended to be worse among patients using OCS

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compared to those not using OCS, when using the generic questionnaires and significantly so when

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using the SGRQ questionnaire (Table 2).

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DISCUSSION

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The societal costs of severe asthma in Sweden were substantial, with a mean annual asthma-related

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cost of about €6,500 per patient. The main disease-related cost drivers of the direct costs were

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hospitalizations followed by drugs, while productivity loss due to early retirement was the main

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cost driver of the indirect costs. Patients using OCS had significantly higher asthma-related direct

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costs compared to non-OCS users. The costs of co-morbid conditions in this severe asthma

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population were substantial, with total costs, for both asthma and co-morbid conditions, amounting

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to approximately €10,700 per patient.

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In a previous Swedish study based on a representative sample of asthmatics from the general

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population, the costs were estimated to about €1,700 per patient per year [32]. The current study

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clearly shows greater costs associated with the severe asthma disease in Sweden, and thus confirms

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previous findings from other countries on greater costs for patients with severe asthma compared to

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patients with mild or moderate asthma [19-22]. There are however only a few studies about costs of

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severe asthma published so far. One study from the United Kingdom, consisting of patients with

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severe uncontrolled eosinophilic asthma, found that the direct costs were four times higher

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compared with the costs for the total asthma population [22]. The few studies reporting both direct

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and indirect costs for obstructive airway diseases have consistently found higher indirect costs

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compared with direct costs for both asthma and COPD [32,33]. Thus, as indirect costs are

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substantial, estimating indirect costs are important for society.

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In the present study, exacerbations were common, with 72% of the patients having at least one

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exacerbation and almost half of the patients had three or more exacerbations. It has previously been

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shown that exacerbations constitute the major part of the costs for drugs, outpatient care and

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hospitalizations [34,35]. In our study the costs for exacerbations are included in the estimated costs

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and thus contribute substantially to the high total costs. No difference in number of exacerbations

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between those with or without maintenance OCS treatment were found, which could be explained

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by the fact that OCS may suppress exacerbations. On the other hand, high doses of steroids, and

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particularly OCS, are related to many side effects such as glaucoma and osteoporosis, thus

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contributing to co-morbidities [36]. In our severe asthmatics, co-morbid conditions were common

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and contributed to about 40% of the total societal costs. Hence, averting co-morbidity should be

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emphasized to reduce the total costs for patients with asthma.

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Early retirement contributed to the high costs, even though only two of the included asthma patients

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actually had an early retirement due to asthma. It should be noticed that 11 out of 32 patients were

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fully retired due to age and 19 patients worked full time or partly. If estimating the indirect costs for

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the working patients only, the indirect costs for severe asthma increased to €7,280 per patient per

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year compared to €4,100 when including the age retired patients. Thus, decreasing the morbidity for

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patients in working age is important to limit the costs for sick leave and early retirement.

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Severe asthma is not only related to high costs but also to decreased HRQOL. We found decreased HRQOL

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both when using the disease-specific as well as the generic instruments, and that patients using OCS have

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even lower scores compared to those not using OCS. In SF-36, a clinically meaningful difference between

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these two groups of patients was found for the physical score, while no difference was found for the mental

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score. Similarly, a clinically meaningful difference between patients using OCS compared to those not using

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OCS was found in SGRQ. Thus, in our severe asthma population we were able to identify a subgroup with

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significantly worse HRQOL, which may reflect an even more severe asthma disease. It should be noticed

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that the HRQOL estimates were stable and did not differ at the end of the study compared to study entry,

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indicating that participation in the present observational study has not impacted patients’ behavior or

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treatment. Other studies have also shown that patients with uncontrolled severe asthma have decreased

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HRQOL compared to patients with mild and moderate asthma [37-39].

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Health economic data may be difficult to compare. One reason for this is that estimates quickly

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become outdated, as unit costs and treatment patterns may change. Comparing data on costs

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between studies from different countries is not straightforward, as study design, unit costs and the

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structure of the health-care sector may differ [40]. The best available method for obtaining true

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costs is to prospectively collect data on health-care resource use and productivity losses among

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well-defined study samples and well-characterized patients. We found that both direct and indirect

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costs were higher in the prospective study compared to retrospective estimations indicating that the

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costs may be underestimated in retrospective studies, probably due to recall bias.

