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\begin{document}

\title{Symptom control and health-related quality of life in allergic rhinitis
with and without comorbid asthma: a multicentre European study}



\author[1]{Isabella Annesi-Maesano}%
\author[2]{Subhabrata Moitra}%
\author[3]{Marzia Simoni}%
\author[3]{Sandra Baldacci}%
\author[3]{Sara Maio}%
\author[3]{Anna Angino}%
\author[3]{Patrizia Silvi}%
\author[3]{G. Viegi}%
\author[4]{Stefania La Grutta}%
\author[3]{Franco Ruggiero}%
\author[3]{Gianni Bedini}%
\author[5]{Francesca Natali}%
\author[6]{Lorenzo Cecchi}%
\author[7]{Uwe Berger}%
\author[7]{Maria Prentovic}%
\author[1]{Amir Gamil}%
\author[1]{Nour Baiz}%
\author[8]{Michel Thibaudon}%
\author[8]{Samuel Monnier}%
\author[1]{Davide Caimmi}%
\author[1]{LUCIANA TANNO}%
\author[1]{Pascal Demoly}%
\author[5]{Simone Orlandini}%
\affil[1]{Montpellier Universite d'Excellence}%
\affil[2]{University of Alberta Department of Medicine}%
\affil[3]{Istituto di Fisiologia Clinica Consiglio Nazionale delle Ricerche}%
\affil[4]{Istituto di Farmacologia Traslazionale Consiglio Nazionale delle Ricerche}%
\affil[5]{Western Colorado University Department of Natural and Environmental Sciences}%
\affil[6]{Universidad Dominicana O\&M Medical School}%
\affil[7]{University of Vienna Polymer and Composites Engineering Group}%
\affil[8]{INSERM}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Allergic rhinitis (AR) is a major non-communicable
disease that affects the health-related quality of life (HRQoL) of
patients. AR is significantly related to asthma also affecting HRQoL.
However, data on HRQoL and symptom control in AR patients with comorbid
asthma are lacking. \textbf{Objective:} To assess the differences of
symptom control and HRQoL in AR patients with and without comorbid
asthma. \textbf{Methods:} In this multicentre, cross-sectional study,
patients with AR were screened and administered questionnaires of
demographic characteristics and health conditions (symptoms/diagnosis of
AR and asthma, disease severity level, and allergic conditions). HRQoL
was assessed using a modified version of the RHINASTHMA questionnaire
and symptom control was evaluated by a modified version of the Control
of Allergic Rhinitis/Asthma Test (CARAT). \textbf{Results:} Out of 643
patients with AR, 500 (78\%) had asthma as a comorbidity, and 54\% had
moderate-severe intermittent AR, followed by moderate-severe persistent
AR (34\%). Patients with both AR and asthma had significantly higher
RHINASTHMA scores than the patients with AR alone (e.g., median
RHINASTHMA-total score 84 vs. 48.5, respectively). Conversely, CARAT
scores were significantly lower in AR with comorbid asthma than in the
patients with AR alone (median CARAT-total score 16.5 vs. 23,
respectively). Upon stratifying asthma based on severity, AR patients
with severe persistent asthma had worse HRQoL and control than AR
patients with mild persistent asthma. \textbf{Conclusions:} Our
observation of poorer HRQoL and symptoms control in AR patients with
comorbid asthma supports the importance of a comprehensive approach for
the management of AR in case of a comorbid allergic condition.%
\end{abstract}%



\sloppy


\textbf{Symptom control and health-related quality of life in allergic
rhinitis with and without comorbid asthma: a multicentre European study}

\textbf{Running head:} HRQoL and control in allergic rhinitis with
asthma

Subhabrata Moitra\textsuperscript{1}, Marzia Simoni\textsuperscript{2},
Sandra Baldacci\textsuperscript{2}, Sara Maio\textsuperscript{2}, Anna
Angino\textsuperscript{2}, Patrizia Silvi\textsuperscript{2}, Giovanni
Viegi\textsuperscript{2}, Stefania La Grutta\textsuperscript{3}, Franco
Ruggiero\textsuperscript{4}, Gianni Bedini\textsuperscript{4}, Francesca
Natali\textsuperscript{5}, Lorenzo Cecchi\textsuperscript{6}, Uwe
Berger\textsuperscript{7}, Maria Prentovic\textsuperscript{7}, Amir
Gamil\textsuperscript{8}, Nour Ba\selectlanguage{ngerman}ïz\textsuperscript{8}, Michel
Thibaudon\textsuperscript{9}, Samuel Monnier\textsuperscript{9}, Davide
Caimmi\textsuperscript{8}, Luciana K. Tanno\textsuperscript{8}, Pascal
Demoly\textsuperscript{8}, Simone Orlandini\textsuperscript{5}, Isabella
Annesi-Maesano\textsuperscript{8}

