the absolute blood eosinophil count a...
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THE ABSOLUTE BLOOD EOSINOPHIL COUNT:
A POTENTIAL BIOMARKER OF RESPONSE TO INHALED
CORTICOSTEROIDS IN RESPIRATORY PATIENTS
A COHORT STUDY INVESTIGATING THE EFFECT OF INHALED CORTICOSTEROIDS
RELATIVE TO DIFFERENT BLOOD EOSINOPHIL COUNTS IN PRIMARY CARE PATIENTS
WITH ASTHMA, COPD AND ACO
A.E.M. van Dijk | s2230577
Supervisor: dr. J.W.H. Kocks | dr. B.M.J. Flokstra-de Blok
Daily supervisor: drs. H.J. Baretta
Department of General Practice | University Medical Center Groningen
July 2017 | Groningen | The Netherlands
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 2
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Abstract
Introduction: The burden of asthma and chronic obstructive pulmonary disease (COPD) on
society is high and therefore research about optimal treatment in these patient groups has
become a wide field of interest. Inhaled corticosteroids (ICS) are used in both asthma and
COPD patients. The peripheral blood eosinophil count (EO-count) has been suggested to be a
promising biomarker for the effectiveness of ICS. However, little is known about the
predicting role of the EO-count in a combined approach of patients with asthma, COPD and
asthma-COPD overlap (ACO) in primary care.
Aim: This study aims to investigate the ICS treatment response in relation to different EO-
counts in real life primary care respiratory patients data.
Methods: This retrospective observational study used anonymized medical data from 2007
till 2016, derived from the Asthma/COPD(AC)-service. Absolute EO-counts were categorized
as follows: ≤150 cells/μL, 151-300 cells/μL, 301-400 cells/μL and > 400 cells/μL. The
primary outcome was the ICS treatment response in terms of improved disease control,
measured by the Asthma Control Questionnaire(ACQ) and Clinical COPD
Questionnaire(CCQ), for the four categories of EO-counts. As secondary outcome, ICS
treatment response in terms of lung function improvement and exacerbation rate was
analyzed. Analyses were performed for all three diseases combined, as well as all three
separately.
Results: 215 asthma patients, 74 COPD patients and 48 ACO patients met study eligibility
criteria. Analyses of the entire study population showed that, after ICS treatment, patients
with an EO-count > 400 cells/μL at baseline were more likely to improve their disease control
compared to patients with an EO-count between 151-300 cells/μL (p=0.005). When
performing specific analyses into patients classified by their diagnosis, similar results were
solely observed in COPD patients. Furthermore, no significant differences in terms of lung
function improvement and exacerbation rate were identified related to the EO-count.
Conclusion: In patients with a high EO-count at baseline, ICS treatment is associated with
larger improvements of disease control compared to patients with a low EO-count. The
absolute EO-count is potentially an important biomarker that could contribute to treatment
decision making in primary care respiratory patients. These results suggest the need for
prospective randomized control trials on larger sample sizes.
Key words: Primary care, Blood eosinophil count, Inhaled corticosteroids, Disease Control
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 4
Samenvatting
Introductie: Astma en chronic obstructive pulmonary disease (COPD) zijn veel
voorkomende chronische aandoeningen in de maatschappij met een hoge ziektelast. Inhalatie
corticosteroïden(ICS) spelen een belangrijke rol in de behandeling van deze respiratoire
ziektes. Het eosinofielen gehalte in het bloed (EO-gehalte) wordt gezien als een mogelijke
voorspeller voor de effectiviteit van de behandeling met ICS, echter is er nog weinig bekend
over de rol van het EO-gehalte als biomarker in de behandeling voor eerstelijns patiënten met
astma, COPD en astma-COPD Overlap (ACO).
Doel: Het doel van deze studie is om de relatie tussen het EO-gehalte en de effectiviteit van
ICS in real-life data van patiënten met astma, COPD en ACO uit de eerste lijn te
onderzoeken.
Methode: Dit betrof een retrospectief observationele studie welke gebruik maakte van
geanonimiseerde data tussen 2007 en 2016 afkomstig van de astma/COPD dienst. Er werd
gebruik gemaakt van het absolute EO-gehalte in vier categorieën: ≤150 cellen/μL, 151-300
cellen/μL, 301-400 cellen/μL, >400 cellen/μL. Als primaire uitkomstmaat werd het verschil
van ICS op de ziekte controle ten opzichte van de vier eosinofiel categorieën geanalyseerd, dit
werd gedaan met behulp van de Asthma Control Questionnaire (ACQ) en Clinical COPD
Questionnaire (CCQ). Secundaire uitkomstmaten betroffen de verschillen in effectiviteit van
ICS met betrekking tot de longfunctie en het aantal exacerbaties. De analyses werden zowel
uitgevoerd op de gehele studie populatie als voor de drie verschillende ziektebeelden
afzonderlijk.
Resultaten: 215 astmapatiënten, 74 COPD-patiënten en 48 ACO-patiënten voldeden aan de
inclusie criteria. Over het gehele cohort toonden patiënten met een EO-gehalte van >400
cellen/μL op baseline een grotere verbetering in hun ziekte controle na behandeling met ICS
dan patiënten met een EO-gehalte tussen 151-300 cellen/μL (p=0.005). De specifieke
analyses in astma-, COPD- en ACO-patiënten toonden alleen een vergelijkbaar resultaat
onder COPD-patiënten. Er werden geen significante verschillen gevonden in effectiviteit van
ICS met betrekking tot de longfunctie en het aantal exacerbaties in relatie tot het EO-gehalte.
Conclusie: Behandeling met ICS is geassocieerd met een grotere verbetering in ziekte
controle bij patiënten met een hoog EO-gehalte op baseline in vergelijking tot patiënten met
een laag EO-gehalte. Het absolute EO-gehalte lijkt een potentiele biomarker die kan bijdragen
aan de besluitvorming voor het starten van een behandeling met ICS bij respiratoire patiënten
in de eerste lijn. De resultaten van deze studie geven het belang weer voor prospectieve en
gerandomiseerde control trials in een grotere patiëntenpopulatie.
Trefwoorden: Eerstelijns zorg, Eosinofiel gehalte, Inhalatie corticosteroïden, Ziekte Controle
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 5
Table of abbreviations
ACO Asthma-COPD overlap
ACQ Asthma control questionnaire
AC-service Asthma/COPD service
ANOVA Analysis of variance
BDT Bronchodilator test
CCQ Clinical COPD questionnaire
COPD Chronic obstructive pulmonary disease
CRQ Chronic respiratory questionnaire
EO-count Peripheral blood eosinophil count
FEV1 Forced expiratory volume in 1 second
FVC Forced vital capacity
GINA Global initiative for asthma
GOLD Global initiative for chronic obstructive lung disease
GP General practitioner
ICS Inhaled corticosteroids
IQR Interquartile range
LABA Long-acting beta2-agonist
LAMA Long-acting muscarinic antagonist
MCID Minimal clinical important difference
NA Not applicable
NS Not significant
SABA Short-acting beta2-agonist
SAMA Short-acting muscarinic antagonist
SD Standard deviation
SGRQ St. George’s respiratory questionnaire
WMO Medical research involving human subjects act
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Table of contents
1. Introduction ................................................................................................................................... 7
1.1. Asthma, COPD and ACO ........................................................................................................ 7
1.2. Blood eosinophil count ............................................................................................................ 8
1.3. Treatment with inhaled corticosteroids ................................................................................... 9
1.4. Role of blood eosinophil count as biomarker ........................................................................ 10
1.5. Real life data .......................................................................................................................... 10
1.6. Aims ...................................................................................................................................... 11
2. Research questions ...................................................................................................................... 12
3. Material and methods ................................................................................................................. 13
3.1. Study design .......................................................................................................................... 13
3.2. Data source ............................................................................................................................ 13
3.3. Participants ............................................................................................................................ 13
3.4. Procedure ............................................................................................................................... 13
3.5. Primary outcome ................................................................................................................... 14
3.6. Secondary outcomes .............................................................................................................. 15
3.7. Data analysis .......................................................................................................................... 15
3.8. Ethics ..................................................................................................................................... 16
4. Results........................................................................................................................................... 17
4.1. Patient characteristics ............................................................................................................ 17
4.2. Follow-up time ...................................................................................................................... 20
4.3. Effect of ICS treatment on disease control ............................................................................ 20
4.4. Effect of ICS treatment on lung function .............................................................................. 22
4.5. Effect of ICS treatment on exacerbation rate ........................................................................ 23
4.6. Sensitivity analyses: differences in follow-up time ............................................................... 23
5. Discussion ..................................................................................................................................... 24
5.1. Main findings ........................................................................................................................ 24
5.2. Comparison with current literature ........................................................................................ 24
5.3. Strength and limitations ......................................................................................................... 26
5.4. Implications and recommendations ....................................................................................... 28
6. Conclusion .................................................................................................................................... 29
7. Acknowledgements ...................................................................................................................... 30
8. References .................................................................................................................................... 31
Appendices ........................................................................................................................................... 35
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1. Introduction The prevalence of respiratory obstructive diseases is increasing worldwide(1,2). Asthma and
chronic obstructive pulmonary disease (COPD) are the two most prevalent of them and have
become an earnest and under-treated health problem with a high mortality rate(1,3,4). In the
Netherlands, currently more than 610,000 patients suffer from asthma and 600,000 patients
are diagnosed with COPD(5,6). Besides, these chronic diseases are responsible for increasing
health care costs and indirect costs by absenteeism and disability(4,7). The burden of asthma
and COPD on society is high and, therefore, over the past decades research about optimal
treatment of these diseases has become a wide field of interest.
1.1. Asthma, COPD and ACO
Asthma
Asthma is described in the Global Initiative for Asthma (GINA) as a chronic inflammatory
disorder of the airways that is usually reversible, either spontaneously or with treatment(8).
