# Adherence to inhaled corticosteroids and long-acting β2-agonists in asthma: A MASK-air study

Bernardo Sousa-Pinto, Renaud E. Louis, Josep María Anto, R. Amaral, Ana Sá-Sousa, Wienczyslawa Czarlewski, Luisa Brussino, Walter G. Canonica, Cláudia Chaves Loureiro, Álvaro Augusto Cruz, et al.

► To cite this version:

Bernardo Sousa-Pinto, Renaud E. Louis, Josep María Anto, R. Amaral, Ana Sá-Sousa, et al. Adherence to inhaled corticosteroids and long-acting β2-agonists in asthma: A MASK-air study. Pulmonology, 2023, 10.1016/j.pulmoe.2023.07.004. hal-04195104

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Submitted on 21 Sep 2023

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ORIGINAL ARTICLE

Adherence to inhaled corticosteroids and long-acting β2-agonists in asthma: A MASK-air study

B. Sousa-Pinto$^{a,b}$, R. Louis$^{c,d}$, J.M. Anto$^{e,f,g}$, R. Amaral$^{a,b}$, A. Sá-Sousa$^{a,b}$, W. Czarlewski$^{h,i}$,
L. Brussino$^{j,k}$, G.W. Canonical$^{l,m}$, C. Chaves Loureiro$^{n}$, A.A. Cruz$^{o}$, B. Gemicioglu$^{p}$,
T. Haahtela$^{q}$, M. Kupczyk$^{r}$, V. Kvedariene$^{s,t}$, D.E. Larenas-Linnemann$^{u}$, Y. Okamoto$^{v,w}$,
M. Ollert$^{x,y}$, O. Pfaar$^{z}$, N. Pham-Thi$^{aa,bb,cc}$, F. Puggioni$^{dd}$, F.S. Regateiro$^{ee,ff,gg}$,
J. Romantowski$^{hh}$, J. Sastre$^{ii}$, N. Scichilone$^{jj}$, L. Taborda-Barata$^{kk,ll}$, M.T. Ventura$^{mm,nn}$,
I. Agache$^{oo}$, A. Bedbrook$^{pp}$, S. Becker$^{qq}$, K.C. Bergmann$^{rr,ss}$, S. Bosnic-Anticevich$^{tt,uu}$,
M. Bonini$^{vv,ww,xx}$, L.-P. Boulet$^{yy}$, G. Brusselle$^{zz}$, R. Buhl$^{aaa}$, L. Cecchi$^{bbb}$, D. Charpin$^{ccc}$,
F. de Blay$^{ddd,eee}$, S. Del Giacco$^{fff}$, J.C. Ivancevich$^{ggg}$, M. Jutel$^{hhh,iii}$, L. Klimek$^{jjj,kkk}$,
H. Kraxner$^{iii}$, P. Kuna$^{r}$, D. Laune$^{mmm}$, M. Makela$^{q}$, M. Morais-Almeida$^{nnn}$, R. Nadif$^{ooo,ppp}$,
M. Niedoszytko$^{qqq}$, N.G. Papadopoulos$^{rrr}$, A. Papi$^{sss}$, V. Patella$^{ttt,uuu,vvv}$, B. Pétré$^{www}$,
D. Rivero Yeverino$^{xxx}$, C. Robalo Cordeiro$^{n}$, N. Roche$^{yyy,zzz}$, P.W. Rouadi$^{aaaa,bbbb}$,
B. Samolinski$^{cccc}$, M. Savouré$^{ooo,ppp}$, M.H. Shamji$^{xx,dddd}$, A. Sheikh$^{eeee}$,
C. Suppli Ulrik$^{ffff,gggg}$, O.S. Usmani$^{xx,hhhh}$, A. Valiulis$^{iiii,jjjj}$, A. Yorgancioglu$^{kkkk}$,
T. Zuberbier$^{rr,ss}$, J.A. Fonseca$^{a,b}$, E.M. Costa$^{llll}$, J. Bousquet$^{rr,ss,ppp,mmmm,*}$

**Abbreviations:** CSMS, EAACI-ARIA allergy combined symptom-medication score; DATs, Digital adherence technologies; e-DASTHMA, Electronic daily control score for asthma; EMDs, Electronic monitoring devices; GDPR, General Data Protection Regulation; INCS, Inhaled corticosteroids; LABA, Long-acting β2 agonists; MART, Maintenance and Reliever Therapy; MASK-air, Mobile Airways Sentinel network for airway diseases; MPR, Medication possession ratio; SABA, Short-acting beta-agonists; VAS, Visual analogue scale.

* Corresponding author at: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.

E-mail address: jean.bousquet@orange.fr (J. Bousquet).

<footnote>$^{a}$ MEDCIDS - Department of Community Medicine, Information and Health Decision Sciences; Faculty of Medicine, University of Porto, Porto, Portugal</footnote>

<footnote>$^{b}$ CINTESIS@RISE - Health Research Network, Faculty of Medicine, University of Porto, Porto, Portugal</footnote>

<footnote>$^{c}$ Department of Pulmonary Medicine, CHU Liège, Liège, Belgium</footnote>

<footnote>$^{d}$ GIGA I3 Research Group, University of Liège, Liège, Belgium</footnote>

<footnote>$^{e}$ ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain</footnote>

<footnote>$^{f}$ Universitat Pompeu Fabra (UPF), Barcelona, Spain</footnote>

<footnote>$^{g}$ CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain</footnote>

<footnote>$^{h}$ Medical Consulting Czarlewski, Levallois, France</footnote>

<footnote>$^{i}$ MASK-air, Montpellier, France</footnote>

<footnote>$^{j}$ Department of Medical Sciences, University of Torino, Torino, Italy</footnote>