\textsuperscript{1}Division of Pulmonary Medicine \& Alberta Respiratory
Centre, Department of Medicine, University of Alberta, Edmonton, Canada.

\textsuperscript{2}Pulmonary Environmental Epidemiology Unit, CNR
Institute of Clinical Physiology (IFC), Pisa, Italy.

\textsuperscript{3}CNR Institute of Translational Pharmacology (IFT),
Palermo, Italy.

\textsuperscript{4}Department of Biology, University of Pisa, Italy.

\textsuperscript{5}Department of Agrifood Production and Environmental
Sciences, University of Florence, Italy.

\textsuperscript{6}Centre of Bioclimatology, University of Florence,
Florence, Italy.

\textsuperscript{7}Research Unit Aerobiology and Pollen information,
Department of Oto-Rhino-Laryngology, Medical University of Vienna,
Vienna, Austria.

\textsuperscript{8}Institut Desbrest of Epidemiology and Santé Publique
INSERM \& Montpellier University, Montpellier, France.

\textsuperscript{9}Reseau National de Surveillance Aerobiologique
(RNSA), Brussieu, France.

\textbf{Correspondence to:} Isabella Annesi-Maesano, IDESP IURC, 641
Avenue du Doyen Gaston Giraud, 34093 Montpellier, France. Tel: +
33-411759831. Email:\emph{isabella.annesi-maesano@inserm.fr}

\textbf{FUNDING \& ACKNOWLEDGEMENT:}

The authors are indebted to the participants. The AIS LIFE+ project was
supported by EU Grant N° \emph{ENV/IT/001 107.}

\textbf{CONFLICT OF INTEREST:}

SM reports personal fees from Synergy Respiratory \& Cardiac Care
(Canada), Permanyer Inc. (Spain), Elsevier Inc., and Apollo Gleneagles
Hospital (India) outside this submitted work. UEB reports grants from
CAMS-32 outside the submitted work. PD received grants from ALK,
Stallergenes Greer, AstraZeneca, ThermoFisherScientific, Ménarini, GSK,
Zambon, Viatris, and personal fees from Chiesi, and Puuressentiel,
outside the submitted work. PD is also the Vice President of the French
Allergy Society and Immediate Past President of the French Allergy
Council. IA-M reports grants from the European Council and other public
bodies outside the submitted work. IA-M is also the President of the IRD
Ethic Committee and Member of the European Respiratory Society Ethic and
Integrity Committee. Other authors do not have any conflict of interest
to declare.

\textbf{Word Count:} 2,511 (except abstract, references, table, and
figure legends)

\textbf{Number of Display Items:} 1 Table and 5 Figures

This manuscript has an online supplement.

\section*{ABSTRACT}

{\label{abstract}}

\textbf{Background:} Allergic rhinitis (AR) is a major non-communicable
disease that affects the health-related quality of life (HRQoL) of
patients. AR is significantly related to asthma also affecting HRQoL.
However, data on HRQoL and symptom control in AR patients with comorbid
asthma are lacking.

\textbf{Objective:} To assess the differences of symptom control and
HRQoL in AR patients with and without comorbid asthma.

\textbf{Methods:} In this multicentre, cross-sectional study, patients
with AR were screened and administered questionnaires of demographic
characteristics and health conditions (symptoms/diagnosis of AR and
asthma, disease severity level, and allergic conditions). HRQoL was
assessed using a modified version of the RHINASTHMA questionnaire and
symptom control was evaluated by a modified version of the Control of
Allergic Rhinitis/Asthma Test (CARAT).