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In the current study the number of patients with regular OCS treatment were few, though it was

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obvious that this group of severe asthma patients had the highest costs, which is in line with a recent

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published register-based study from Sweden [23]. Our study was performed before the new

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generation of asthma medications had been commonly prescribed in the study area and none of the

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study participants were using biologic medications. The high burden of exacerbations and impaired

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quality of life reflect the need of better treatment options for patients with severe asthma. Treatment

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with OCS, and also with very high doses of ICS, result in systemic effects that may contribute to

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increased burden of co-morbidities. Drug development of the so called biologics targeting specific

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mediators in the disease progress have shown promising results particularly regarding asthma

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exacerbations [41] and this could lead to future changes in the costs for severe asthma.

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One important strength is the prospective design of our study where annual societal costs were

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estimated using data obtained from interviews with three-month intervals, which is widely

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considered to be an adequate recall period [42]. Furthermore, all interviews were performed by the

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same person, and diaries were used to limit the risk of recall bias in-between interviews. In addition,

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the use of drugs was validated by the patients having the drugs or their prescriptions at hand during

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the telephone interviews. The same daily doses of medication were used at study entry and at the

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end of the study, which confirm that the patients fulfilled the criteria for severe asthma and that no

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intervention was performed. Finally, data collected by interviews are more detailed than data from

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official registries. A weakness of the present study is that the study is based on relatively few

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subjects, which could lead to high variability in the data.

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CONCLUSIONS

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In this severe asthma population in Sweden, societal costs were substantial. Costs for co-morbid

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conditions contributed substantially to both direct and indirect costs. The direct costs were

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significantly higher in the maintenance OCS-group compared to the non-maintenance OCS-group.

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Furthermore, the OCS-group had significantly lower HRQOL compared to the non-OCS group.

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These results indicate a need for improved management and treatment regimens for patients with

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severe asthma.

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ACKNOWLEDGEMENTS

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All authors (SAJ, HB, MA, GT, AL, CS, BL and ER) participated in the study conception, design,

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and statistical analysis planning. SAJ performed the interviews, statistical analyses, drafting of the

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manuscript and interpretation of data. All authors performed manuscript revisions. All authors had

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access to complete study data, and had authority over manuscript preparation, approval of final

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version and the decision to submit for publication.

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G. Telg and M. Andersson are full-time employees of the study sponsor, AstraZeneca. B. Lundbäck

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reports grants from AstraZeneca and GSK, personal fees from AstraZeneca, GSK, Novartis, and

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Sanofi, outside the submitted work. H. Backman reports personal fees from Boehringer Ingelheim

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and AstraZeneca, outside the submitted work. A. Lindberg reports personal fees from Boehringer-

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Ingelheim, AstraZeneca, Novartis, and Active Care, outside the submitted work. E. Rönmark

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reports grants from Norrbotten County Council and AstraZeneca during the conduct of the study,

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and grants from GSK, Swedish Heart and Lung foundation, NordForsk, and ALF, Umeå university,

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outside the submitted work. SA. Jansson and C. Stridsman have no conflicts to report.

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This work was supported by AstraZeneca and Norrbotten County Council.

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Legends to figures

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Figure 3. Distribution (percentage) of indirect costs among patients with severe asthma estimated prospectively during 12 months.

Figure 1. Flow chart of the study. Figure 2. Distribution (percentage) of direct costs among patients with severe asthma estimated prospectively during 12 months.

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FIGURES

Figure 1. Flow chart of the study.

17

16.4

16.7

12.4 21.5 12.5 20.5

Drugs asthma

Drugs co-morbid conditions

Outpatient care asthma

Outpatient care co-morbid conditions

Hospitalisations asthma

Hospitalisations co-morbid conditions

Figure 2. Distribution (percentage) of direct costs among patients with severe asthma estimated prospectively during 12 months.