<footnote>$^{k}$ Allergy and Clinical Immunology Unit, Mauriziano Hospital, Torino, Italy</footnote>
¹ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy

m IRCCS Humanitas Research Center, Rozzano, Milan, Italy

n Department of Pneumology, University of Coimbra, Medicine Faculty, Coimbra, Portugal

o Fundação ProAR, Federal University of Bahia and GARD/WHO Planning Group, Salvador, Bahia, Brazil

p Department of Pulmonary Diseases, Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Istanbul, Turkey

q Skin and Allergy Hospital, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland

r Division of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland

s Institute of Clinical Medicine, Clinic of Chest Diseases and Allergology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania

t Institute of Biomedical Sciences, Department of Pathology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania

u Center of Excellence in Asthma and Allergy, Médica Sur Clinical Foundation and Hospital, México City, Mexico

v Chiba Rosai Hospital, Chiba, Japan

w Chiba University Hospital, Chiba, Japan

x Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg

y Odense Research Center for Anaphylaxis (ORCA), and Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark

z Section of Rhinology and Allergy, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany

aa Ecole Polytechnique de Palaiseau, Palaiseau, France

bb IRBA (Institut de Recherche Bio-Médicale des Armées), Brétigny sur Orge, France

cc Université Paris Cité, Paris, France

dd IRCCS Humanitas Research Center, Personalized Medicine Asthma & Allergy, Rozzano, Milan, Italy

ee Allergy and Clinical Immunology Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

ff Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine, University of Coimbra, Coimbra, Portugal

gg Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

hh Medical University of Gdańsk, Department of Allergology, Gdansk, Poland

ii Allergy Service, Fundacion Jimenez Diaz, Autonoma University of Madrid, CIBERES-ISCIII, Madrid, Spain

jj PROMISE Department, University of Palermo, Palermo, Italy

kk Department of Immunoallergology, Cova da Beira University Hospital Centre, Covilhã, Portugal

ll UBIAir - Clinical & Experimental Lung Centre and CICS-UBI Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal

mm Allergy and Clinical Immunology, University of Bari Medical School, Bari, Italy

nn Institute of Sciences of Food Production, National Research Council (ISPA-CNR), Bari, Italy

oo Faculty of Medicine, Transylvania University of Brasov, Brasov, Romania

pp ARIA, Montpellier, France

qq Department of Otorhinolaryngology, University of Tübingen, Tübingen, Germany

rr Institute of Allergology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

ss Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany

tt Quality Use of Respiratory Medicines Group, Woolcock Institute of Medical Research, Sydney, NSW, Australia

uu Macquarie Medical School, Macquarie University, Macquarie Park, NSW, Australia

vv Department of Cardiovascular and Respiratory Sciences, Universita Cattolica del Sacro Cuore, Rome, Italy

ww Department of Neurological, ENT and Thoracic Sciences, Fondazione Policlinico Universitario A Gemelli - IRCCS, Rome, Italy

xx National Heart and Lung Institute (NHLI), Imperial College London, London, UK

yy Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada

zz Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium

aaa Department of Pulmonary Medicine, Mainz University Hospital, Mainz, Germany

bbb SOS Allergology and Clinical Immunology, USL Toscana Centro, Prato, Italy

ccc Clinique des Bronches, Allergie et Sommeil, Hopital Nord, Marseille, France

ddd Allergy Division, Chest Disease Department, University Hospital of Strasbourg, Strasbourg, France

eee Federation of Translational Medicine, University of Strasbourg, Strasbourg, France

fff Department of Medical Sciences and Public Health and Unit of Allergy and Clinical Immunology, University Hospital "Duilio Casula", University of Cagliari, Cagliari, Italy

ggg Servicio de Alergia e Immunologia, Clinica Santa Isabel, Buenos Aires, Argentina

hhh Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland

iii ALL-MED Medical Research Institute, Wroclaw, Poland

jjj Department of Otolaryngology, Head and Neck Surgery, Universitätsmedizin Mainz, Mainz, Germany

kkk Center for Rhinology and Allergology, Wiesbaden, Germany

lll Department of Otorhinolaryngology, Head and Neck Surgery, Semmelweis University, Budapest, Hungary

mmm KYomed INNOV, Montpellier, France

nnn Allergy Center, CUF Descobertas Hospital, Lisbon, Portugal

ooo Université Paris-Saclay, UVSQ, Univ. Paris-Sud, Villejuif, France

ppp Inserm, Equipe d'Epidémiologie Respiratoire Intégrative, CESP, Villejuif, France
qqq Department of Allergology, Medical University of Gdańsk, Gdansk, Poland

rrr Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece

sss Respiratory Medicine, Department of Translational Medicine, University of Ferrara, Ferrara, Italy

ttt Division of Allergy and Clinical Immunology, Department of Medicine, "Santa Maria della Speranza" Hospital, Battipaglia, Salerno, Italy

uuu Agency of Health ASL, Salerno, Italy

vvv Postgraduate Programme in Allergy and Clinical Immunology, University of Naples Federico II, Naples, Italy

www Department of Public Health, University of Liège, Liège, Belgium

xxx Servicio de Alergia e Inmunología clínica, Hospital Universitario de Puebla, Puebla, México

yyy Pneumologie, AP-HP Centre Université de Paris Cité, Hôpital Cochin, Paris, France

zzz UMR 1016, Institut Cochin, Paris, France

aaaa Department of Otolaryngology-Head and Neck Surgery, Eye and Ear University Hospital, Beirut, Lebanon

bbbb Department of Otorhinolaryngology-Head and Neck Surgery, Dar Al Shifa Hospital, Salmiya, Kuwait

cccc Department of Prevention of Environmental Hazards, Allergology and Immunology, Medical University of Warsaw, Warsaw, Poland

dddd NIHR Imperial Biomedical Research Centre, London, UK

eeee Usher Institute, The University of Edinburgh, Edinburgh, UK

ffff Department of Respiratory Medicine, Copenhagen University Hospital-Hvidovre, Copenhagen, Denmark