\textbf{Results:} Out of 643 patients with AR, 500 (78\%) had asthma as
a comorbidity, and 54\% had moderate-severe intermittent AR, followed by
moderate-severe persistent AR (34\%). Patients with both AR and asthma
had significantly higher RHINASTHMA scores than the patients with AR
alone (e.g., median RHINASTHMA-total score 84 vs. 48.5, respectively).
Conversely, CARAT scores were significantly lower in AR with comorbid
asthma than in the patients with AR alone (median CARAT-total score 16.5
vs. 23, respectively). Upon stratifying asthma based on severity, AR
patients with severe persistent asthma had worse HRQoL and control than
AR patients with mild persistent asthma.

\textbf{Conclusions:} Our observation of poorer HRQoL and symptoms
control in AR patients with comorbid asthma supports the importance of a
comprehensive approach for the management of AR in case of a comorbid
allergic condition.

\textbf{KEYWORDS} : allergy treatment, food allergy, pollen, rhinitis,
vaccines

\section*{INTRODUCTION}

{\label{introduction}}

Allergic rhinitis (AR) is a type-2 chronic inflammatory disease
affecting the nasal mucosa and characterized by nasal symptoms such as
sneezing, rhinorrhoea (nasal discharge), pruritus, and nasal
congestion\textsuperscript{1-3}. It is one of the most common
non-communicable chronic diseases in the world, affecting over 400
million people of all ages, particularly the paediatric
population\textsuperscript{1-6}. While the prevalence of
physician-diagnosed AR in the United States has been observed as high as
15\% and 30\%, based on self-reported nasal
symptoms\textsuperscript{7,8}, the prevalence was as high as up to 50\%
in many European countries\textsuperscript{9}. According to the Allergic
Rhinitis and its Impact on Asthma (ARIA) and the Global Alliance against
Chronic Respiratory Diseases (GARD) statements, severe, refractory, or
mixed forms of AR are significantly increasing across the globe and have
contributed substantially to the socio-economic burden of the
disease\textsuperscript{10-12}.

AR often coexists with other conditions, such as atopic dermatitis,
rhinosinusitis, rhino-conjunctivitis, and particularly asthma -- a
coherent feature often referred to as `the atopic march' due to common
systemic inflammatory processes\textsuperscript{2,4}. 40-50\% of
patients with AR also have asthma whereas the prevalence of AR as a
comorbidity in asthmatic patients is even higher, i.e.,
70-90\%\textsuperscript{13}. Several reports described that the patients
suffering from AR show a poorer quality of life (QoL), being affected by
impaired sleep pattern, increased amount of fatigue, depression, risk of
driving accident, and altered physical and social
functions\textsuperscript{8,14-16}. Often, a poor perception of AR
symptoms is associated with poor control of AR\textsuperscript{17}.
However, studies assessing health-related quality of life (HRQoL) and
symptoms control in AR patients with concomitant asthma are lacking.

The Aerobiological Information Systems and allergic respiratory disease
management (AIS Life +) study focused on this aspect, by using
specifically designed and validated questionnaires on quality of life
and control for AR with comorbid asthma.



\section*{METHODS}

{\label{methods}}

\subsection*{Study design and
participants}

{\label{study-design-and-participants}}

In the international multi-centre (Austria, France, and Italy)
cross-sectional AIS Life + study, conducted between 2013 and 2014, we
enrolled participants suffering from nasal allergy. A convenient sample
of individuals with an active condition of pollen-induced AR was
selected from pre-existing epidemiological study databases or through
web advertisement (Pisa, Italy), clinics of general practitioners
(Paris, France) or public health database and pulmonary clinics (Vienna,
Austria) and invited to participate in this epidemiological survey. All
potential participants were administered a screening questionnaire
through a telephone interview to check whether they were eligible for
the study. We included individuals who: 1) were adults (\selectlanguage{english}[?] 18 years of
either sex); 2) reported allergic rhinitis diagnosis/symptoms or
positive clinical tests to pollen in the last 12 months; 3) spent most
of the week (at least 5 days/week) living, studying, or working in the
areas where this study was conducted; and 4) were not treated with
allergen immunotherapy over the previous 6 years.