Classically, asthma consists of three components: airflow limitation, airway hyper
responsiveness and bronchial inflammation. Many cells and cellular elements play a role in
the bronchial inflammation like T-lymphocytes, mast cells and eosinophils. Therefore, asthma
is seen as a Th2-mediated eosinophilic disease(9,10). The T-lymphocytes, mast cells and
eosinophils provide edema, smooth muscle hypertrophy, matrix deposition, mucus plugging
and epithelial damage(3). Wheezing, dyspnea, and predominantly nightly or early morning
coughing are the characteristic symptoms of asthma(8). Usually, allergic agents play a role in
the development of asthma. Therefore, bronchus obstruction is often a result of increased
sensitivity of the respiratory tract to allergic stimuli which consequentially causes the
inflammation(1,3,7).Besides, more than half of asthma patients are atopic and have an
increased immunoglobulin E (IgE) level against specific antigens in their blood, explaining
the allergic reaction of their immune system(5,11). Therefore, atopic diseases like allergic
rhinitis and eczema are frequent comorbidities in patients with asthma(7,12). Most of the
time, asthma typically develops in childhood but, occasionally, the disease becomes active for
the first time at later age(7).
COPD
COPD is a chronical disorder characterized by airflow limitation that is progressive and not
entirely reversible(2–4,13). The airflow limitation is associated with an abnormal
inflammatory response of the lungs to toxic particles and gases and is caused by a mixture of
small airways disease (obstructive bronchiolitis) and parenchymal destruction
(emphysema)(13). Cigarette smoking is the main risk exposure for COPD(13). The risk of
developing COPD is proportional to the number of cigarettes smoked per day(3,14). Less
frequent causes are climate change, biomass fuel exposure and air pollution(3). The
symptoms of COPD are comparable to asthma and comprises productive cough with clear
sputum, dyspnea and wheeze(3,13). Exacerbations contribute to the overall severity in
patients with COPD(13). Exacerbations are provoked by viral or bacterial airway infections
(50% to 70%) or environmental factors like air pollution(4). Different inflammatory cells are
consistently present in the airways and responsible for airflow obstruction in COPD(9).
Neutrophils and CD8+ T lymphocytes are the most important ones and have shown to
demonstrate themselves at all levels of the lung in exacerbations(9,10,12,15). In contrast to
asthma, allergic agents do not contribute to exacerbations in individual patients with
COPD(4). The differences and diagnostic features of both asthma and COPD are listed in
Table 1.
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Table 1: Differences between asthma and COPD(7,12,13,16)
Asthma
COPD
Most important risk factor Atopy Tobacco smoking
Airway obstruction Reversible Not completely reversible
Pathophysiology Chronic inflammation in all
airways with good response to
corticosteroids
Chronic inflammation of the small airways,
relatively unresponsive to corticosteroids
Onset Usually childhood Mid-life (>40 years)
Symptoms Dyspnea, cough, wheeze
Varies from day to day
Dyspnea, cough, mucus production
Slowly progressive
Co-morbidities Allergy, rhinitis and/or eczema
are often present
Chronic diseases like heart disease,
osteoporosis, diabetes mellitus and
depression
Lung function Predominantly normal with
good treatment
Persistent reduced, even with optimal
treatment
Life expectancy Normal life expectancy Reduced life expectancy
Inhaled corticosteroids Indicated Not indicated, unless suffering from
exacerbations frequently (≥ 2 exacerbations
per year) Abbreviations: COPD, chronic obstructive pulmonary disease
ACO
In addition to asthma and COPD there is a group of patients who have airway inflammation
with features of both asthma and COPD. The Global Initiative for Chronic Obstructive Lung
Disease (GOLD) and GINA describe a so called Asthma-COPD Overlap Syndrome
(ACOS)(17), which is currently renamed to Asthma-COPD Overlap (ACO) as it does not
describe a single disease entity(8). ACO is characterized by persistent airflow limitation with
several features usually associated with asthma and several features associated with
COPD(10,18,19). However, there is still no generally accepted definition of ACO. Miravitlles
et al. recently proposed an algorithm to identify ACO among patients with COPD or
asthma(20). This algorithm is illustrated in Figure 1. Literature shows that one in four patients
with COPD have ACO(21,22). Unfortunately, less is known about the prevalence of ACO in
those with pre-existing asthma(22). It is important to distinguish ACO from both asthma and
COPD because previous research indicates that patients with ACO have exacerbations more
frequently, are hospitalized more, have worse health-related quality of life and higher
healthcare costs than those with pure asthma or pure COPD(21,22). Contrary, patients with
ACO appear to have a better mortality rate after 1 year compared to patients with pure
COPD(19).
1.2. Blood eosinophil count
As described previously, the airway inflammation of asthma and COPD is different. COPD is
characterized by neutrophilic inflammation, whereas asthma is characterized by inflammation
involving T lymphocytes and eosinophils(10). Often, the presence of eosinophilic
inflammation is viewed as a distinguishing feature between asthma and COPD(9).
However, it is important to note that eosinophilic airway inflammation has been
demonstrated in tissue samples and in 20%-40% of induced sputum samples of patients with
stable COPD(9,12,15). In exacerbations, this airway eosinophilia is increased(9,23).
Comparison of bronchial biopsies taken during acute exacerbations to those of patients with
stable COPD, shows a 30-fold increase in the number of eosinophils(9).
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 9
Figure 1: Diagnostic algorithm of
asthma-COPD overlap(20)
Persistent airflow limitation (FEV1/FVC <0.7)
must be confirmed after treatment with
bronchodilators and inhaled corticosteroids or
after a course of oral corticosteroids, when
required. Abbreviations: ACO, asthma-COPD overlap;
COPD, chronic obstructive pulmonary disease;
BDT, bronchodilator test; FEV1, forced
expiratory volume in 1 second; FVC, forced
vital capacity.
Several studies concluded that there is a significant positive relationship between the sputum
eosinophil count and blood eosinophil parameters, in terms of percentage or absolute count,
during exacerbations in patients with asthma, COPD and ACO(23–25).
Previous research showed that peripheral blood eosinophilia is associated with an
increase in all-cause mortality in patients with respiratory diseases(26,27). Therefore, the
peripheral blood eosinophil count(EO-count) is considered a predictor for the severity of the
disease(28).
In a cohort study, Price et al.(29) demonstrated that asthma patients with an EO-count
>400 cells/µL experience more severe exacerbations. This study also investigated the degree
of disease control and health status relative to different EO-counts. It was demonstrated that a
high EO-count >400 cells/µL was associated with a poorer asthma control. However, health
status deterioration was also observed for COPD patients with low EO-counts(30).
Furthermore, there is possibly a relation between EO-count and lung function in
patients with respiratory diseases. A high EO-count might contribute to a greater decline in
lung function, as measured by the forced expiratory volume in one second (FEV1), in patients
with asthma(31). In contrast, in COPD patients with an EO-count persistently >2%, the
predicted FEV1 was higher than that of the control group with an EO-count persistently
<2%(30,32). It is important to note that the differences between these groups were very small
and, therefore, the outcome of doubtful clinical relevance(30,32).
1.3. Treatment with inhaled corticosteroids
Inhaled corticosteroids (ICS) are preferred anti-inflammatory treatment for symptom
reduction, lung function improvement, exacerbation reduction and quality of life
improvement in patients with (allergic) asthma(7). Therefore, over the past decades, ICS have
taken an important role in asthma treatment. Moreover, there is an abundance of evidence
underlining the effectiveness of ICS for patients with asthma(8,33,34).
Several studies described that COPD patients are often unresponsive to corticosteroid
treatment because of their airway inflammation characteristics(12,35,36). Besides, it is known
that cigarette smoking impairs the efficiency of ICS treatment, which clarifies the nonexistent
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 10
response to ICS in COPD patients(37,38). However, literature also shows that when the
airway inflammation is dominated by high levels of eosinophils, it is more responsive to
corticosteroids(12,39). As described previously, in patients with severe COPD and frequent
exacerbations, the airway inflammation often consists of eosinophils too, which explains
responsiveness to corticosteroids in severe COPD patients(12). Research proved that ICS,
either solely or combined with long-acting beta2-agonists (LABA), decrease the risk of
exacerbations in COPD patients(40–42).
However, ICS therapy in patients with COPD is associated with more serious side
effects like pneumonia, bone fracture, diabetes and skin thinning(12,43–47). This increased
risk is possibly due to the typically older age and frequent comorbidities, like cardiovascular
diseases(4,12). Possibly, that is why general practitioners (GPs) are generally reserved in
prescribing ICS. Besides, lack of evidence of the effectiveness of ICS in COPD has led to
recommendations in which the use of ICS is restricted to severe COPD and frequent
exacerbations(12).
For patients suffering from ACO, there is a lack of randomized controlled studies
about the effectiveness of ICS(10). However, research does show that COPD patients with
asthma-like-features could benefit from treatment with ICS and might respond better to ICS
treatment than those with pure COPD(22,48,49).
1.4. Role of blood eosinophil count as biomarker
Due to the described side effects and lack of evidence of its effectiveness, the choice to start
with ICS treatment in primary care respiratory patients is a complicated decision, affording a
growing need for a biomarker that can predict the ICS treatment response.
The EO-count might be a possible predictor of the effectiveness of ICS in patients
with asthma, COPD and ACO(15,29). Previous studies suggest that patients with a higher
EO-count will have a better response to treatment with corticosteroids(23,28,39,50–52).
Patients with an EO-count >2% are significant less likely to experience exacerbations when
treated with ICS(51,52). Moreover, it was concluded that withdrawing ICS from patients with
an EO-count >4% or >300 cells/µL induced deleterious effects, like severe exacerbations,
which was not seen in patients with an EO-count below these thresholds(15).
However, the exact role of the EO-count and the effectiveness of ICS still remains
unclear in primary care respiratory patients, given the contradictory results in this field of
research to date. Therefore, research is required to investigate the ICS responsiveness more
extensively in a combined approach of asthma, COPD and ACO patients. To make
personalized care possible, well-defined real-life data on patient characteristics are required to
allow for comparison between patients with a good or poor response to ICS treatment.
1.5. Real life data
Most of previous described knowledge is derived from post-hoc analysis of clinical trials and
retrospective studies while solely a few studies used real life data. Real-life data are health
care data collected under real life practice circumstances. This provides a better representation
of the current care population due to a lack of precise inclusion and exclusion criteria(53).