gggg Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

hhhh Royal Brompton Hospital, Airways Disease Section, London, UK

iii Interdisciplinary Research Group of Human Ecology, Institute of Clinical Medicine and Institute of Health Sciences, Medical Faculty of Vilnius University, Vilnius, Lithuania

jjjj European Academy of Paediatrics (EAP/UEMS-SP), Brussel, Belgium

kkkk Department of Pulmonary Diseases, Celal Bayar University, Faculty of Medicine, Manisa, Turkey

llll UCIBIO, REQUINTE, Faculty of Pharmacy and Competence Center on Active and Healthy Ageing of University of Porto (Porto4Ageing), Porto, Portugal

mmmm University Hospital Montpellier, Montpellier, France

Received 12 June 2023; accepted 15 July 2023

Available online xxx

KEYWORDS

Asthma;
Adherence;
Inhaled
corticosteroids;
Formoterol;
Long-acting-β2
agonist

Abstract

**Introduction:** Adherence to controller medication is a major problem in asthma management, being difficult to assess and tackle. mHealth apps can be used to assess adherence. We aimed to assess the adherence to inhaled corticosteroids+long-acting β2-agonists (ICS+LABA) in users of the MASK-air® app, comparing the adherence to ICS+formoterol (ICS+F) with that to ICS+other LABA.

**Materials and methods:** We analysed complete weeks of MASK-air® data (2015-2022; 27 countries) from patients with self-reported asthma and ICS+LABA use. We compared patients reporting ICS+F versus ICS+other LABA on adherence levels, symptoms and symptom-medication scores. We built regression models to assess whether adherence to ICS+LABA was associated with asthma control or short-acting beta-agonist (SABA) use. Sensitivity analyses were performed considering the weeks with no more than one missing day.

**Results:** In 2598 ICS+LABA users, 621 (23.9%) reported 4824 complete weeks and 866 (33.3%) reported weeks with at most one missing day. Higher adherence (use of medication ≥80% of weekly days) was observed for ICS+other LABA (75.1%) when compared to ICS+F (59.3%), despite both groups displaying similar asthma control and work productivity. The ICS+other LABA group was associated with more days of SABA use than the ICS+F group (median=71.4% versus 57.1% days). Each additional weekly day of ICS+F use was associated with a 4.1% less risk in weekly SABA use (95%CI=-6.5;-1.6%;p=0.001). For ICS+other LABA, the percentage was 8.2 (95%CI= -11.6;-5.0%;p<0.001).

**Conclusions:** In asthma patients adherent to the MASK-air app, adherence to ICS+LABA was high. ICS+F users reported lower adherence but also a lower SABA use and a similar level of control.

© 2023 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)).
Introduction

Suboptimal adherence is common in asthma.¹ It is associated
with poor control, increased risk of exacerbations and
increased healthcare utilisation², with an unnecessary
increase of potentially harmful and/or expensive treat-
ments.³ While assessing adherence in asthma is particularly
relevant, it may be extremely challenging, given the need
to capture individual day-to-day variability patterns.⁴,⁵

The assessment of adherence can be estimated using several methods.⁶ Such methods may involve the use of digital adherence technologies (DATs), which are digital systems used to aid adherence measurement and management. Electronic monitoring devices (EMDs, including smart inhalers) are DATs that directly and automatically measure the time and date of a dose being administered. They collect data on inhaler usage and transmit them through an app.⁶ EMDs are highly accurate⁷,⁸ but there is potential for dose dumping.⁹ Moreover, they are often associated with a single product and therefore (i) EMDs do not report the entire treatment¹⁰ and (ii) when patients switch their medication, they can no longer be used. Other DATs that have been used in asthma to assess adherence include mHealth apps without sensors.¹¹⁻¹⁵ An observational cross-sectional study in rhinitis using the MASK-air® app has assessed the medication possession ratio (MPR) in 1887 users, of whom only 11% were adherent.¹⁶

Considering the relevance of proper adherence to asthma control medication, we used the MASK-air® app¹⁶ to investigate adherence to inhaled corticosteroids (ICS) + long-acting β2-agonists (LABA) as well as its association with asthma control. In particular, we compared patients treated with ICS+formoterol (ICS+F) versus ICS+other LABA, given the fact that, contrary to ICS+other LABA, ICS+F can not only be used as a maintenance therapy but also as a reliever treatment.

Methods

In this longitudinal analysis, we analysed MASK-air® data
from patients with self-reported asthma who reported com-
plete weeks and at least one day of ICS use. We compared
adherence levels in patients using ICS+F versus those using
ICS+other LABA. In addition, we compared these groups on
reported symptoms and symptom-medication scores, per-
forming stratified analyses according to weekly adherence
levels. Finally, we built regression models to assess whether
the weekly use of ICS+F or ICS+other LABA was associated
with the weekly use of short-acting beta-agonists (SABA).

Setting and participants

MASK-air® (www mask-air.com) is freely available in 27
countries and can be downloaded via the Apple App and Go-
gle Play Stores.

We assessed MASK-air® users aged 16–75 years (or
13–75 years in countries with a lower age of digital con-
sent), with self-reported asthma and who reported at least
one day of ICS+F or ICS+other LABA use. Patients who
reported both ICS+F and ICS+other LABA use were excluded.
We analysed all weeks (sets of seven consecutive days) from

May 2015 to December 2022 during which patients answered
to the MASK-air® daily monitoring questionnaire on all
days.¹⁷ For sensitivity analyses, we analysed (i) all weeks
within the same period during which patients had at most
one missing day of MASK-air® reporting and (ii) all months
during which patients answered to the MASK-air® daily moni-
toring questionnaire on most days (i.e., having at most four
missing days).