The study was approved by the ethics committees of the participating
centres in Italy (Ethics Committee of University-Hospital of Pisa;
Protocol No. 14248) and in Austria (Berlin Charite University Ethics:
EA1/119/12), and signed informed consents were obtained from all the
participants before recruitment. In France, the approval by an external
ethic committee was declared as not applicable at that time: instead,
the study was approved by the Hospital ethic committee, by the National
Committee for Information Management on Medical Research (\emph{Comite'
Consultatif sur le Traitement de l'Information en Matiere de Recherche
dans le domaine de la sante'} ) and by the National Commission on
Informatics and Health (CNIL, \emph{Commission Nationale Informatique et
Liberte'} ). In France, the CNIL approved in 2016 that all data acquired
prior to 2016, without the previous need of an authorization of an Ethic
Committee, could still be utilized. In any case, patients were seen in
the frame of routine care (``\emph{soins courants} ''). The AIS study
was conducted according to the Declaration of Helsinki and reported as
per the Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) guidelines\textsuperscript{18}.

\subsection*{Instruments and variables}

{\label{instruments-and-variables}}

A standardized health questionnaire was administered to all eligible
individuals in order to obtain information on their demographic
characteristics (age, gender, body mass index {[}BMI{]}, level of
education), and potential risk factors (smoking status, exposure to
second-hand smoke, and drug consumption), on symptoms/diagnosis of AR
and asthma, disease severity level, as well as on previous clinical
tests (spirometry, skin prick test and serum level of immunoglobulin E
{[}IgE{]}).

The health-related quality of life (HRQoL) of the participants was
assessed using a modified version of the validated RHINASTHMA
questionnaire (the higher the score, the lower the HRQoL), i.e., the
only available instrument that allows evaluating the concomitant impact
of AR and asthma on HRQoL\textsuperscript{19}. This 30-item
questionnaire provides individual scores for upper airways, lower
airways, respiratory allergy impact, and a composite score (the Global
Summary {[}GS{]} score, which indicates the overall impact of the
disease). The details of the instrument and the scoring system can be
found elsewhere\textsuperscript{19}. Patients used a five-point Likert
scale ('not at all', 'a little', 'fairly', 'much', 'very much') to
indicate the extent to which they were bothered by each AR and asthma
during the year preceding the completion of the questionnaire. These
responses are then converted into scores, from 0 to 100, with larger
scores corresponding to worse HRQoL. A RHINASTHMA-GS score from 0 to 20,
indicating minimal or absent disease impact on patient life, was
considered reflective of optimal HRQoL.

The control of AR and asthma was evaluated by a modified version of the
Control of Allergic Rhinitis/Asthma Test (CARAT) (the higher the score,
the higher the disease control)\textsuperscript{20,21}. CARAT is a
10-item questionnaire containing information about the frequency of
symptoms, sleep impairment, activities limitation, and need for more
medication: the response options for all the questions follow a 4-point
Likert scale (range 0-3). The range of CARAT score is 0--30, 0 being the
complete absence of control: the minimal clinically important difference
(MCID) is 3.5\textsuperscript{22}. The Global Initiative for Asthma
(GINA) classification 2017\textsuperscript{23} and ARIA
(2008)\textsuperscript{6} were used to classify asthma according to its
severity.

\subsection*{Statistical analyses}

{\label{statistical-analyses}}

Data were described as frequency (\%), mean (standard deviation
{[}SD{]}), or median (interquartile range {[}IQR{]}) for categorical,
continuous, and ordinal variables, respectively. To test the association
among quality of life and control (RHINASTHMA and CARAT -- total and
subdomains) scores, and AR-asthma (independent variable), we first used
a bivariate analysis using Wilcoxon rank-sum test. Then, we constructed
univariable (unadjusted) and multivariable (adjusted) regression models
among the independent variable and HRQoL and control scores using a
mixed effect Poisson regression model. As potential confounders, we
tested fixed factors (age, sex, BMI, smoking status, exposure to smoke,
education, ARIA grade, sensitivity to allergens, and drugs taken in the
last 12 months) and a random factor (the country). To include
confounders in the regression models, we used \emph{a priori} evidence
criteria, i.e., covariates were considered as confounders if were found
consistent in previous literature. However, confounders were retained in
the model if they modified the estimates of the remaining variables by
more than 10\%. We checked the collinearity of the confounders using the
variance inflation factor (VIF). The parsimony of the models was
confirmed by Akaike's information criteria (AIC).