The asthma/COPD service (AC-service) in Groningen, the Netherlands, is a supporting
service to improve the primary care treatment of asthma, COPD and ACO and consists of
real-life data of primary care respiratory patients(54). This service provides a unique
opportunity for the use of real life data to investigate the effectiveness of ICS relative to
different EO-counts in primary care respiratory patients.
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 11
1.6. Aims
This study aims to gain insight into the effect of ICS treatment for different EO-counts in real
life patient data.
The disease control gives a personalized approach to the real health status of the
patient, rather than lung function or exacerbation rate data that only addresses the condition of
the airways(55,56). Therefore, the primary objective is to investigate ICS treatment
effectiveness in terms of improved disease control (by means of the Asthma Control
Questionnaire (ACQ) and the Clinical COPD Questionnaire (CCQ) scores) for different EO-
counts. As secondary objectives the effectiveness of ICS treatment in terms of exacerbation
rate and lung function for different EO-counts will be analyzed.
According to previous work in the field, it is hypothesized that, in primary care
respiratory patients with asthma, COPD and ACO, higher EO-counts will lead to better
treatment response of ICS in terms of disease control, exacerbation rate and lung function.
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 12
2. Research questions
The primary research question is:
What is the effectiveness of ICS treatment in terms of improved disease control for
different EO-counts in patients with asthma, COPD and ACO?
Secondary research questions are:
What is the effectiveness of ICS treatment in terms of exacerbation rate for different
EO-counts in patients with asthma, COPD and ACO?
What is the effectiveness of ICS treatment in terms of lung function for different EO-
counts in patients with asthma, COPD and ACO?
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 13
3. Material and methods
3.1. Study design
This was a retrospective observational database study in primary care.
3.2. Data source
For this study, data were derived from the AC-service and Certe. The AC-service is part of
Certe, an organization for medical diagnostics and advice in primary and secondary care.
Asthma/COPD service
The AC-service, established in 2007 in Groningen, the Netherlands, is a service in which
general practitioners (GPs) are supported by pulmonologists to diagnose and manage their
asthma and COPD patients. GPs, from the Northern part of the Netherlands, can refer all
patients (≥ 8 years) with complaints indicative of asthma, COPD or ACO. Referred patients
complete a medical history questionnaire, the ACQ, the CCQ and different lung function tests
by spirometry. These data are assessed by an pulmonologist and recommendations concerning
diagnosis, medical and non-medical interventions are made. The GP receives the
pulmonologist’s recommendations within five working days after sending the patient to the
AC-service. Implementation of these recommendations is decided by the GP who is
ultimately responsible for the disease management. However, when a change in medication is
advised by the pulmonologist, patients are normally scheduled for an additional follow-up
visit after 3 months (range 2-4 months) by the AC-service. When no medication change is
advised but the GP does request a follow-up visit, patients will be assessed after 12 months
(range 10-14 months) by the AC-service(54,57). A cross sectional study on the feasibility and
effectiveness of this service showed that 60% of all adult patients with asthma, COPD and
ACO in the target area were assessed by the AC-service at least once(54). Asthma, COPD and
ACO patients visiting the service all showed improved health status and disease control
within three months. The service’ aim is to improve the management of primary care asthma,
COPD and ACO, however, data of included patients are also available for research, providing
a unique opportunity in exploring a large population. The aforementioned study included data
of 11,401 asthma, COPD and ACO patients assessed by the AC-service in 2014(54). Since
2014 the AC-service has continued assessing primary care respiratory patients and their data
were added to the database.
3.3. Participants
Patients who were referred to the AC-service from 2007 till 2016 were eligible for this study.
The first consultation of the AC-service was defined as the indexation date. In Table 2 an
overview of inclusion and exclusion criteria is depicted.
3.4. Procedure
A dataset was created with data from 2007 till 2016 selected from the AC-service database.
This data was combined on patient level with eosinophil data from the Certe-database. For
each patient, the most recent EO-count at the indexation date was used in analyses. Data from
the first follow-up visit after the indexation date were analyzed and compared to the baseline
data at the indexation date. All data concerning demographics (age, weight, height, medical
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 14
history, family history etc.), disease control (ACQ and CCQ), lung function, exacerbations
and medical advices given by the pulmonologist were analyzed.
Because the time between the indexation date and first follow-up visit differed per
patient, two different time periods for the follow-up visits were made. Based on previous
work of Metting et al.(54) and the distribution of the follow-up time among the included
patients in this study, these time periods were determined as < 6 months and ≥ 6 months. Sub
analyzes into the comparison between these time periods were performed.
Since this was a database study, a formal power calculation was not applicable.
Table 2: Inclusion and exclusion criteria of population
Inclusion criteria
Exclusion criterion
Age > 7 years
A diagnosis of asthma, COPD or ACO
confirmed by a pulmonologist on or previous
to the indexation date
At least one follow-up visit
Use of ICS treatment on the follow-up visit
A documented blood eosinophil count within
two years prior to the indexation date
Use of either inhaled or systemic
corticosteroids on or prior to the
indexation date
Abbreviations: AC-service, Asthma/COPD service; COPD, chronic obstructive pulmonary disease; ACO, asthma-COPD
overlap; ICS, inhaled corticosteroids.
3.5. Primary outcome
The primary outcome of this study was the difference in disease control after the start of ICS
in patients with asthma, COPD and ACO for different EO-counts. The outcomes were
analyzed for all three diseases combined as well as all three separately.
Patients were divided into subgroups based on their documented EO-count on the
indexation date. A valid EO-count was defined as a numerical value in blood eosinophil
concentrations of cells x 109
per L. Values were transformed to blood eosinophils per µL. The
four different groups were categorized according to the previous work of Watz et al.(15):
Group 1: Blood eosinophil count ≤150 cells/µL
Group 2: Blood eosinophil count 151-300 cells/µL
Group 3: Blood eosinophil count 301-400 cells/µL
Group 4: Blood eosinophil count > 400 cells/µL
To measure disease control, the validated self-administered ACQ and the CCQ were
used(55,58); see Appendices I and II. After referral to the AC-service, every patient needed
to complete both questionnaires.
These questionnaires are helpful for clinicians to not only recognize the clinical status
of the airways, but also emotional dysfunction and activity limitation in patients with asthma
and COPD. The responsiveness, reliability and validity of both questionnaires were proven by
qualitative research and observational studies(55,58). The ACQ includes five questions about
symptoms and one question about short-acting beta2-agonist (SABA) use. The COPD
questionnaire on the other hand includes ten questions divided into three subdomains with two
questions about mental status, four questions about functional status and four questions about
symptoms(55). Both questionnaires use a range of 0 to 6 to score the questions. Stable or
‘controlled’ asthma and COPD were respectively defined as an ACQ-score < 0,75 and CCQ-
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 15
score <1 respectively. Unstable asthma and COPD were defined as an ACQ-score ≥ 1.5 and
CCQ-score ≥ 1.7 respectively(59,60).
To measure the disease control, both questionnaires were used for all three diseases
combined. For specific analyzes into asthma patients, the ACQ-score was used to measure the
disease control. For specific analyzes into COPD patients, the CCQ-score was used. Both
questionnaires and equal scoring were used for patients with ACO. The means of disease
control scores at baseline and the first follow-up visit were compared.
It is questioned whether the ACQ- and CCQ-score results might be used for analyses
on the entire cohort and in ACO patients, because the ACQ is only validated for asthma
patients and the CCQ only for COPD patients(55,58). However, use of the ACQ-score for
COPD patients and vice versa is previously described in literature(61–63). Moreover, a
Pearson Correlation of 0.82 (p < 0,001) between the two questionnaires suggests that both
scores are representative for the non-validated patient population as well; see Appendix III.
3.6. Secondary outcomes
Secondary outcomes of this study were the difference in 1) lung function and 2) exacerbation
rate in ICS users with asthma, COPD and ACO for different EO-counts. The secondary
outcomes were analyzed in the same EO-count subgroups as the primary outcomes.
Differences in lung function and exacerbation rate between the baseline and the first follow-
up visit were analyzed. The secondary outcomes were analyzed for all three diseases
combined as well as all three separately.
The lung function was measured by post bronchodilator spirometry in terms of the
FEV1 in percentage of predicted, the FEV1 in liters and the forced vital capacity (FVC) in
liters. The FEV1/FVC ratio and the reversibility were determined both at the indexation date
and the first follow-up visit. The reversibility was defined as the increase in pre-
bronchodilator FEV1 compared to post-bronchodilator FEV1(54).
The exacerbation rate at the indexation date was defined as the number of patient-
reported exacerbations in the year prior to the indexation date. At the first follow-up visit, the
exacerbation rate was defined as the number of patient-reported exacerbations per year in the
period between the indexation date and the follow-up visit. Only the available reported
exacerbation rates of follow-up visits before June 2012 were analyzed, because the AC-
service steering group changed the way in which exacerbation rate data was obtained at the
follow-up visits performed after June 2012.
3.7. Data analysis
Statistical analyses were performed using the program IBM SPSS Statistics version 22.0. All
patients who met the inclusion criteria were included in the statistical analysis.
The baseline population was described by age, gender, body mass index, smoking
history, disease control (ACQ and CCQ), lung function performance and exacerbation history
for the different EO-count subgroups. Normally distributed variables were presented as mean
and standard deviation (SD). Nonnormally distributed scale variables were presented as
median and interquartile range (IQR). Categorized variables were presented as frequency of
appearance (n) and percentage (%). Normality of distributions was assessed by the calculated
Kurtosis and Skewness of histograms. Variables with values between -1 and 1 were
considered to be normally distributed. Furthermore, histograms of variables were interpreted
visually to assess the normality of distributions.
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 16
Analysis of the primary and secondary outcomes of this study were performed with
dependent sample t-test for normally distributed data and with the Wilcoxon Rank test for
nonnormally distributed data. The Mc Nemar test was used for dichotomous variables.