Ethics

MASK-air® follows the General Data Protection Regulation.¹⁸
An independent review board approval was not required for
this study as (i) the use of MASK-air® data for research pur-
poses has been approved by an independent review board
(Köln-Bonn, Germany),¹⁹ (ii) all data were anonymised
before the study and (iii) users agreed to the analysis of their
data in the terms of use (translated into all languages and
customised according to the legislation of each country).

Data sources and variables

The MASK-air® app comprises a daily monitoring question-
naire assessing (i) the daily asthma and rhinitis symptoms by
means of 0–100 visual analogue scales (VASs) (e-Table 1)
and (ii) asthma and rhinitis daily medication use available
from country-specific lists.¹⁷ Information on the MASK-air®
daily monitoring questionnaire allows for the computation
of two symptom-medication scores: the combined symptom-
medication score (CSMS)²⁰ and the electronic daily control
score for asthma (e-DASTHMA).²¹

Data analysis

When responding to the MASK-air® daily monitoring ques-
tionnaire, it is not possible to skip any of the questions. Data
are saved to the dataset only after the final answer, which
precludes any missing data. All analyses were performed
using the software R.

We computed effect size measures for all comparisons
between weeks from patients under ICS+F versus ICS+other
LABA (effect size helps to understand the magnitude of dif-
ferences, whereas statistical significance examines whether
the findings are likely to be due to chance. With large sam-
ples, *p*-values are very often significant, rendering it impor-
tant to use the effect size). Values >0.2 were considered to
represent meaningful differences (i.e., sufficiently large dif-
ferences to be potentially relevant from a clinical point of
view). Values of 0.2-0.5 were considered to represent small
effect sizes, 0.5-0.8 medium effect sizes and >0.8 large
effect sizes.²²

We compared weeks reported by patients under ICS+F
versus those reported by patients under ICS+other LABA on
(i) weekly median and maximum VAS,¹⁷ CSMS²⁰ and e-
DASTHMA²¹ levels and (ii) adherence levels. We considered
that there was medication adherence for the weeks when
the self-reported use of ICS+F or ICS+other LABA occurred in
>80% of the days (therefore, estimating adherence in an
analogous way to the MPR).¹⁶ For weeks when adherence
was not reached, we performed separate analyses for those
in which the aforementioned medication (i) was not used,
(ii) was used on 1-40% of the days and (iii) was used on 41-80% of the days.

We compared patients under ICS+F versus those under ICS +other LABA. Stratified analyses were performed, according to weekly adherence levels, on VAS asthma levels (both as a continuous variable and categorised according to its cut-offs), e-DASTHMA²¹ levels and frequency of SABA use.

We built mixed-effects linear regression models to compare, for both ICS+F and ICS+other LABA groups, VAS asthma levels on days when such medication was used versus those on which it was not used. Observations were clustered by patient (i.e., the patient was set as a random-effect). Analyses were performed considering (i) all weeks and (ii) weeks with adherence.

We built Poisson regression models²³ to assess the association between weekly adherence to ICS+F or ICS+other LABA (independent variable) and number of days within a week with use of SABA (outcome variable). We built both univariable and multivariable regression models, with the latter involving an adjustment for weekly median VAS asthma levels.

## Results

In MASK-air®, 9721 users had self-reported asthma. Of these users, 4753 reported at least one day of treatment: 1705 users (60,521 days) reported at least one day of ICS+F and 893 (26,396 days) at least one day of ICS+other LABA (e-Figure 1).

In our main analysis (no missing days per week), we analysed 4824 weeks (621 users, 23.9% of all ICS+LABA users), including 3154 weeks from 429 users under ICS+F and 1670 weeks from 192 users under ICS+other LABA (Table 1, e-Table 2, e-Fig. 1). In the sensitivity analysis assessing

weeks with at most one missing day, we analysed 6444 weeks (866 users, 34.0% of all ICS+LABA users), including 4272 weeks from 600 users under ICS+F and 2172 weeks from 266 users under ICS+other LABA.

Similar descriptive results were observed for full weeks and for weeks with at most one missing day (Table 1).

Users reporting ICS+F had a similar asthma control to those reporting ICS+other LABA for VAS global, VAS asthma and e-DASTHMA levels, with no meaningful differences observed (Table 1). Median VAS work was higher in the ICS +other LABA group (effect sizes=0.29–0.30).

## Adherence to asthma treatment

In the main analysis, adherence (MPR>80%) was observed in 3125 weeks (64.8%). It was meaningfully higher in the ICS +other LABA group (75.1%) than in the ICS+F group (59.3%) (effect size=0.34) (e-Table 3). In 267 weeks (5.5%), there was partial adherence (MPR 41–80%), in 236 (4.9%) low adherence (MPR 1–40%) and in 1196 (24.8%) no adherence (MPR=0%) to ICS+LABA. We observed a bimodal adherence pattern, with most weeks associated with adherence or no adherence. VAS asthma and e-DASTHMA levels tended to be higher in ICS+F than in ICS+other LABA users (effect size range: 0.06–0.68, e-Table 3). Meaningful differences between both groups were not observed for weeks with adherence.

Considering VAS asthma cut-off values, uncontrolled asthma (VAS≥36/100) was mostly found in patients with at least partial adherence in both groups (e-Table 4; Fig. 1). Partly-controlled asthma (VAS 20-35/100) was found mostly in ICS+LABA-adherent patients and in adherent or totally non-adherent patients of the ICS+F group.