We also performed two secondary analyses. Firstly, we tested if there
was any effect modification by obesity on the association between
AR-asthma, and the HRQoL and control scores. Secondly, we performed
meta-analyses to determine if there were any heterogeneity in the HRQoL
and control (total) scores between the participating countries. All
analyses were conducted using a complete case approach in Stata V.16
(StataCorp, College Station, TX, USA), and a p-value \textless{} 0.05
was considered statistically significant.

\section*{RESULTS}

{\label{results}}

Demographic and clinical characteristics of all the participants,
stratified by country, are presented in Table 1. Of all participants,
nearly 40\% were males with a mean age of 44 (standard deviation, SD:
14) years, 15\% of the participants were obese, 47\% were smokers and
nearly 33\% reported exposure to smoke, 78\% of the participants had
asthma as a comorbidity, 54\% had moderate-severe intermittent AR and
34\% had moderate-severe persistent AR. As for allergic sensitization,
pollens were the most prevalent allergen (89\%) among the participants,
followed by house dust mites (57\%). Concerning the HRQoL parameters,
the participants had a median (IQR) RHINASTHMA-total score of 76 (53,
91) and CARAT-total score of 18 (14, 22). In the bivariate analysis, we
found that participants with both AR and asthma had significantly higher
RHINASTHMA (total and subdomain) scores than the participants with AR
alone (\textbf{Figure 1} ). Moreover, CARAT (total and subdomain) scores
were significantly lower in AR with comorbid asthma than in AR alone
(\textbf{Figure 2} ).

Table 1

Figure 1 \& 2

In the multivariable analysis, we observed that, compared to AR alone,
AR with comorbid asthma was significantly associated with poorer quality
of life (regression coefficient {[}\selectlanguage{english}\selectlanguage{greek}β{]} for RHINASTHMA-total score:
0.22; 95\% confidence interval {[}CI{]}: 0.19, 0.25). The association
was persistent in RHINASTHMA subdomain scores; however, the magnitude of
the estimates was different, being the highest for lower airways (0.36;
0.31, 0.41) and the lowest for upper airways (0.09; 0.04, 0.14). Upon
stratifying asthma, based on the 2017 GINA grades, the magnitude of the
association was the highest in AR patients with severe persistent asthma
(\selectlanguage{greek}β \selectlanguage{english}for RHINASTHMA-total score: 0.25; 95\%CI: 0.22, 0.29), and the lowest
in AR patients with mild persistent asthma (0.15; 0.10, 0.20)
(\textbf{Figure 3 and Supplementary Table 1} ). We did not find any
multicollinearity between the covariates (VIF\textless{}3).

Figure 3

We observed a poorer control of symptoms in AR patients with asthma
comorbidity than in patients with AR alone (\selectlanguage{greek}β \selectlanguage{english}for CARAT-total score:
-0.20; 95\%CI: -0.25, -0.15); the lower airway symptoms were more poorly
controlled (-0.23; -0.29, -0.17) than the upper airway symptoms (-0.11;
-0.20, -0.01). Upon stratifying asthma according to GINA grade, AR
patients with severe persistent asthma had the poorest control (\selectlanguage{greek}β \selectlanguage{english}for
CARAT-total score: -0.25; 95\%CI: -0.31, -0.19) than those with mild
persistent asthma (-0.06; -0.14, 0.03) (\textbf{Figure 4 and
Supplementary Table 2} ).

Figure 4

In the sensitivity analysis for effect modification by obesity
(\textbf{Supplementary Table 3} ), we found that the association between
AR+asthma and RHINASTHMA-total score was marginally higher among
non-obese participants (\selectlanguage{greek}β: \selectlanguage{english}0.23; 95\%CI: 0.19, 0.26) than obese ones
(0.16; 0.07, 0.25) (\emph{p-value} for interaction = 0.09). The
difference was more pronounced for upper airways, the association being
significantly higher among non-obese participants (\selectlanguage{greek}β \selectlanguage{english}for
RHINASTHMA-upper: 0.10; 0.05, 0.15) than obese ones (0.01; -0.13, 0.15)
(\emph{p-value} for interaction = 0.04). However, we did not observe
significant differences in other subdomains. We did not observe any
effect modification by obesity for CARAT scores (\textbf{Supplementary
Table 4} ).