To prove differences between the four groups, the Analysis of Variance (oneway-
ANOVA) was used for normally distributed data and the Kruskall Wallis test was used for
nonnormally distributed data. The Chi-square test was used to compare groups for
dichotomous variables. Two tailed P values of less than 0,05 were taken as the threshold of
statistical significance(64).
3.8. Ethics
Patients who were referred to the AC-service agreed to anonymous usage of their data for
scientific research. The anonymous data were stored in a secure area.
Given this is a retrospective observational study and not an intervention study, this
study did not fall under the Medical Research Involving Human Subjects Act (WMO).
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 17
4. Results
4.1. Patient characteristics
Between January 2007 and December 2016 17,497 patients were referred to the AC-service.
Of these patients 11,567 were identified with asthma, COPD or ACO. Nine hundred sixty
patients met study eligibility criteria, of whom 337 (35%) had a documented EO-count. The
main reasons for exclusion were ICS treatment prior to or at indexation, or absence of ICS
treatment at the follow-up visit. In Figure 2 an overview of the selection criteria for eligible
patients is depicted.
Figure 2: Flow diagram of the
identification of eligible patients
Abbreviations: AC-service, Asthma/COPD
service; COPD, chronic obstructive pulmonary
disease; ACO, asthma-COPD overlap; ICS,
inhaled corticosteroids. *A valid blood eosinophil count was defined as a
numerical value for blood eosinophils recorded
within 2 years before the indexation date. 81% (n
= 274) was recorded within 1 year before the
indexation date.
Of all 337 patients included in the study, 126(37%) patients had a documented EO-count ≤
150 cells/µL, 151(45%) patients between 151-300 cells/µL, 31(9%) patients between 301-400
cells/µL and 29(9%) patients had an EO-count > 400 cells/µL. The median of EO-count
across all patients was 200 cells/µL (IQR 100-300). Of the entire study population, 215(64%)
patients were diagnosed with asthma, 74(22%) with COPD and 48(14%) with ACO.
38% (n = 129) of all included patients were male. However, higher male proportions
were observed in the patient groups with an EO-count between 301-400 cells/µL and > 400
cells/µL (p = 0,013). The median age across all patients was 55 years (IQR 41-65). Across the
different EO-count groups, the median age was the lowest among the patient group with an
EO-count > 400 cells/µL (median 44, IQR 24-59, p = 0,028).
When considering the smoking status of the entire study population, 33% (112
patients) were current smokers. Similar proportions of current smokers were obtained within
17,497 patients
referred to AC-
service
11,567 patients
with asthma,
COPD or ACO
960 patients
used ICS on
follow-up
337 patients
matched
inclusion criteria
Excluded:
diagnosis uncertain
n = 5,930
Excluded: current
or previous use of
ICS at baseline
n = 5,473
Excluded: no
documented blood
eosinophil count*
n = 623
6,094 patients
were ICS naive
at baseline
Exluded: no use of
ICS at follow up
n = 5,134
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 18
the different EO-count groups. SABA was the most received treatment at baseline (n = 107,
32%). Short-acting muscarinic antagonist (SAMA) treatment was used the least (n = 9, 3%).
This holds for all patients combined, as well as for the different patient groups stratified by
EO-count.
Baseline patient characteristics are presented in Table 3 and Table 4, respectively for
all patients together and for four groups of patients based on their EO-count. Supplemental
Table 1, appendix IV shows additionally baseline patient characteristics by asthma, COPD
and ACO diagnosis.
Table 3: Baseline characteristics for all included patients
Variable
Total
Demographics
Gender, male, n(%)
Age, years, median (IQR)
Body–mass index, kg/m2, median(IQR)
n=337
129 (38)
55 (41–65)
27 (23–31)
Smoking status
Current smoker, n(%)
Ex–smoker, n(%)
Smoke exposure, years, median (IQR)
n=337
112 (33)
132 (39)
22 (0–30)
Diagnosis, n(%)
Asthma
COPD
ACO
n=337
215 (64)
74 (22)
48 (14)
Age of disease onset or onset of symptoms, median (IQR)
Mean disease duration, years, median (IQR)
n=320 40 (13–58)
9 (2–24)
Current treatment at first consultation, n(%)
SABA
SAMA
LABA
LAMA
n=337
107 (32)
9 (3)
19 (6)
27 (8)
Disease control, median (IQR)
ACQ
CCQ
n=337
n=326
1.5 (0.8–2.0)
1.6 (1.0–2.4)
Lung function: post bronchodilator spirometry, mean (±SD)
FEV1% predicted
FEV1/FVC
Reversibility*, median (IQR)
n=337
n=320
86 (±19)
71 (±14)
6.7 (2.5-12.4)
≥ 1 exacerbation last year$, n(%) n=168 65 (39)
Abbreviations: COPD, chronic obstructive pulmonary disease; ACO, asthma–COPD overlap;
IQR, interquartile range; SABA, short–acting beta2-agonist; SAMA, short–acting muscarinic
antagonist; LABA, long–acting beta2-agonist; LAMA, long–acting muscarinic antagonist;
ACQ, asthma control questionnaire; CCQ, clinical COPD questionnaire; FEV1, forced expiratory
volume in 1 second; FVC, forced vital capacity.
*Increase in FEV1 pre bronchodilator compared with FEV1 post bronchodilator. $ Exacerbations are defined as having used oral corticosteroids or antibiotics for lung problems last year
Table 4: Baseline characteristics of patients for different EO-count groups
Abbreviations: EO-count, peripheral blood eosinophil count; IQR, interquartile range; COPD, chronic obstructive pulmonary disease; ACO, asthma–COPD overlap; SABA, short–acting beta2-
agonist; SAMA, short–acting muscarinic antagonist; LABA, long–acting beta2-agonist; LAMA, long–acting muscarinic antagonist; ACQ, asthma control questionnaire; CCQ, clinical COPD
questionnaire; SD, standard deviation; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; NS, not significant.
*Increase in FEV1 pre bronchodilator compared with FEV1 post bronchodilator. $Exacerbations are defined as having used oral corticosteroids or antibiotics for lung problems last year.
†Chi-square, **Kruskall-Wallis, ‡ 0ne-way ANOVA, p-values are two-sided and considered significant ≤ 0.05.
Variable
Eosinophils ≤150
cells/µL
Eosinophils 151–300
cells/µL
Eosinophils 301–400
cells/µL
Eosinophils >400
cells/µL
p - value
Demographics
Gender, male, n(%)
Age, years, median (IQR)
Body–mass index, kg/m2, median(IQR)
n=126
41 (33)
54 (37-64)
26 (23-31)
n=151
54 (36)
57 (47-66)
28 (25-32)
n=31
18 (58)
52 (39-72)
27 (23-29)
n=29
16 (55)
44 (24-59)
27 (23-31)
0.013† 0.028** 0.033**
Smoking status
Current smoker, n(%)
Ex–smoker, n(%)
Smoke exposure, years, median (IQR)
n=126
41 (33)
47 (37)
21 (0-29)
n=151
56 (37)
61 (40)
24 (6-31)
n=31
10 (32)
10 (32)
25 (0-33)
n=29
5 (16)
14 (48)
16 (0-27)
NS†
NS†
NS**
Diagnosis, n(%)
Asthma
COPD
ACO
n=126
81 (64)
25 (20)
20 (16)
n=151
92 (61)
35 (23)
24 (16)
n=31
19 (61)
9 (29)
3 (10)
n=29
23 (80)
5 (17)
1 (3)
NS† NS†
NS†
Age of disease onset, median (IQR)
Mean disease duration, years, median (IQR)
n=117 35 (14-56)
9 (2-27)
n=144 42 (15-59)
8 (2-25)
n=30 40 (11-60)
12 (3-19)
n=29 32 (8-49)
8( 3-23) NS**
NS**
Current treatment at first consultation, n(%)
SABA
SAMA
LABA
LAMA
n=126
38 (30)
4 (3)
7 (6)
10 (8)
n=151
46 (31)
5 (3)
8 (5)
13 (9)
n=31
10 (32)
0 (0)
3 (10)
2 (7)
n=29
13 (45)
0 (0)
1 (3)
2 (7)
NS†
NS†
NS†
NS†
Disease control, median (IQR)
ACQ
CCQ
n=126
n=122
1.4 (0.8-2.0)
1.6 (1.1-2.3)
n=151
n=147
1.3 (0.7-2.0)
1.6 (1.0-2.3)
n=31
n=30
1.8 (1.2-2.3)
1.7 (1.2-2.6)
n=29
n=27
1.7 (1.0-2.1)
1.6 (0.8-2.5)
NS**
NS**
Lung function post bronchodilator, mean (±SD)
FEV1% predicted
FEV1/FVC
Reversibility*, median (IQR)
n=126
n=118
86 (±19)
72 (±15)
6.1(2.9-12.1)
n=151
n=144
86(±18)
70(±13)
7.4(2.3-13.0)
n=31
n=30
83(±17)
70(±15)
6.9(4.2-13.3)
n=29
n=28
88(±21)
76(±14)
4.6(0.4-9.2)
NS‡
NS‡
NS**
≥ 1 exacerbation last year$, n(%) n=66 26 (39) n=68 24 (35) n=19 8 (42) n=15 7 (47) NS†
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 20
4.2. Follow-up time
The median follow-up time after starting ICS treatment was 5 months (IQR 3-13). For the
patient group with a follow-up time ≤ 6 months and > 6 months the medians of the follow-up
time were 3 months (IQR 3-4) and 14 months (IQR 11-36) respectively. Figure 3 shows an
overview of the distribution of follow-up time.
Figure 3: Follow-up time in
months
*Follow-up time is the period
between the first and second visit
to the AC-service.
4.3. Effect of ICS treatment on disease control
The disease control, measured by the ACQ- and CCQ-score, improved in most of the patients
after starting with ICS treatment (mean decrease of the ACQ-score and the CCQ-score was
0.39 (SD 0.33) and 0.37 (SD 0.30) respectively). In all four patients groups classified by EO-
count, there was a significant decline in the ACQ- and CCQ-score between baseline and
follow-up; see Table 5.