<table><caption>**Table 1** Characteristics of the main sample (A. weeks with no missing days) and of one of the samples assessed in sensitivity analysis (B. weeks with at most one missing day).</caption><thead><tr><th rowspan="2"></th><th colspan="3">A. Weeks with no missing days</th><th colspan="3">B. Weeks with at most one missing day</th></tr><tr><th>ICS+ Formoterol</th><th>ICS+other LABA</th><th>Effect size</th><th>ICS+ Formoterol</th><th>ICS+other LABA</th><th>Effect size</th></tr></thead><tbody><tr><td>N weeks (N users)</td><td>3154 (429)</td><td>1670 (192)</td><td>-</td><td>4272 (600)</td><td>2172 (266)</td><td>-</td></tr><tr><td>Females - N (%)</td><td>1916 (60.7)</td><td>1050 (62.9)</td><td>0.05</td><td>2690 (63.0)</td><td>1346 (62.0)</td><td>0.02</td></tr><tr><td>Age - mean (SD)</td><td>44.7 (12.3)</td><td>44.7 (16.5)</td><td>0</td><td>44.6 (12.9)</td><td>44.5 (16.1)</td><td>0.01</td></tr><tr><td>VAS global</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weekly median - median (IQR)</td><td>11 (17)</td><td>9 (18)</td><td>0.16</td><td>11 (18)</td><td>9 (19)</td><td>0.16</td></tr><tr><td>Weekly maximum - median (IQR)</td><td>18 (25)</td><td>16 (33)</td><td>0.11</td><td>19 (29)</td><td>17 (34)</td><td>0.10</td></tr><tr><td>VAS asthma</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weekly median - median (IQR)</td><td>9 (17)</td><td>8 (20)</td><td>0.08</td><td>9 (18)</td><td>8 (21)</td><td>0.08</td></tr><tr><td>Weekly maximum - median (IQR)</td><td>18 (28)</td><td>16 (32)</td><td>0.11</td><td>19 (30)</td><td>17 (33)</td><td>0.10</td></tr><tr><td>VAS work</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weekly median - median (IQR)</td><td>8 (16)</td><td>12 (21)</td><td>0.30</td><td>8 (17)</td><td>11 (22)</td><td>0.22</td></tr><tr><td>Weekly maximum - median (IQR)</td><td>13 (22)</td><td>18 (28)</td><td>0.29</td><td>13 (24)</td><td>17 (28)</td><td>0.23</td></tr><tr><td>e-DASTHMA</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weekly median - median (IQR)</td><td>12.9 (11.8)</td><td>11.8 (19.5)</td><td>0.14</td><td>12.9 (12.1)</td><td>12.1 (19.0)</td><td>0.09</td></tr><tr><td>Weekly maximum - median (IQR)</td><td>19.2 (17.6)</td><td>17.3 (28.1)</td><td>0.13</td><td>19.6 (19.3)</td><td>18.4 (27.3)</td><td>0.08</td></tr><tr><td>CSMS</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weekly median - median (IQR)</td><td>11.7 (11.8)</td><td>12.6 (14.9)</td><td>0.09</td><td>11.9 (13.2)</td><td>12.6 (16.1)</td><td>0.07</td></tr><tr><td>Weekly maximum - median (IQR)</td><td>17.2 (18.6)</td><td>17.6 (22.1)</td><td>0.03</td><td>17.7 (20.2)</td><td>18.1 (23.3)</td><td>0.03</td></tr></tbody></table>

CSMS=Combined symptom-medication score; e-DASTHMA= Electronic daily control score for asthma; ICS=Inhaled corticosteroids; IQR=Interquartile range; LABA=Long-acting beta-agonists; VAS=Visual analogue scale.
<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 1** Frequency (percentage – A; absolute number – B) of weeks by median VAS asthma and adherence levels to inhaled corticosteroids (ICS) + long-acting beta-agonists (LABA).</figcaption></figure>

Similar results were observed in sensitivity analyses concerning weeks with at most one missing day of MASK-air® data. We also assessed 907 months with at most four missing days of MASK-air® reporting, with similar results observed (N users=214; e-Tables 5-7).

## Days with and without ICS+LABA

Considering all weeks, higher VAS asthma levels were observed for days on which ICS+LABA were used versus those on which such medications were not used (Table 2). These associations were observed both for ICS+F (regression coefficient=5.6; 95%CI=5.0;6.1; *p*<0.001) and for ICS+other LABA

(regression coefficient=2.8; 95%CI=1.8;3.7); *p*<0.001). However, these differences were not observed when only weeks with adherence (MPR>80%) were considered. Similar results were noted in sensitivity analyses (e-Table 8).

## ICS+LABA adherence and SABA use

The number of weeks with SABA use was higher in ICS+other LABA users (23.3%) than in ICS+F users (15.5%; effect size=0.20, e-Table 3). Furthermore, in weeks with SABA use, there were more days of SABA use in ICS+other LABA (median=71.4% days) than in ICS+F users (median=57.1% days) (effect size=0.26). This trend was also found when analysing only weeks with adherence (MPR>80%) to ICS+LABA (median for ICS+F=57.1%, median for ICS+other LABA=71.4%, effect size=0.26) (e-Table 3).

Increased adherence to ICS+F or ICS+other LABA was associated with lower SABA use, even after adjustment for VAS asthma levels. Each additional weekly day of ICS+F use was associated with a 4.1% average decrease in the risk of weekly SABA use (95%CI=-6.5%, -1.6%; *p*=0.001) compared to a 8.2% decrease with ICS+other LABA (95%CI=-11.6%, -5.0%; *p*<0.001) (Table 3).

Similar results were observed in sensitivity analyses when considering weeks with at most one day of missing data (e-Tables 6 and 9) or when considering monthly data (e-Table 7).