The association of AR+asthma with RHINASTHMA-total score was highly
heterogeneous (I\textsuperscript{2}: 87\%; p-value for heterogeneity =
\textless{}0.001) across the participating countries (\textbf{Figure 5A}
). While the association was the highest in Austria (\selectlanguage{greek}β: \selectlanguage{english}0.29; 95\%CI:
0.24, 0.34), it tended towards null in France (0.07, -0.06, 0.19).
Similar heterogeneity was observed for CARAT-total score
(I\textsuperscript{2}: 79\%, p = 0.008) (\textbf{Figure 5B} ). However,
the overall estimates from the meta-analyses for the association between
AR+asthma, and RHINASTHMA-total and CARAT-total scores were similar to
the ones reported in the main analysis.

Figure 5

\section*{DISCUSSION}

{\label{discussion}}\par\null

In our study, we found a significantly worse quality of life (RHINASTHMA
total and subdomain scores) and symptoms control (CARAT total and
subdomain scores) in AR patients with comorbid asthma than in patients
with AR alone. Such associations were not influenced by any
physiological variables. However, we found that the association was
significantly higher among non-obese participants compared to obese
ones, when assessed through RHINASTHMA-upper symptoms score but not with
CARAT. We also observed country-specific variations in the RHINASTHMA
and CARAT total scores. Although one previous study compared the
individual/social burden of disease between asthmatics and asthmatics
with concomitant AR, unlike ours, that study did not compare the
difference of disease control and HRQoL between the two groups of
patients\textsuperscript{24}.

It is well-known that several triggers such as seasonal meteorological
changes, pollen season, air pollution, or even occupational exposures
may lead to poor quality of life of asthmatic patients with or without
AR \textsuperscript{8,25-27}. It has also been observed that AR patients
are often reported to have poor control over their symptoms if
persistent comorbid asthma is present\textsuperscript{28-31}. Although
no direct comparative study on the control and HRQoL of AR and AR with
asthma has been reported yet, our findings well reciprocate the previous
results. Asthma and AR share eight common genes (\emph{CLC, EMR4P,
IL5RA, FRRS1, HRH4, SLC29A1, SIGLEC8, IL1RL1} ) that are presumed to
describe the link for multimorbidity\textsuperscript{32}. They also
share common risk factors such as atopic genetic background (for the
allergic endotypes), environmental exposures (allergens, moulds, indoor
and outdoor air pollution, some respiratory viruses, etc.), type of
occupation, and active tobacco smoking.

Our findings add important clinical knowledge to the existing strategies
for the management of AR with concomitant asthma. Although AR and asthma
are two different diseases with distinct clinical features, when AR
persists with asthma, either condition is often
overlooked\textsuperscript{31,33} due to the lack of a combined tool for
monitoring control and HRQoL of both diseases at the same time. Despite
the well-established guidelines of ARIA and GARD for a new management
protocol for AR and asthma together\textsuperscript{10,12,34-37},
reports adopting these guidelines in the management of AR with
persistent asthma are still lacking. Our findings would help guide
practitioners to use the appropriate assessment tools while treating
such patients. Our findings underline the impact of respiratory
hypersensitivity conditions in the quality of life of patients and call
for prevention and public health strategies to diminish the burden of
these conditions. Currently there are effective treatments for AR and
asthma, several risk factors are known (\emph{e.g.,} allergies,
rhinitis, tobacco smoke) and tools to control the disease have been
developed. However, we are still uncertain how to prevent AR patients
from developing asthma, allergen immunotherapy being the current only
attempt. Preventive measures should be able to change the natural
history of the disorder, avoiding asthma development in patients with AR
and/or evolution through providing its control\textsuperscript{38}.