Table 5: Effect of ICS treatment on disease control (all included patients)
Abbreviations: ICS, inhaled corticosteroids; ACQ, asthma control questionnaire; CCQ, clinical COPD questionnaire;
COPD, chronic obstructive pulmonary disease; IQR, interquartile range; NS, not significant. $ Wilcoxon matched-pair signed rank test, p-values are two-sided and considered significant ≤ 0.05.
ACQ Baseline Follow-up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 124 1.4 (0.8–2.0) 1.0 (0.5–1.7) <0.001
Eosinophils 151-300 cells/µL 150 1.3 (0.7–2.0) 1.0 (0.5–1.7) <0.001
Eosinophils 301-400 cells/µL 29 1.8 (1.2–2.3) 1.0 (0.4–1.7) <0.001
Eosinophils > 400 cells/µL 28 1.7 (1.0–2.1) 0.6 (0.2–1.3) <0.001
CCQ Baseline
Follow–up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 101 1.6 (1.1–2.3) 1.3 (0.8–1.9) <0.001
Eosinophils 151-300 cells/µL 130 1.6 (1.0–2.3) 1.3 (0.7–1.9) <0.001
Eosinophils 301-400 cells/µL 25 1.7 (1.2–2.6) 1.5 (1.0–1.9) 0.016
Eosinophils > 400 cells/µL 23 1.6 (0.8–2.5) 0.6 (0.4–1.7) 0.018
n = 337
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 21
The Kruskal-Wallis H test showed that there was a significant difference in decrease of ACQ-
scores between the different EO-count groups; X2(3) = 12.991, p = 0.005, with a mean rank
ACQ-score of 161 for eosinophils ≤ 150 cells/µL, 155 for eosinophils 151-300 cells/µL, 202
for eosinophils 301-400 cells/µL and 211 for eosinophils > 400 cells/µL. Therefore, post-hoc
tests were performed to specify in which groups significant differences in decrease of ACQ-
scores arose. The Mann-Whitney U test only showed a significant difference between the
groups with an EO-count between 151-300 cells/µL and an EO-count > 400 cells/µL (p =
0,005); see Figure 4. The Kruskal-Wallis H test did not show significant differences in the
decrease of CCQ-scores between the different EO-count groups, in analyses of all included
patients.
Figure 4: Boxplot of decrease
in ACQ score between
baseline and follow up for the
four groups categorized on
blood eosinophil count (all
included patients)
Abbreviations: ACQ, Asthma
Control Questionnaire; MCID,
minimal clinical important difference *Decrease of ACQ-score
In stratified analyses for diagnosis, asthma patients showed a significant decline of the ACQ
score for all EO-count groups after starting ICS treatment; see Supplemental Table 2,
appendix IV. COPD patients also demonstrated a significant decrease in CCQ-score after
starting ICS treatment for all EO-count groups, apart from those with an EO-count between
151-300 cells/µL; see Supplemental Table3, appendix IV. No significant decreases in ACQ
and CCQ scores between baseline and follow-up were observed in patients with ACO; see
Supplemental Table 4, appendix IV.
Between the different EO-count groups, specific analyses into asthma patients did not
show any statistically significant difference in decrease of ACQ-scores. However, specific
analyses for COPD patients did show a significant difference in decrease of the CCQ-scores
between the different EO-count groups (Kruskal-Wallis H test; X2(3) = 10.571, p = 0.048,
with a mean rank CCQ-score of 44 for eosinophils ≤ 150 cells/µL, 31 for eosinophils 151-300
cells/µL, 38 for eosinophils 301-400 cells/µL and 53 for eosinophils > 400 cells/µL). Post-hoc
tests, using the Mann-Whitney U test, showed significant differences in decrease of CCQ-
scores between the groups with an EO-count 151-300 cells/µL and an EO-count > 400
cells/µL (p = 0.052) and between the groups with an EO-count ≤ 150 cells/µL and an EO-
count 151-300 cells/µL (p = 0.021). The latter showed a significant greater decrease of CCQ-
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 22
score in patients with an EO-count ≤ 150 cells/µL compared to patients with an EO-count
between 151-300 cells/µL; see Figure 5.
The Kruskal-Wallis H test was not performed for the sub analyses into ACO patients,
due to the too small sample sizes within the different EO-count groups.
Figure 5: Boxplot of decrease
in CCQ score between
baseline and follow up for the
four groups categorized on
blood eosinophil count
(COPD patients)
Abbreviations: CCQ, Clinical
COPD questionnaire; COPD, chronic
obstructive pulmonary disease;
MCID, minimal clinical important
difference *Decrease of CCQ-score
4.4. Effect of ICS treatment on lung function
After starting ICS treatment, no significant improvement was found for both the FEV1%
predicted and FEV1/FVC-ratio between baseline and follow-up for all patients classified by
EO-count. Patients with an EO-count between 151-300 cells/µL even showed a significant
reduction in the FEV1/FVC-ratio after starting with ICS treatment (p = 0.022); see Table 6.
Analyses between the different EO-count groups did not show significant differences
in the degree of lung function improvement in both the FEV1% predicted and FEV1/FVC-
ratio, using the Kruskal-Wallis H test.
Stratified analyses for diagnosis did not show any significant differences in FEV1%
predicted after starting ICS treatment in asthma patients. However, significant declines in
FEV1/FVC-ratio were observed in patients with an EO-count ≤ 150 cells/µL (p = 0,001) and
in patients with an EO-count between 151-300 cells/µL (p = 0.011) after ICS treatment; see
Supplemental Table 5, appendix IV.
Analyses within COPD patients demonstrated an improvement of the FEV1%
predicted after starting ICS treatment only in the group with an EO-count > 400 cells/µL (p =
0,042). None of the four EO-count groups showed an improvement in FEV1/FVC-ratio after
starting ICS treatment; see Supplemental Table 6, appendix IV.
Analyses of patients with ACO did not provide any significant differences in both the
FEV1% predicted and FEV1/FEV-ratio after starting with ICS treatment; see Supplemental
Table 7, appendix IV.
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 23
Table 6: Effect of ICS treatment on lung function (all included patients)
Abbreviations: ICS, inhaled corticosteroids; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; IQR,
interquartile range; NS, not significant. $ Wilcoxon matched-pair signed rank test, p-values are two-sided and considered significant ≤ 0.05.
4.5. Effect of ICS treatment on exacerbation rate
There was a decline in the number of patients experiencing ≥ 1 exacerbation per year after
starting with ICS treatment in all four EO-count groups. However, these declines were only
significant in patients with an EO-count ≤ 150 cells/µL (p = 0.003) and between 301-400
cells/µL (p = 0.031); see Table 7.
Analyses between different EO-count groups, using the Chi square test, did not
demonstrate any significant difference in the decline of the number of exacerbations.
Analyses on asthma patients showed only a significant decline in the number of
exacerbations per year in the patient groups with an EO-count ≤ 150 cells/µL; see
Supplemental Table 8, appendix IV.
Specific analyses of COPD patients only and ACO patients only showed no significant
decrease in the number of patients experiencing ≥1 exacerbation per year after starting ICS
treatment. Also no decrease were observed in all four EO-count groups; see Supplemental
Table 9 and Table 10, appendix IV.
Table 7: Effect of ICS treatment on number of exacerbations (all included patients)
Abbreviations: ICS, inhaled corticosteroids; NS, not significant. *Exacerbation: number of patients experiencing ≥1 exacerbation per year, defined as having used oral corticosteroids or
antibiotics for lung problems $McNemar test, p-values are two-sided and considered significant ≤ 0.05.
4.6. Sensitivity analyses: differences in follow-up time
Sensitivity analyses were performed to account for patients with a follow-up time ≤ 6 months
and > 6 months after starting with ICS treatment. However, stratified analyses based on
follow-up time did not demonstrate any significant differences in the effect of ICS treatment
on disease control, number of exacerbations or lung function (data not shown).
FEV1% predicted Baseline Follow-up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 126 86 (73–99) 86 (72–98) NS
Eosinophils 151-300 cells/µL 151 88 (73–99) 86 (75–98) NS
Eosinophils 301-400 cells/µL 31 84 (67–96) 83 (75–100) NS
Eosinophils > 400 cells/µL 29 94 (77–104) 95 (76–105) NS
FEV1/FVC Baseline
Follow-up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 126 74 (62–82) 72 (62–80) NS
Eosinophils 151-300 cells/µL 151 72 (64–80) 72 (61–79) 0.022
Eosinophils 301-400 cells/µL 31 74 (63–81) 72 (65–83) NS
Eosinophils > 400 cells/µL 29 78 (73–83) 78 (71–82) NS
≥ 1 exacerbation per year* Baseline Follow-up p-value$
n n(%) n(%)
Eosinophils ≤ 150 cells/µL 57 25 (43.9%) 11 (19.3%) 0.003
Eosinophils 151-300 cells/µL 64 22 (34.4%) 16 (25.0%) NS
Eosinophils 301-400 cells/µL 19 8 (42.1%) 2 (10.5%) 0.031
Eosinophils > 400 cells/µL 15 7 (46.7%) 2 (13.3%) NS
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 24
5. Discussion
5.1. Main findings
The aim of this study was to gain insight into the effect of ICS treatment for different EO-
counts in real life patient data. Analyses on the entire cohort of 337 real-life primary care
respiratory patients showed that, after ICS treatment, patients with a high EO-count at
baseline were more likely to improve their disease control based on their ACQ-score. This
suggests that a high EO-count is associated with a better response to ICS treatment,
confirming our hypothesis. Although improvement of the CCQ-score after ICS treatment was
observed, this was not related to the EO-count.
Specific analyses of patient subgroups classified by their diagnosis did show
improvement of both the ACQ- and CCQ-score after ICS treatment respectively for asthma
and COPD patients. However, this improvement was only related to the EO-count in COPD
patients. In ACO patients, no improvement on disease control was observed after ICS
treatment.
Furthermore, the hypothesized beneficial effect of ICS on lung function and
exacerbation rate was not related to the EO-count, though the latter did show improvement
after ICS treatment in some of the EO-count groups.
The main findings will be discussed in more detail below.