<table><caption>**Table 2** Results of linear regression models comparing days with versus without use of ICS + LABA on VAS asthma levels.</caption><thead><tr><th>Independent variable</th><th>VAS asthma – coefficient<br>(95%CI) [p-value]</th></tr></thead><tbody><tr><td>ICS+Formoterol</td><td></td></tr><tr><td>All weeks</td><td>5.56 (4.98;6.14) [<0.001]</td></tr><tr><td>Adherent weeks</td><td>-0.83 (-2.14;0.48) [0.216]</td></tr><tr><td>ICS+other LABA</td><td></td></tr><tr><td>All weeks</td><td>2.78 (1.83;3.73) [<0.001]</td></tr><tr><td>Adherent weeks</td><td>1.40 (-0.32;3.13) [0.111]</td></tr></tbody><tfoot><tr><td colspan="2">CI=Confidence interval; ICS=Inhaled corticosteroids; LABA=Long-acting beta-agonist; VAS=Visual analogue scale.</td></tr></tfoot></table>
<table><caption>**Table 3** Results of univariable and multivariable Poisson regression models modelling the percentage change in weekly SABA use per unit increase of the (i) number of weekly days of ICS+LABA use and/or (ii) median VAS asthma. Results are presented as percentage change (95% confidence intervals) [p-value].</caption><thead><tr><th colspan="3">A. Models involving ICS+Formoterol</th></tr><tr><th></th><th>Univariable models</th><th>Multivariable models</th></tr></thead><tbody><tr><td>Weekly days of ICS+Formoterol use</td><td>-3.2% (-5.6%; -0.7%) [0.012]</td><td>-4.1% (-6.5%; -1.6%) [0.001]</td></tr><tr><td>Median VAS asthma</td><td>2.0% (1.6%; 2.4%) [<0.001]</td><td>2.0% (1.6%; 2.4%) [<0.001]</td></tr></tbody><thead><tr><th colspan="3">B. Models involving ICS+other LABA</th></tr><tr><th></th><th>Univariable models</th><th>Multivariable models</th></tr></thead><tbody><tr><td>Weekly days of ICS+other LABA use</td><td>-6.0% (-9.1%; -2.8%) [<0.001]</td><td>-8.2% (-11.6%; -5.0%) [<0.001]</td></tr><tr><td>Median VAS asthma</td><td>2.3% (1.9%; 2.7%) [<0.001]</td><td>2.4% (2.0%; 2.8%) [<0.001]</td></tr></tbody></table>

ICS=Inhaled corticosteroids; LABA – Long-acting beta-agonists; SABA=Short-acting beta-agonists; VAS=Visual analogue scale.

Discussion

In this study, there was an overall good adherence to ICS +LABA. Adherence was higher for ICS+other LABA than for ICS+F, but ICS+F was associated with lower SABA use and similar VAS asthma, e-DASTHMA or VAS work levels. Overall, increased adherence to ICS+LABA was associated with decreased SABA use.

As in any mHealth study, there are several limitations to be considered.²⁴ First, there is the possibility of selection biases. MASK-air® users may not be representative of the general population with asthma (being younger and, potentially, with higher access to care). This is exemplified by the fact that, in this study, ICS+F was used more frequently than ICS+other LABA, although this does not occur in many countries. Among MASK-air® users, those who report larger volumes of data may also be different from the remainder. In fact, only 9% of self-reported asthma MASK-air® users (33% of those using ICS-LABA) fulfilled the inclusion criteria (which were set so as to have a sufficiently large continuous period of data collection in order to enable an estimation of medication adherence). This selection may represent another bias since adherence may be lower in weeks with incomplete reporting. However, in a previous study, we found that adherence to the app was not related to adherence to medications.¹⁶

Patients were not necessarily enrolled by physicians and we relied on the reported use of asthma medication for identifying patients with asthma. However, in a MASK-air® sub-study of 69 patients, we found that 93% of those with an asthma treatment had a physician diagnosis of current or previous asthma.²⁵ Moreover, ICS+LABA are only used in asthma and chronic obstructive pulmonary disease, with the latter being potentially rare in a sample of patients composed mostly of young adults. Additional limitations include the fact that the severity of asthma, the strength of ICS +LABA and the number of puffs/day were not assessed.

This study also has important strengths. The sample size is quite large, pointing to the possibility of assessing relevant amounts of real-world longitudinal mHealth data from patients with asthma. Additional strengths concern the assessment of (i) periods with no missing data (allowing a full assessment of medication adherence) and (ii) clinically

relevant outcomes, such as the use of SABA. Finally, we used data directly provided by the patients, allowing us to overcome information biases in data collection or provision resulting from researchers' or participants' expectations about a study.

Even though the use of MASK-air® itself may promote higher medication adherence (currently unclear, to be explored in future studies), the high medication adherence levels found may be largely related to selection biases. In particular, among MASK-air® users, an overrepresentation is expected, not only of younger and more-schooled patients, but also of patients with higher access to specialised health care (even though the app can be found by patients themselves, we estimate that a large amount of them were advised to do so by their physicians). In addition, users highly adherent to the app may be generally more concerned about their asthma and, therefore, more adherent to treatment. This has to be confirmed in new studies. In the assessed patients, medication adherence was higher to ICS +F than to ICS+other LABA. Finding a difference between both medications also suggests that app adherence is unlikely to be the major criterion explaining differences in adherence between different medication schemes. Moreover, this difference was expected, as patients reporting ICS +F may use the medication in the context of the MART approach (Maintenance and Reliever Therapy²⁶) or purely on an on-demand basis.²⁷ Even though this is not possible to assess in MASK-air®, this hypothesis is supported by the fact that ICS+F was associated with a slightly worse control than ICS+other LABA for VAS asthma and e-DASTHMA (although differences were non-meaningful). In the MART approach, patients under ICS+F adapt their treatment depending on symptoms, whereas patients under ICS+other LABA should use regular treatment and SABA when feeling worse.

When patients used ICS+LABA, they were reporting higher VAS asthma and e-DASTHMA levels. This indicates that most patients only use medication when they are not well.

In weeks with SABA use, the percentage of days with SABA differed between ICS+F and ICS+other LABA. This effect was replicated when considering only weeks with adherence. This finding appears to be important, confirming clinical trials and some phase 4 studies with real-life data. Each additional day of ICS+F or ICS+other LABA use is associated with
a significant average decrease in weekly SABA use, pointing to the positive impact of a good medication adherence to ICS+LABA.

There were no differences in rhinitis control (CSMS) between ICS+F and ICS+other LABA, supporting the observed results in asthma control.