Our study has some limitations. Firstly, considering that subjective
symptom-rating scales may not be entirely accurate, the risk for
potential bias could not be completely avoided. However, we used
standardized instruments, and therefore the possibility of such bias was
marginal. Secondly, the considered period might be insufficient to
evaluate the quality of life and the control appropriately. Thirdly,
other comorbidities might have modified the patients' responses. Despite
these limitations, our findings are derived from incident patients drawn
from the general population of three European countries in which AR and
asthma diagnoses were made by a doctor. However, due to the small sample
size, it is not possible to indicate whether these results may be
generalized. Further studies, after controlling for potential
confounders and biases in larger populations, are therefore warranted.

\section*{CONCLUSION}

{\label{conclusion}}

In summary, using combined assessment tools for AR and asthma, we found
that AR patients with comorbid asthma have a poorer quality of life and
symptoms control than those with AR alone. This finding highlights the
importance of a comprehensive approach for the management of AR in case
of a comorbid allergic condition for optimum care, and such strategies
would be the gateway for reducing the global burden of these diseases.

\section*{AUTHOR CONTRIBUTIONS}

{\label{author-contributions}}

All authors made substantial contributions to the conception and design
of or acquisition of data or analysis and interpretation of data. All
authors gave input to the manuscript and revised the manuscript
critically for important intellectual content. All authors gave final
approval of the version to be published. Sandra Baldacci, Maria
Prentovic, and Isabella Annesi-Maesano were principal investigators of
their respective centres. Subhabrata Moitra was responsible for
statistical analyses.

\section*{REFERENCES}

{\label{references}}

1. Bousquet J, Anto JM, Bachert C, et al. Allergic rhinitis. \emph{Nat
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Table 1: Descriptive statistics of the study patients overall and by
country\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{All (N=643)}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{IT (N=245)}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{FR (N=212)}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{AT (N=186)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Sex (male), n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
249 (38.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
89 (36.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
104 (49.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
56 (30.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age (years), mean (SD)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
44.1 (14.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
47.4 (14.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
41.6 (15.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
42.3 (12.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
BMI, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Underweight\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31 (4.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6 (2.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
21 (10.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 (2.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Normal weight\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
358 (56.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
144 (59.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
118 (56.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
96 (52.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Overweight\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
154 (24.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
61 (25.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40 (19.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
53 (29.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Obese\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
92 (14.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33 (13.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30 (14.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 (15.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Smokers, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
302 (47)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
103 (42)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
104 (49)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
95 (51)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Exposure to smoke, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
209 (32.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
63 (25.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
97 (45.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
49 (26.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Education, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Maximum 8 years\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
166 (25.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
56 (22.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
69 (32.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
41 (22.0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9-13 years\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
231 (36.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
115 (46.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
67 (31.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
49 (26.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textgreater{}13 years\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
244 (38.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
74 (30.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
74 (35.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
96 (51.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
GINA grade, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
No asthma\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
141 (22.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
88 (35.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (1.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
50 (26.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Intermittent\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
190 (29.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
63 (25.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
58 (27.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
69 (37.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mild persistent\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
36 (5.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13 (5.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13 (6.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10 (5.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Moderate persistent\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60 (9.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 (8.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (12.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13 (7.0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Severe persistent\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
214 (33.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
61 (24.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
109 (51.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
44 (23.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ARIA grade, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mild intermittent\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60 (9.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40 (17.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7 (3.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13 (7.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mild persistent\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11 (1.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7 (3.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (0.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (1.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Moderate-severe intermittent\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
336 (54.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
111 (48.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
149 (71.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
76 (42.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Moderate-severe persistent\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
212 (34.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
73 (31.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
53 (25.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
86 (48.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Sensitivity to allergens, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Sensitivity to at least one allergen\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
579 (90)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
199 (81.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
212 (100)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
168 (90.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
House dust mite\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
357 (56.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
152 (64.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
112 (53.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
93 (51.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Moulds\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
123 (19.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32 (13.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
51 (24.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40 (22.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Pollen\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
561 (89.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
186 (78.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
212 (100.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
163 (90.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Dog\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
143 (22.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
68 (28.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
21 (10.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
54 (30.0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Cat\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
284 (45.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
90 (38.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
102 (48.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
92 (51.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Birch\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
225 (35.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
39 (16.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
50 (23.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
136 (75.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Cypress\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
110 (17.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
38 (16.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
57 (27.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15 (8.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Grass\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
275 (43.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
149 (62.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
53 (25.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
73 (40.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Artemisia\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
82 (13.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6 (2.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
47 (22.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 (16.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Olive tree\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
173 (27.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
78 (32.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
57 (27.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
38 (21.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{Parietaria sp.}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
127 (20.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
63 (26.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
56 (26.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (4.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{Platanus sp.}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
100 (15.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 (8.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60 (28.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 (11.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{Ambrosia sp.}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
87 (13.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (3.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 (9.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
59 (32.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Drugs taken in the last 12 months, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
464 (72.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
190 (77.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
100 (47.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
174 (93.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
RHINASTHMA score, median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
RHIN-total (30 not at all -- 150 very much)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
76 (53, 91)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
52 (43, 67)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
91 (85, 95)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
70 (59, 91)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
RHIN - upper respiratory (9 not at all -- 45 very much)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
25 (20, 29)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
20 (16, 25)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
27 (24, 30)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
27 (21, 34)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
RHIN - lower respiratory (13 not at all -- 65 very much)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
30 (21, 39)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
20 (16, 26)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
39 (36, 43)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
28 (22, 36)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
RHIN - respiratory allergy impact (8 not at all -- 40 very much)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
17 (12, 24)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
12 (10, 15)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
24 (22, 27)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
16 (12, 21)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CARAT score, median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
CARAT-total (0 worst -- 30 best)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
18 (14, 22)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
22 (18, 25)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
15 (13, 18)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
16 (12, 20)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
CARAT- upper respiratory (0 worst -- 12 best)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6 (4, 8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
7 (4, 8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6 (5, 8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
4 (1, 6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
CARAT- lower respiratory (0 worst -- 18 best)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
12 (9, 16)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
16 (13, 17)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
9 (7, 11)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
12 (9, 15)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Data presented as mean (SD) for continuous variables, median
(interquartile range {[}IQR{]}) for ordinal variables, and frequency
(\%) for categorical variables.