5.2. Comparison with current literature
Improvement of disease control related to the EO-count
The observed improvement of disease control could not be substantiated with current
literature, regarding asthma, COPD and ACO patients as a whole. As far as known from
previous research, knowledge on this subject is derived from studies on COPD patients only.
In asthma and ACO patients, there is a lack of substantial evidence on this subject.
When considering COPD patients independently, several studies show similar
results(65–67). These studies demonstrated an improvement of disease control related to the
EO-count after ICS treatment. However, contradictory results are observed in current
literature as well(28,35). To specify, one study showed improvement of disease control after
ICS treatment, but this was not related to the EO-count(28). Another study did not even
observe an improvement at all in any of the EO-count groups(35).
Comparison of our results with this existing literature is difficult since the studies
show a great difference in study design. This may also explain in part the observed
heterogeneity in results. First, oral corticosteroids were used in some studies instead of
ICS(28,65). Second, compared to our study all five studies used the EO-count percentages or
levels of sputum eosinophils(28,35,65,66) instead of the absolute EO-count, in which the
latter provides a more accurate representation of the actual number of blood eosinophils.
Moreover, the Chronic Respiratory Questionnaire (CRQ) and St. George’s Respiratory
Questionnaire (SGRQ) were used in the aforementioned studies. While it has been
demonstrated that change in CCQ scores correlates significantly with change in these latter
questionnaires(63), the three questionnaires do differ. For example, the CCQ scores are more
responsive to the effects of pulmonary rehabilitation(68).
In asthma and ACO patients it remains unclear whether the effect of ICS on disease
control is related to different EO-counts, based on our study results. No significant relation
was found between disease control improvement and the EO-count after ICS treatment, when
considering the ACQ-score for asthma patients and both the ACQ- and CCQ-score for ACO
patients. However, the absence of a relation between EO-count and disease control after ICS
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 25
treatment in these two diseases separately might be due to the small sample sizes of these
subgroups. Therefore, future research into asthma and ACO patients should include a larger
study sample to be more certain about the effect of ICS on disease control by EO-count.
It is important to note that statistically significant improvement is not the same as
clinically relevant improvement. In this study statistically significant differences were
observed in both the ACQ and CCQ questionnaire when comparing baseline scores with
follow-up scores for different levels of EO-count. However, for patient groups with a low EO-
count (≤ 150 cells/µL) these differences were not of clinical importance in both the ACQ- and
CCQ-score (ΔACQ-score = 0.4, ΔCCQ-score = 0.3), given the minimal clinical importance
difference (MCID) is 0.5 and 0.4 for the ACQ- and CCQ-score respectively(69–71).
Regarding patient groups with a high EO-count (> 400 cells/µL), the observed improvement
on disease control was both statistically significant and clinically relevant (ΔACQ-score =
1.1, ΔCCQ-score = 1.0). There is only one earlier study(65) on this subject which provided a
MCID. In this study by Brightling et al., the Chronic Respiratory Questionnaire (CRQ) scores
were used to assess the effect of ICS on disease control in relation to sputum eosinophils.
Similar to our study, although we used the EO-count instead of sputum eosinophils, results
were only of clinical importance in the group with high eosinophils (<4.5%). Among the other
groups (i.e. <1.3% and 1.3-4.5%), improvements on disease control were proven to be
trivial(65).
No improvement of lung function related to the EO-count
For the entire cohort of respiratory patients, improvement of lung function after ICS treatment
was not observed in any of the EO-count groups. Most likely the chronic progressive
character of the respiratory diseases in this study has contributed to this lack of lung function
improvement. According to previous literature(31,65,66,72–74), on the other hand, it was
expected to observe differences between patients with a low EO-count compared to patients
with a high EO-count, in which a larger improvement was expected in the latter patient group.
In our study, within COPD patients, an improvement of lung function was solely
demonstrated in the group with an EO-count > 400 cells/µL (p = 0,042). However, a relation
between EO-count and lung function improvement after ICS treatment was not identified. In
contrast, according to previous work in the field of COPD patients, a relation between EO-
count and lung function improvement does exist. High sputum eosinophils were associated
with an improvement of the FEV1 when receiving systemic corticosteroids(65) or ICS(67).
This was substantiated by Park et al., showing that a high EO-count was associated with an
improved lung function after 3-months of ICS/LABA treatment in COPD patients(72).
Furthermore, Barnes and colleagues concluded that patients with an EO-count <2% had a
similar rate of post-bronchodilator FEV1 decline with fluticasone propionate as placebo, while
in patients with an EO-count ≥2% the rate of decline decreased with the use of fluticasone
propionate versus placebo(66).
In asthma and ACO patients, the effect of ICS on lung function in relation to different
EO-counts is investigated before as well(31,73,74). The response of lung function to ICS
treatment, measured by the FEV1, was poorer in both asthma and ACO patients with low
sputum and EO-counts compared to patients with high levels of sputum or EO-
counts(31,73,74). In our study, neither improvement of lung function nor a relation between
EO-count and lung function improvement was observed within asthma and ACO patients.
The fact that such a relation between EO-count and lung function improvement was
not observed in this study may be related to the use of four EO-count categories within an
already small sample size of patient groups. To compare, the aforementioned studies used a
maximum of two subgroups classified by EO-count(66,72–74). In present study four EO-
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 26
count groups were defined, because using four cutoff values provides a better representation
of the role of EO-count relative to ICS treatment response.
Another explanation for not finding an improvement of lung function after ICS
treatment might be the relatively long follow-up time, given the progressive character over
time (75,76) and the loss of lung function in early stages of the respiratory diseases(77). In
present study the median follow-up time was 5 months (IQR 3-13 months), which is long
compared to the follow-up time used in current literature, ranging from two weeks to three
months(67,72,74).
No improvement of exacerbation rate related to the EO-count
When analyzing the entire study population, a significant decline in the number of self-
reported exacerbations was observed in some of the EO-count groups (i.e. EO-count ≤ 150
cells/µL and EO-count 301-400 cells/µL). The observed declines of the exacerbation
frequency in the other groups (i.e. EO-count 151-300 cells/µL and EO-count > 400 cells/µL)
were not significant, however, these declines can be considered of clinical relevance given the
extent to which the frequencies decreased (9% and 33% respectively for EO-count 151-300
cells/µL and EO-count > 400 cells/µL). The identified declines in exacerbation rate after ICS
treatment were not related to EO-count, which was not in line with our expectation
considering previous work in the field(52,66,78).
Within COPD patients, many previous studies showed that the EO-count at baseline
was related to the exacerbation rate after ICS treatment(52,66,78). Compared to those with a
low EO-count, patients with a high EO-count gained more benefit from treatment with ICS in
terms of a reduced exacerbation frequency(52,66,78). In the present study, the absence of an
association between ICS treatment and reduced exacerbation frequency related to the EO-
count, may be again related to insufficient statistical power, since analyses were performed on
a total of 155 patients and specific analyses on solely 28 COPD patients. Compared to
previous work of Barnes et al.(66) and Pascoe et al.(52), more COPD patients were included
in their studies, respectively 738 and 3.177 patients. They also classified the COPD patients
into two different EO-count based sub groups (< 2% vs. ≥ 2%) instead of the four subgroups
used in the present study. Furthermore, comparison is also difficult because the present study
differs methodologically from the aforementioned studies, in which post-hoc analyses were
performed comparing an ICS treatment group with a control group receiving
placebo(52,66,78).
When considering asthma patients, previous studies did demonstrate a relation
between a higher EO-count and an increased risk of exacerbations, however, whether the
effect of ICS on the exacerbation rate is related to the EO-count is not investigated(29,79).
Belda et al. concluded that asthma patients with stable and well-controlled asthma are at risk
of exacerbation despite regular ICS treatment, especially in patients with an EO-count ≥ 400
cells/µL(79). This result is in contrast to our work, in which we do see a small clinically
relevant improvement of the exacerbation rate after starting with ICS treatment, although not
statistically significant.
Since ACO is a relatively new diagnosis, this is the first study to examine the effect of
ICS on health outcomes within EO-count groups. Unfortunately, the very small sample size of
ACO patients with available data on exacerbation rate withholds us to draw any conclusions.
5.3. Strength and limitations
To the best of our knowledge, this is the first study in primary care that examined the effect of
ICS on disease control, in relation to different EO-counts. Disease control measured by the
ACQ and CCQ reflects patients’ real functional status and health condition, rather than their
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 27
clinical observations. Moreover, as far as known, this is the first study investigating ICS
effectiveness in a combined approach of primary care respiratory patients with asthma, COPD
and ACO.
The strength of this study is the use of real life primary care data, which provides a
better representation of the actual situation of such a population with respiratory diseases(53).
In randomized control trials, on the other hand, it is mandatory to use strict inclusion and
exclusion criteria. Therefore, those study populations do not reflect the real patient
population.
Furthermore, in this study the absolute EO-count was used while many previous
studies(28,30,50–52,66,78) defined subgroups based on EO-count percentages. The latter can
be affected by total white blood cells and therefore, the absolute EO-count gives a more
accurate representation of the actual number of blood eosinophils. Besides, our study used
four cut off values instead of two cut off values used in previous studies(28,30,50,51,66,78).
Using more cut off values provides more insight into the exact role of the EO-count in
relation to the ICS treatment response.
A limitation of our study is that no control group was available because data were not
collected prospectively. A control group could have been created retrospectively, but this
would have biased the results because such a control group would consist of patients that did
not receive the advice to start ICS treatment. Hence, these patients were probably already
healthier. Without control group, it is not possible to conclude that the observed
improvements of the outcome measurement are due to ICS treatment alone. The observed
findings could partially be due to spontaneous changes(80). Therefore, our conclusions are
limited to implying a relation between EO-count and the effect size of ICS treatment, rather
than establishing a firm relation. However, both prospective(28,35,65,67,72) and retrospective
studies(15,52,66,78) using patient control groups, also showed an effect of ICS treatment on
related to EO-count. This does substantiate our implied relation.
A further shortcoming is that the AC-service is not established for scientific reasons.
Data derived from the AC-service could potentially be less accurate. For example, we could
not assess whether patients had used their ICS and determine their treatment adherence.