9.9

31.8 58.3

Sick leave asthma

Sick leave co-morbid conditions

Early retirement asthma

Figure 3. Distribution (percentage) of indirect costs among patients with severe asthma estimated prospectively during 12 months. 18

TABLES Table 1. Unit costs (€) obtained from the Northern healthcare region’s price list of 2017. Type of cost

Unit

Unit cost (€)

Physician, primary care

Visit

196

Physician, dept. of pulmonary medicine

Visit

560

Physician, dept. of medicine

Visit

394

Physician, emergency room

Visit

351

Allied health professionals

Visit

80

Hospitalisation, dept. of pulmonary medicine

Day

1124

Hospitalisation, dept. of medicine

Day

1057

Hospitalisation, dept. of orthopaedics

Day

1431

19

Table 2. Asthma control and HRQOL at the end of the study, all patients and comparing patients with and without maintenance therapy with oral corticosteroids (OCS). All patients n=30* ACT, n (%) - Controlled - Partly controlled - Un-controlled HRQOL, mean (min-max) - EQ-5D$ - SGRQ# - Symptoms - Activity - Impacts - SF-36¤ - MCS - PCS

Maintenance OCS n=8

2 (6.7) 12 (40.0) 16 (53.3)

0 (0.0) 3 (37.5) 5 (62.5)

Non-maintenance OCS n=22

p-value

2 (9.1) 9 (40.9) 11 (50.0)

0.79 (0.16-1.00)

0.71 (0.26-1.00)

0.83 (0.16-1.00)

n.s

29.4 (1.6-75.9) 39.7 (6.7-83.1) 41.8 (0.0-93.3) 19.2 (0.0-73.7)

43.1 (15.6-64.5) 54.7 (7.7-83.1) 60.9 (12.1-85.9) 29.4 (8.0-56.5)

24.5 (1.6-75.9) 34.2 (6.7-75.1) 34.9 (0.0-93.3) 15.5 (0.0-73.7)

0.013 0.031 0.024 n.s

52.9 (30.8-63.0) 43.8 (19.5-59.9)

52.1 (30.8-59.3) 37.0 (19.5-50.5)

53.2 (34.1-63.0) 46.3 (25.5-59.9)

n.s n.s

*Two patients did not respond to the HRQOL-questionnaires. $

lower score indicates worse HRQOL.

#

higher score indicates worse HRQOL.

¤

lower score indicates worse HRQOL.

20

Table 3. Number of exacerbations, health-care utilization and mean annual costs (€) per patient during 12 months based on the retrospective and the prospective estimates, respectively.

Exacerbations, n (%) - 0 - 1 - 2 - 3 - 4 - 5 or 6 Number of visits due to asthma, mean (n/ visits) - Specialist physician: Visits - Specialist physician: Telephone - Primary care physician: Visits - Primary care physician: Telephone - Allied health professionals*: Visits - Allied health professionals*: Telephone - Hospitalisations Direct asthma-related costs per patient, € - Asthma drugs - Specialist physician: Contacts - Primary care physician: Contacts - Allied health professionals*: Contacts - Costs for all contacts - Costs for hospitalizations - Total direct costs Indirect asthma-related costs per patient, € - Sick leave - Early retirement - Total indirect costs Total costs, € * Nurses, physiotherapists and occupational therapists.

Retrospective study n=32

Prospective study n=32

14 (43.8) 10 (31.3) 2 (6.3) 3 (9.4) 2 (6.3) 1 (3.1)

9 (28.1) 5 (15.6) 4 (12.5) 7 (21.9) 6 (18.8) 1 (3.1)

0.9 (10/28) 0.0 (1/1) 0.6 (9/20) 0.2 (2/7) 0.0 (1/1) 0.8 (8/27) 0.1 (1/2)

0.7 (12/23) 0.2 (4/5) 0.8 (18/27) 0.1 (2/2) 0.6 (10/20) 1.3 (24/40) 0.1 (3/3)

731 412 129 20 561 237 1,529

791 347 168 76 591 1,018 2,400

769 3,499 4,268 5,797

596 3,499 4,095 6,495

21

Table 4. Health-care utilization and mean annual direct costs (€) per patient during 12 months, comparing patients with and without maintenance therapy with oral corticosteroids (OCS) in the prospective study.