In conclusion, we compared patients using ICS+F versus ICS+other LABA on their medication adherence. While users under ICS+other LABA displayed higher adherence than those under ICS+F, similar levels of asthma control were observed across the two groups. However, patients under ICS+other LABA displayed a higher frequency of SABA use. An increased medication adherence was found to be associated with lower frequency of SABA use, pointing to the importance of maintaining a high ICS+LABA adherence. Overall, this study shows the potential of mHealth tools in the longitudinal assessment of patients with asthma, allowing physicians and patients to monitor their medication adherence, control and SABA use.

## Author contributions

BSP and EMC participated in the study design, data analysis and manuscript writing (original draft); JB and RL participated in the conceptualisation, study design, data analysis, supervision and manuscript writing (original draft); TZ, JMA and JAF participated in the study design, supervision and manuscript writing (revision and editing). All remaining authors participated in the data collection and manuscript writing (revision and editing).

## Funding information and role of the sponsors

MASK-air® has been supported by EU grants (POLLAR, EIT Health; Structural and Development Funds, Twinning, EIP on AHA, H2020 and Horizon Europe) and by educational grants from Mylan-Viatris, ALK, GSK, Novartis and Uriach. There was no specific funding for this paper.

## Conflicts of interest

JS reports grants and personal fees from SANOFI, personal fees from GSK, personal fees from NOVARTIS, personal fees from ASTRA ZENECA, personal fees from MUNDIPHARMA, personal fees from FAES FARMA, outside the submitted work.

BS reports personal fees from Polpharma, personal fees from Viatris, grants and personal fees from AstraZeneca, personal fees from TEVA, personal fees from patient ombudsman, personal fees from Polish Allergology Society, grants from GSK, outside the submitted work.

SBA reports grants from TEVA, personal fees from TEVA, personal fees from TEVA, personal fees from AstraZeneca, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Boehringer Ingelheim, personal fees from GSK, personal fees from Sanofi, personal fees from Mylan, personal fees from Menarini, outside the submitted work.

BG reports grants from Chiesi, grants from Sandoz, grants from GSK, grants from AstraZeneca, grants from Deva, grants from Abdi Ibrahim, outside the submitted work.

RL reports grants and personal fees from AZ, grants and personal fees from GSK, grants from Chiesi, outside the submitted work.

MK reports personal fees from Astra Zeneca, personal fees from Chiesi, personal fees from GSK, personal fees from Novartis, personal fees from Berlin Chemie, personal fees from Zentiva, personal fees from Allergopharma, personal fees from LEK-AM, personal fees from Polpharma, personal fees from Teva, personal fees from Sanofi, personal fees from Adamed, personal fees from Sandoz, personal fees from EMMA, outside the submitted work.

FDB reports other from NOVARTIS, other from ALK, other from STALLERGENES, other from REGENERON, other from DBV, other from SANOFI, other from BOEHRINGER, other from ASTRAZENECA, outside the submitted work.

CSU reports grants and personal fees from AZ, personal fees from GSK, personal fees from TEVA, grants and personal fees from Sanofi, grants and personal fees from BI, personal fees from Novartis, personal fees and non-financial support from Orion Pharma, personal fees from Chiesi, personal fees from TFF Pharmaceuticals, personal fees from Takeda, personal fees from Pfizer, personal fees from Covis Pharma, outside the submitted work.

NP reports grants from Capricare, personal fees from Nestle, personal fees from Numil, personal fees from Vianex, outside the submitted work.

FR reports personal fees from Novartis, personal fees from Sanofi, personal fees from AstraZeneca, personal fees from GSK, personal fees from Medinfar, personal fees from Azentis, outside the submitted work.

TZ reports grants and personal fees from Novartis, grants and personal fees from Henkel, personal fees from Bayer, personal fees from FAES, personal fees from Astra Zeneca, personal fees from AbbVie, personal fees from ALK, personal fees from Almirall, personal fees from Astellas, personal fees from Bayer, personal fees from Bencard, personal fees from Berlin Chemie, personal fees from FAES, personal fees from Hal, personal fees from Leti, personal fees from Mesa, personal fees from Menarini, personal fees from Merck, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Sanofi, personal fees from Stallergenes, personal fees from Takeda, personal fees from Teva, personal fees from UCB, personal fees from Henkel, personal fees from Kryolan, personal fees from L'Oreal, outside the submitted work; and Organizational affiliations: Committee member: WHO-Initiative "Allergic Rhinitis and Its Impact on Asthma" (ARIA); Member of the Board: German Society for Allergy and Clinical Immunology (DGAKI); Head: European Centre for Allergy Research Foundation (ECARF); President: Global Allergy and Asthma European Network (GAZLEN); Member: Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO).

AP reports grants from CHIESI, ASTRAZENECA, GSK, SANOFI, personal fees from CHIESI, ASTRAZENECA, GSK, NOVARTIS, SANOFI, IQVIA, AVILLION, ELPEN PHARMACEUTICALS, personal fees from CHIESI, ASTRAZENECA, GSK, BI, MENARINI, NOVARTIS, ZAMBON, MUNDIPHARMA, TEVA, SANOFI, EDMOND PHARMA, IQVIA, MSD, AVILLION, ELPEN PHARMACEUTICALS, outside the submitted work.
RB reports grants from Boehringer Ingelheim, GlaxoSmithKline, Novartis and Roche, personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Novartis, Sanofi, Roche and Teva, outside the submitted work.

LTB reports personal fees from DIATER, personal fees from Novartis, personal fees from LETI, outside the submitted work.

JF reports personal fees from Viatris/Mylan, personal fees from AstraZeneca, outside the submitted work; and being co-founder of an SME that develops mHealth technologies, such as digital biomarkers and has the copyright of the CARAT and CARATkids PROM.

VK reports non-financial support from Norameda, non-financial support from Berlin CHemie Menarini, outside the submitted work.