However, poor adherence to ICS would lead to poor disease control(81,82), while in our study
an improvement of disease control was demonstrated. Therefore, it is considered unlikely that
the aforementioned limitation would have affected the quality and outcome of this research
substantially.
Additionally, some patients in the study population used other inhalator medication
simultaneously with their ICS treatment, for which it is unknown whether the patients started
with these treatments concurrently. Therefore, it remains unclear whether the observed
treatment response is solely due to ICS or that other medication plays a role as well. However,
of the included patients only LABA or long-acting muscarinic antagonist (LAMA) treatment
was advised concurrently with ICS and for those treatments it is known that their effect is
greater when combined with ICS treatment(41,83–85).
Finally, as mentioned before, the small number of subjects limited us to draw firm
conclusions. While in very small patients groups it is difficult to find significant results, the
significant differences should also be treated with caution. Accordingly, further adjustments
for potential confounders like sex and age in multivariable linear regression analyses, could
not be performed due to the restricted study size. On the other hand, our study population size
was still larger than those employed in numerous previous studies(28,35,72,79,86).
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 28
5.4. Implications and recommendations
This study gives insight into the effect of ICS in relation to different EO-counts in primary
care respiratory patients. In practice, health care providers can expect that primary care
respiratory patients with a high EO-count will experience a better response to ICS treatment
than patients with a low EO-count. Therefore, the EO-count could be an attractive biomarker
to use in clinical practice. Moreover, EO-count measurement is convenient, widely available
and reliable in comparison to sputum eosinophil measurement which requires more skilled
technical support(28).
Further research is needed to further substantiate the observed improvement of disease
control, exacerbation rate and lung function with ICS treatment for patients with a high EO-
count. Especially in patients with asthma or ACO more research is required because of the
lack of evidence in this study population. Therefore, prospective studies with larger sample
sizes are required, also allowing for regression analyses. Moreover, to determine the effect
size of ICS treatment, study results have to be compared with a patient control group without
ICS treatment.
Towards more substantiation in future retrospective studies using real life data, use of
a pharmacy database linked at patient level would be advised to provide dispense data and
accurate data of medication collection. This affords additional information on the duration of
ICS treatment and allows for more extensive investigation into the combined use of ICS with
LABA or LAMA. Besides, the self-reported exacerbation rate could then also be checked by
correlation with the administration of oral corticosteroids or antibiotics.
Additionally, the predictive value of the EO-count in relation to ICS response remains
unclear. Generally, the EO-count tends to stay reasonably stable in individual patients over
time(87,88), however the exact time period over which EO-count can be assumed stable is
currently unknown. Therefore more information is still needed on the positive and negative
predictive value of this stability to define reliable stability ranges. With a firm conclusion on
the stability of eosinophils, it will be evident whether the EO-count is a promising biomarker
to guide disease management.
Finally this study shows that disease control is a promising measure to investigate the
effectiveness of ICS treatment relative to different EO-counts. However, to measure disease
control in primary care respiratory patients, a uniform questionnaire for asthma, COPD and
ACO patients is required, due to the overlap of current questionnaires and lack of a specific
questionnaire for ACO patients(62,63). Moreover, accuracy of the specific questionnaires per
diagnosis is also questionable given the different syndromes are comprised of various
phenotypes. Therefore, development of a general tool assessing the burden of chronic
respiratory conditions in primary care is required and should be used in further research on
this subject.
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 29
6. Conclusion
In primary care respiratory patients with a high EO-count at baseline, ICS treatment is
associated with larger improvements of disease control compared to subgroups of patients
with lower EO-counts. The beneficial effect of ICS on lung function and exacerbation rate
showed no correlation with the EO-count. The EO-count is potentially an important
biomarker that could contribute to treatment decision making in primary care respiratory
patients. These findings suggest the need for further studies, including prospective control
trials on larger sample sizes.
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 30
7. Acknowledgements
I would like to thank all members of the department of general practice (University Medical
Center Groningen) for their support and for providing me the opportunity to perform a
research project in the interesting field of primary care. Thanks to dr. J.W.H. Kocks (assistant
professor and program leader GRIAC-Primary Care) and dr. B.M.J. Flokstra- de Blok
(assistant professor) for their guidance and feedback. Special thanks to drs. H.J. Baretta and
dr. S.N. Slagter for their enthusiasm, commitment, encouragement and critical view in
completing the research project. A final thanks to drs. E.I. Metting for her assistance and
advice in the statistical analyses.
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 31
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70. Kocks J, Tuinenga M, Uil S, van den Berg
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M, Schuler M, Blok BF, et al. Health status
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pulmonary rehabilitation: defining a
minimal clinically important difference.
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2016;26(1):16041.
72. Park HY, Lee H, Koh W-J, Kim S, Jeong I,
Koo H-K, et al. Association of blood
eosinophils and plasma periostin with FEV
1 response after 3-month inhaled
corticosteroid and long-acting beta 2 -
agonist treatment in stable COPD patients.
Int J COPD. 2016;11:23–30.
73. Pavord ID, Brightling CE, Woltmann G,
Wardlaw AJ. Non-eosinophilic
corticosteroid unresponsive asthma. Lancet.
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74. Kitaguchi Y, Komatsu Y, Fujimoto K,
Hanaoka M, Kubo K. Sputum eosinophilia
can predict responsiveness to inhaled
corticosteroid treatment in patients with
overlap syndrome of COPD and asthma. Int
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75. Vestbo J, Edwards LD, Scanlon PD, Yates
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76. Drummond MB, Hansel NN, Connett JE,
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Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 35
Appendices Appendix I Asthma Control Questionnaire
Appendix II Clinical COPD Questionnaire
Appendix III Pearson Correlation
Appendix IV Supplementary tables
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 36
Appendix I Asthma Control Questionnaire
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 37
Appendix I Asthma Control Questionnaire
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 38
Appendix II Clinical COPD Questionnaire
COPD VRAGENLIJST
Omcirkel het nummer dat
het beste beschrijft hoe u zich de afgelopen week heeft gevoeld.
(Slechts één antwoord per vraag)
Hoe vaak voelde u zich in de
nooit
zelden
af en toe
regelmatig
heel vaak
meestal
altijd afgelopen week …
1. Kortademig in rust?
0
1
2
3
4
5
6
2. Kortademig gedurende
lichamelijke inspanning?
0
1
2
3
4
5
6
3. Angstig/bezorgd voor de
volgende benauwdheidsaanval?
0
1
2
3
4
5
6
4. Neerslachtig vanwege uw
ademhalingsproblemen?
0
1
2
3
4
5
6
In de afgelopen week, hoe vaak heeft
u …
5. Gehoest? 0 1 2 3 4 5 6
6. Slijm opgehoest?
0
1
2
3
4
5
6
In welke mate voelde u zich in de
helemaal
héél
een
tamelijk
erg
héél
volledig
afgelopen week beperkt door uw
ademhalingsproblemen bij het
uitvoeren van …
niet
beperkt
weinig
beperkt
beetje
beperkt
beperkt beperkt erg
beperkt
beperkt/
of niet
mogelijk
7. Zware lichamelijke activiteiten
(trap lopen, haasten, sporten)?
0
1
2
3
4
5
6
8. Matige lichamelijke activiteiten
(wandelen, huishoudelijk werk,
0
1
2
3
4
5
6
boodschappen doen)?
9. Dagelijkse activiteiten 0 1 2 3 4 5 6
(u zelf aankleden, wassen)?
10. Sociale activiteiten
(praten, omgaan met kinderen,
0
1
2
3
4
5
6
vrienden/familie bezoeken)?
© University Medical Center Groningen , T. van der Molen
© Op de CCQ berust copyright. De vragenlijst mag niet worden veranderd, verkocht (op papier of elektronisch), vertaald of aange-
past voor een ander medium zonder de toestemming van T. van der Molen, Huisartsgeneeskunde, University Medical Center
Groningen, Postbus 196, 9700 AD Groningen, Nederland.
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 39
Appendix III Pearson Correlation
Table 1: Baseline characteristics of patients population per diagnosis
Variable
Asthma
COPD
ACO
Demographics
Gender, male, n(%)
Age, years, median (IQR)
Mean body-mass index, kg/m2, median (IQR)
n=215
66 (31)
47 (30–59)
27 (23–32)
n=74
41 (55)
64 (57–71)
26 (24–30)
n=48
22 (46)
63 (56–70)
27 (25–30)
Smoking status
Current smoker, n(%)
Ex-smoker, n(%)
Smoke exposure, years, median (IQR)
n=215
44 (20)
80 (37)
10 (0–24)
n=74
40 (54)
32 (43)
31 (27–36)
n=48
28 (58)
20 (42)
29 (24–35)
Age of disease onset or onset of symptoms, years
Mean disease duration, years
n=209 25 (10–49)
10 (2–24)
n=65 60 (50–64)
4 (1–12)
n=46 41 (19–57)
20 (5–38)
Current treatment at first consultation, n(%)
SABA
SAMA
LABA
LAMA
n=215
85 (40)
6 (3)
9 (4)
5 (2)
n=74
10 (14)
1 (1)
7 (9)
17 (23)
n=48
12 (25)
2 (4)
3 (6)
5 (10)
Disease control, median (IQR)
ACQ
CCQ
n=215
n=204
1.5 (0.8–2.2)
1.6 (1.0–2.4)
n=74
1.3 (0.8–2.0)
1.8 (1.1–2.4)
n=48
1.2 (0.7–2.0)
1.5 (0.9–2.3)
Lung function post bronchodilator, mean(±SD)
FEV1% predicted
FEV1/FVC
Reversibility*, median (IQR)
n=215
n=209
94 (±15)
79 (±9)
5.4 (2.2–10.3)
n=74
n=65
70 (±16)
56 (±10)
7.2 (1.3–11.9)
n=48
n=46
74 (±16)
61 (±9)
12 (8.0–15.9)
≥ 1 exacerbation last year$, n(%) n=121 46 (39) n=29 13 (45) n=18 6 (33)
Blood eosinophil count
Baseline EO-count, median (IQR)
Eosinophils ≤150 cells/µL, n(%)
Eosinophils 151-300 cells/µL, n(%)
Eosinophils 301-400 cells/µL, n(%)
Eosinophils ˃400 cells/µL, n(%)
n=215
200 (100–300)
81 (38)
92 (43)
19 (9)
23 (11)
n=74
200 (100–300)
25 (34)
35 (47)
9 (12)
6 (8)
n=48
100 (100–200)
20 (42)
24 (50)
3 (6)
1 (2) Abbreviations: COPD, chronic obstructive pulmonary disease; ACO, asthma-COPD overlap; IQR, interquartile range, SABA, short-acting beta2-agonist; SAMA, short-acting muscarinic
antagonist; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; ACQ, asthma control questionnaire; CCQ, clinical COPD questionnaire; FEV1, forced expiratory
volume in 1 second; FVC, forced vital capacity; EO-count, peripheral blood eosinophil count.