Abbreviations: ARIA: Allergic Rhinitis Impact on Asthma guidelines; BMI:
Body Mass Index; CARAT: Control of Allergic Rhinitis and Asthma Test;
GINA: Global Initiative for Asthma; FR: France; IT: Italy; AT: Austria

Figure Legends:

\textbf{Figure 1: Differences of RHINASTHMA-Total and subdomain scores
between patients with AR alone and AR with asthma.}

Data presented as median (solid line) and interquartile range {[}IQR{]}
(dashed line) unless otherwise stated. P-values were calculated from
Wilcoxon-ranked sum test.

\textbf{Figure 2: Differences of CARAT-Total and subdomain scores
between patients with AR alone and AR with asthma.}

Data presented as median (solid line) and interquartile range {[}IQR{]}
(dashed line) unless otherwise stated. P-values were calculated from
Wilcoxon-ranked sum test.

\textbf{Figure 3: Adjusted association between AR+asthma and
RHINASTHMA-Total and subdomain scores.}

Data presented as regression coefficient (\selectlanguage{greek}β\selectlanguage{english}) (symbol) and 95\%
confidence interval {[}CI{]} (horizontal bar) unless otherwise stated.
Models were adjusted for age, sex, BMI, smoking status, exposure to
smoke, education, ARIA grade, sensitivity to allergens, and drugs taken
in the last 12 months as fixed factors, and country as a random factor.

\textbf{Figure 4: Adjusted association between AR+asthma and CARAT-Total
and subdomain scores.}

Data presented as regression coefficient (\selectlanguage{greek}β\selectlanguage{english}) (symbol) and 95\%
confidence interval {[}CI{]} (horizontal bar) unless otherwise stated.
Models were adjusted for age, sex, BMI, smoking status, exposure to
smoke, education, ARIA grade, sensitivity to allergens, and drugs taken
in the last 12 months as fixed factors, and country as a random factor.

\textbf{Figure 5: Meta-analysis results of the association between
AR+asthma and (A) RHIN-Total score and (B) CARAT-Total score, stratified
by countries.}

Models were adjusted for sex, age, smoking status, exposure to smoke,
education, ARIA grade, sensitivity to allergens, and drugs taken in the
last 12 months as fixed factors. I-squared, variation in estimated
effect attributable to heterogeneity.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5/Figure-5}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