NR reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, grants and personal fees from GSK, personal fees from AstraZeneca, personal fees from Chiesi, grants and personal fees from Pfizer, personal fees from Sanofi, personal fees from Zambon, personal fees from MSD, personal fees from Austral, outside the submitted work.

SB reports personal fees from Sanofi Genzyme, personal fees from AstraZeneca, grants from Auris medical, personal fees from Allergopharma, personal fees from ALK Abello, grants, personal fees and non-financial support from Ben card Allergy, personal fees from Allergy Therapeutics, non-financial support from Smart Reporting, personal fees from Stryker, personal fees from MSD, personal fees from Mylan, personal fees from GSK, outside the submitted work.

JB reports personal fees from Cipla, Menarini, Mylan, Novartis, Purina, Sanofi-Aventis, Teva, Uriach, other from KYomed-Innov, other from Mask-air-SAS, outside the submitted work.

TH reports personal fees from Orion Pharma, outside the submitted work.

LC reports personal fees from Thermofisher, personal fees from Novartis, personal fees from ALK, personal fees from Sanofi, personal fees from GSK, personal fees from Astra Zeneca, outside the submitted work.

LPB reports grants from Time frame: past 36 months Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Sanofi-Regeneron, personal fees from AstraZeneca, Novartis, GlaxoSmithKline, Merck, Sanofi-Regeneron, personal fees from AstraZeneca, Covis, Cipla, GlaxoSmithKline, Novartis, Merck, Sanofi, outside the submitted work.

SDG reports grants and personal fees from AstraZeneca, personal fees from Chiesi, grants and personal fees from GSK, grants and personal fees from Novartis, personal fees from Guidotti, personal fees from Sanofi, outside the submitted work.

PK reports personal fees from Adamed, personal fees from Berlin Chemie Menarini, personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Glenmark, personal fees from Novartis, personal fees from Polpharma, personal fees from GSK, personal fees from Sanofi, personal fees from Chiesi, personal fees from Celon Pharma, outside the submitted work.

AC reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GSK, personal fees from Eurofarma, personal

fees from Novartis, personal fees from Sanofi, outside the submitted work.

MS reports grants from Immune Tolerance Network, grants from Medical Research Council, grants and personal fees from Allergy Therapeutics, grants and personal fees from LETI Laboratorios, grants from Revolo biotherapeutics, grants from Angany Inc, personal fees from Bristol Myers Squibb, outside the submitted work.

GB reports personal fees from Astra Zeneca, personal fees from Boehringer-Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, personal fees from Novartis, personal fees from Sanofi, grants from Merck-Sharp&Dohme, outside the submitted work.

MJ reports personal fees from ALK-Abello, personal fees from Allergopharma, personal fees from Stallergenes, personal fees from Anergis, personal fees from Allergy Therapeutics, personal fees from Leti, personal fees from HAL, during the conduct of the study; personal fees from GSK, personal fees from Novartis, personal fees from Teva, personal fees from Takeda, personal fees from Chiesi, outside the submitted work.

DLL reports personal fees from ALK, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GSK national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Carnot, grants from Abbvie, Bayer, Lilly, Sanofi, AstraZeneca, Lilly, Pfizer, Novartis, Circassia, UCB, GSK, Purina institute., outside the submitted work.

OP reports grants and personal fees from ALK-Abelló, grants and personal fees from Allergopharma, grants and personal fees from Stallergenes Greer, grants and personal fees from HAL Allergy Holding B.V./HAL Allergie GmbH, grants from Bencard Allergie GmbH/Allergy Therapeutics, grants from Lofarma, grants and personal fees from ASIT Biotech Tools S.A., grants and personal fees from Laboratorios LETI/LETI Pharma, grants and personal fees from GlaxoSmithKline, personal fees from ROXALL Medizin, personal fees from Novartis, grants and personal fees from Sanofi-Aventis and Sanofi-Genzyme, personal fees from Med Update Europe GmbH, personal fees from streamlinedup! GmbH, grants from Pohl-Boskamp, grants from Inmunotek S.L., personal fees from John Wiley and Sons, AS, personal fees from Paul-Martini-Stiftung (PMS), personal fees from Regeneron Pharmaceuticals Inc., personal fees from RG Aerztefortbildung, personal fees from Institut für Disease Management, personal fees from Springer GmbH, grants and personal fees from AstraZeneca, personal fees from IQVIA Commercial, personal fees from Ingress Health, personal fees from Wort&Bild Verlag, personal fees from Verlag ME, personal fees from Procter& Gamble, personal fees from ALTAMIRA, personal fees from Meinhardt Congress GmbH, personal fees from Deutsche Forschungsgemeinschaft, personal fees from Thieme, grants from Deutsche AllergieLiga e.V., personal fees from AeDA, personal fees from Alfred-Krupp Krankenhaus, personal fees from Red Maple Trials Inc., personal fees from TU Dresden, outside the submitted work.

YO reports personal fees from Torii pharmaceutical Co., LTD., personal fees from Tanabe-Mitsubishi Pharmaceutical Co., Ltd., personal fees from Kirin Holdings Co., Ltd., personal fees from Novartis Co., Ltd., personal fees from Allergologisk Laboratorium København, personal fees from Shionogi Co., Ltd., outside the submitted work.
JCI reports personal fees and non-financial support from Laboratorios Casasco, personal fees from Abbott Ecuador. personal fees from Laboratorios Bago Bolvia, personal fees from Faes Farma, outside the submitted work.

HK reports personal fees from Mylan/Viatris, personal fees from Sanofi, outside the submitted work.

MO reports personal fees from Hycor Diagnostics, outside the submitted work; and Scientific Co-Founder, Tolerogenics SARL, Luxembourg.

The other authors have no COIs to disclose, outside the submitted work.

Supplementary materials

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.pulmoe.2023.07.004.

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