Number of visits per patient, mean (n/visits) - Specialist physician: Visits - Specialist physician: Telephone - Primary care physician: Visits - Primary care physician: Telephone - Allied health professionals*: Visits - Allied health professionals*: Telephone - Hospitalisations Direct costs per patient, SEK - Asthma drugs - Specialist physician: Contacts - Primary care physician: Contacts - Allied health professionals*: Contacts - Costs for all contacts - Costs for hospitalisations Direct costs _______________________________

Maintenance OCS n=8

Non-maintenance OCS n=24

1.3 (4/10) 0.3 (2/2) 0.5 (4/4) 0.0 (0/0) 0.8 (4/6) 1.3 (6/10) 0.3 (2/2)

0.5 (8/13) 0.1 (2/3) 1.0 (14/27) 0.1 (2/2) 0.5 (6/11) 1.3 (24/30) 0.0 (1/1)

1026 632 98 86 816 2107 3949

712 252 192 73 517 656 1885

_________________

_________________

p-value

0.046 n.s n.s n.s n.s n.s 0.033 _______________

* Nurses, physiotherapists and occupational therapists

22

Table A.1. Demographics and clinical characteristics at study entry

Female n (%) Mean age (min-max) BMI, mean (min-max) Smoking status, n (%) - Smokers - Ex-smokers - Non-smokers Working status, n (%) - Working - Part time working/Part time retirement - Early retirement - Retirement FEV1 % Mean predicted (min-max) Eosinophils n>0.3 Neutrophils n> 0.5 Phadiatop positive n (%) Comorbidities, n (%) - Hypertension - Heart disease - Diabetes - Other metabolic disorder - Ulcer or gastritis - Gastroesophageal reflux - Fracture and/or osteoporosis - Glaucoma or other eye diseases - Depression or anxiety - Sinusitis - Nasal polyps ACT, n (%) - Controlled - Partly controlled - Not controlled

n=32 24 (75.0) 59.6 (23-82) 30.6 (28.4-32.9) 0 (0.0) 13 (40.6) 19 (59.4) 14 (43.8) 5 (15.6) 2 (6.3) 11 (34.4) 66.8 (62.9-70.7) 14 (43.8) 10 (31.3) 13 (40.6) 12 (37.5) 12 (37.5) 6 (18.8) 3 (9.4) 11 (34.4) 13 (40.6) 16 (50.0) 5 (15.6) 1 (3.1) 12 (37.5) 9 (28.1) 2 (6.7) 12 (40.0) 16 (53.3)

23

Table A.2. Asthma medication at study entry.

Asthma medication used on regular basis N ICS

1 Budesonide 1 Budesonide

ICS Daily dose (ug) 1200 1600

1 Fluticasone

1000

Formoterol

18

1 Fluticasone 1 Fluticasone

1000 2000

Salmeterol Formoterol

100 18

1 2 1 1

Budesonide/formoterol Budesonide/formoterol Budesonide/formoterol Budesonide/formoterol

320 960 960 1280

9 27 27 36

1 Budesonide/formoterol

1280

36

7 1 3 1 2 1

Fluticasone*/salmeterol Fluticasone*/salmeterol Fluticasone*/salmeterol Fluticasone*/salmeterol Fluticasone*/salmeterol Fluticasone*/salmeterol

1000 1000 1000 1000 1000 1000

100 100 100 100 100 100

1 Fluticasone*/salmeterol

1500

150

1 Fluticasone*/salmeterol 1 Fluticasone*/salmeterol 1 Fluticasone*/salmeterol

2000 2000 2000

200 200 200

1 Fluticasone$/vilanterol

184

22

1 Ciklesonide 640 *fluticasone proprionate $

LABA

Formoterol

Formoterol

LABA Daily dose (ug) 18

18

Other treatment

Periodic OCS use Daily dose

Bricanyl

0.5 mg

Bricanyl Teofyllin Montelukast Tiotropium Montelukast

2 mg 300 mg 10 mg 18 ug 10 mg

Bricanyl Bricanyl Montelukast

OCS

OCS Daily dose (mg)

Prednisolon Prednisolon

5

Prednisolon

5

4.5 mg 2 mg 10 mg

Tiotropium Montelukast Bricanyl Ventoline Ventoline, Montelukast Ventoline Montelukast Teofyllin Montelukast Bricanyl Ventoline

18 ug 10 mg 3.5 mg 0.4 mg 0.8 mg 10 mg 0.8 mg 10 mg 600 mg 10 mg 0.5 mg 2 mg

Tiotropium, Teofyllin

36 ug 300 mg

Prednisolon Prednisolon

10

Prednisolon

5

Betapred Prednisolon

12,5

Betapred

fluticasone furoate

24