*Increase in FEV1 pre bronchodilator compared with FEV1 post bronchodilator. $Exacerbations are defined as having used oral corticosteroids or antibiotics for lung problems last year.
Appendix IV Supplementary tables
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 41
Table 2: Effect of ICS treatment on disease control in asthma patients
Abbreviations: ICS, inhaled corticosteroids; ACQ, asthma control questionnaire; IQR, interquartile range. $ Wilcoxon matched-pair signed rank test, p-values are two-sided and considered significant ≤ 0.05.
Table 3: Effect of ICS treatment on disease control in COPD patients
Abbreviations: ICS, inhaled corticosteroids; COPD, chronic obstructive pulmonary disease; CCQ, clinical COPD
questionnaire; IQR, interquartile range; NS, not significant. $ Wilcoxon matched-pair signed rank test, p-values are two-sided and considered significant ≤ 0.05.
Table 4: Effect of ICS treatment on disease control in ACO patients
Abbreviations: ICS, inhaled corticosteroids; ACO, asthma-COPD overlap; COPD, chronic obstructive pulmonary disease;
ACQ, asthma control questionnaire; CCQ, clinical COPD questionnaire, IQR, interquartile range; NS, not significant; NA,
not applicable. $ Wilcoxon matched-pair signed rank test, p-values are two-sided and considered significant ≤ 0.05.
Appendix IV Supplementary tables
ACQ Baseline Follow-up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 81 1.5 (1.0–2.2) 1.2 (0.7–1.7) <0.001
Eosinophils 151-300 cells/µL 92 1.3 (0.7–2.0) 1.0 (0.5–1.5) <0.001
Eosinophils 301-400 cells/µL 19 1.8 (1.5–2.2) 1.3 (0.3–1.8) 0.002
Eosinophils > 400 cells/µL 23 1.7 (0.8–2.2) 0.7 (0.2–1.3) 0.002
CCQ Baseline
Follow-up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 25 1.7 (1.2–2.4) 1.1 (0.7–1.6) <0.001
Eosinophils 151-300 cells/µL 35 1.6 (1.0–2.2) 1.5 (0.9–2.0) NS
Eosinophils 301-400 cells/µL 9 1.8 (1.2–2.8) 1.2 (0.8–2.1) 0.042
Eosinophils > 400 cells/µL 5 2.0 (0.7–2.7) 0.5 (0.2–1.1) 0.042
ACQ Baseline Follow-up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 20 1.1 (0.3–1.5) 1.0 (0.2–1.6) NS
Eosinophils 151-300 cells/µL 24 1.6 (0.8–2.3) 1.0 (0.7–2.0) NS
Eosinophils 301-400 cells/µL 3 0.7 (0.3–3,8) 0.5 (0.3–1,0) NS
Eosinophils > 400 cells/µL 1 1.3 0.0 NA
CCQ Baseline
Follow–up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 18 1.3 (0.6–1.9) 1.2 (0.7–1.9) NS
Eosinophils 151-300 cells/µL 22 1.8 (0.9–2.7) 1.3 (0.9–2.4) NS
Eosinophils 301-400 cells/µL 3 1.1 (0.4–2,9) 1.5 (1.3–1,7) NS
Eosinophils > 400 cells/µL 1 1.6 0.6 NA
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 42
Table 5: Effect of ICS treatment on lung function in asthma patients
Abbreviations: ICS, inhaled corticosteroids; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; IQR,
interquartile range; NS, not significant. $ Wilcoxon matched-pair signed rank test, p-values are two-sided and considered significant ≤ 0.05.
Table 6: Effect of ICS treatment on lung function in COPD patients
Abbreviations: ICS, inhaled corticosteroids; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume
in 1 second; FVC, forced vital capacity; IQR, interquartile range; NS, not significant. $ Wilcoxon matched pair signed rank test, p-values are two-sided and considered significant ≤ 0.05.
Table 7: Effect of ICS treatment on lung function (ACO patients)
Abbreviations: ICS, inhaled corticosteroids; ACO, asthma-COPD overlap; COPD, chronic obstructive pulmonary disease;
FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; IQR, interquartile range; NS, not significant; NA,
not applicable. $ Wilcoxon matched-pair signed rank test, p-values are two-sided and considered significant ≤ 0.05.
Appendix IV Supplementary tables
FEV1% predicted Baseline Follow-up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 81 93 (84–106) 93 (83–103) NS
Eosinophils 151-300 cells/µL 92 94 (85–102) 95 (84–103) NS
Eosinophils 301-400 cells/µL 19 91 (84–98) 92 (82–105) NS
Eosinophils > 400 cells/µL 23 97 (89–106) 99 (92–106) NS
FEV1/FVC Baseline
Follow–up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 81 79 (74–87) 78 (72–85) 0.001
Eosinophils 151-300 cells/µL 92 78 (73–83) 77 (73–81) 0.011
Eosinophils 301-400 cells/µL 19 79 (74–84) 81 (71–85) NS
Eosinophils > 400 cells/µL 23 80 (77–85) 79 (75–83) NS
FEV1% predicted Baseline Follow-up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 25 69 (60–80) 69 (60–81) NS
Eosinophils 151-300 cells/µL 35 72 (60–83) 75 (62–82) NS
Eosinophils 301-400 cells/µL 9 64 (53–85) 75 (57–81) NS
Eosinophils > 400 cells/µL 5 51 (43–62) 65 (48–73) 0.042
FEV1/FVC n Baseline
Follow–up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 25 55 (52–65) 55 (51–65) NS
Eosinophils 151-300 cells/µL 35 58 (47–67) 58 (48–66) NS
Eosinophils 301-400 cells/µL 9 57 (45–62) 57 (47–65) NS
Eosinophils > 400 cells/µL 5 48 (44–56) 52 (45–61) NS
FEV1% predicted Baseline Follow-up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 20 71 (60–78) 73 (59–82) NS
Eosinophils 151-300 cells/µL 24 74 (62–91) 73 (62–88) NS
Eosinophils 301-400 cells/µL 3 67 (62–74) 75 (74–87) NS
Eosinophils > 400 cells/µL 1 74 76 NA
FEV1/FVC Baseline
Follow–up p-value$
n median (IQR) median (IQR)
Eosinophils ≤ 150 cells/µL 20 61 (53–66) 59 (52–66) NS
Eosinophils 151-300 cells/µL 24 64 (56–67) 62 (57–67) NS
Eosinophils 301-400 cells/µL 3 63 (63–77) 72 (66–80) NS
Eosinophils > 400 cells/µL 1 76 71 NA
Effectiveness of inhaled corticosteroids relative to different blood eosinophil counts in primary care respiratory patients - 43
Table 8: Effect of ICS treatment on number of exacerbations in asthma patients
Abbreviations: ICS; inhaled corticosteroids; NS, not significant. *Exacerbation: number of patients experiencing ≥1 exacerbation per year, defined as having used oral corticosteroids or
antibiotics for lung problems. $McNemar test, p-values are two-sided and considered significant ≤ 0.05.
Table 9: Effect of ICS treatment on number of exacerbations in COPD patients
Abbreviations: ICS, inhaled corticosteroids; COPD, chronic obstructive pulmonary disease; NS, not significant. *Exacerbation: number of patients experiencing ≥1 exacerbation per year, defined as having used oral corticosteroids or
antibiotics for lung problems. $McNemar test, p-values are two-sided and considered significant ≤ 0.05.
Table 10: Effect of ICS treatment on number of exacerbations in ACO patients
Abbreviations: ICS, inhaled corticosteroids; ACO, asthma-COPD overlap; COPD, chronic obstructive pulmonary disease;
NS, not significant; NA, not applicable. *Exacerbation: number of patients experiencing ≥1 exacerbation per year, defined as having used oral corticosteroids or
antibiotics for lung problems. $McNemar test, p-values are two-sided and considered significant ≤ 0.05.
Appendix IV Supplementary tables
≥ 1 exacerbation per year*
n Baseline Follow-up p-value$
n n (%) n (%)
Eosinophils ≤ 150 cells/µL 44 17 (38.6%) 7 (15.9%) 0.021
Eosinophils 151-300 cells/µL 42 16 (38.1%) 10 (23.8%) NS
Eosinophils 301-400 cells/µL 12 6 (50.0%) 2 (16.7%) NS
Eosinophils > 400 cells/µL 12 5 (41.7%) 2 (16.7%) NS
≥ 1 exacerbation per year*
Baseline Follow-up p-value$
n n (%) n (%)
Eosinophils ≤ 150 cells/µL 9 6 (66.7%) 4 (44.4%) NS
Eosinophils 151-300 cells/µL 11 2 (18.2%) 3 (27.3%) NS
Eosinophils 301-400 cells/µL 5 2 (40.0%) 0 NS
Eosinophils > 400 cells/µL 3 2 (66.7%) 0 NS
≥ 1 exacerbation per year*
Baseline Follow-up p-value$
n n (%) n (%)
Eosinophils ≤ 150 cells/µL 4 2 (0.50%) 0 NS
Eosinophils 151-300 cells/µL 11 4 (36.4%) 3 (27.3%) NS
Eosinophils 301-400 cells/µL 2 0 0 NA
Eosinophils > 400 cells/µL - – – NA