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\begin{document}
\title{Longitudinal assessment of loss and gain of lung function in childhood
asthma}
\author[1]{Bruno Mahut}%
\author[2]{Plamen Bokov}%
\author[3]{Nicole Beydon}%
\author[2]{Christophe Delclaux}%
\affil[1]{La Berma}%
\affil[2]{Hopital Universitaire Robert-Debre}%
\affil[3]{AP-HP, Hôpital Armand Trousseau}%
\vspace{-1em}
\date{\today}
\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup
\selectlanguage{english}
\begin{abstract}
Background: The Childhood Asthma Management Program study revealed that
25.7\% of children with mild to moderate asthma exhibit a loss of lung
function. The objective was to assess the trajectories of function by
means of serial FEV1 in asthmatic children participating in
out-of-hospital follow-up. Methods: A total of 295 children (199 boys)
who had undergone at least 10 spirometry tests from the age of 8 were
selected from a single-center open cohort. The annualized rate of change
(slope) for prebronchodilator FEV1 (percent predicted) was estimated for
each participant and three patterns were defined: significantly positive
slope, significantly negative slope, and null slope (non-significant
P-value in the Pearson test). The standard deviation (SD) of each
individual slope was recorded as a variability criterion of FEV1.
Results: The median (25th and 75th percentile) age at inclusion and the
last visit was 8.5 (8.2, 9.3) and 15.4 (14.8, 16.0) years, respectively.
Tracking of function (null slope) was observed in 68.8\% of the
children, while 27.8\% showed a loss of function (negative slope) and
3.4\% showed a gain in function (positive slope). The children
characterized by loss of function depicted a better initial function and
a lower FEV1 variability during their follow-up than children with
tracking or gain of lung function. At the last visit, these children
were characterized by a lower lung function than children with tracking
or gain of lung function. Conclusion: Children with a better initial
FEV1 value and less FEV1 variability are more prone to loss of lung
function.%
\end{abstract}%
\sloppy
\textbf{Longitudinal assessment of loss and gain of lung function in
childhood asthma}
\textbf{Bruno Mahut MD \textsuperscript{1}, Plamen Bokov MD,
PhD\textsuperscript{2}, Nicole Beydon MD \textsuperscript{3} and
Christophe Delclaux MD, PhD \textsuperscript{2}}
\textsuperscript{1}: Clinique La Berma, F-92002 Antony, France
\textsuperscript{2}: Universit\selectlanguage{ngerman}é de Paris, AP-HP, Hôpital Robert Debré,
Service de Physiologie Pédiatrique-Centre du Sommeil, INSERM
NeuroDiderot, F-75019 Paris, France
\textsuperscript{3}: AP-HP, Hôpital Armand Trousseau, Service de
Physiologie Pédiatrique-Centre du Sommeil, F-75012 Paris, France
Correspondence: Pr Christophe Delclaux
Service de Physiologie Pédiatrique Hôpital Robert Debré 48, boulevard
Sérurier 75019 Paris Email~:\emph{christophe.delclaux@aphp.fr}
This study has not been founded
\textbf{Word count of the text:} 2190
\textbf{Key words:} spirometry; forced expiratory volume in 1 s; lung
function variability
\textbf{Abbreviated title:} Lung function in childhood asthma
The authors have no competing interests to declare
\textbf{Abstract}
\textbf{Word count: 249}
\textbf{Background} : The Childhood Asthma Management Program study
revealed that 25.7\% of children with mild to moderate asthma exhibit a
loss of lung function. The objective was to assess the trajectories of
function by means of serial FEV\textsubscript{1} in asthmatic children
participating in out-of-hospital follow-up.
\textbf{Methods} : A total of 295 children (199 boys) who had undergone
at least 10 spirometry tests from the age of 8 were selected from a
single-center open cohort. The annualized rate of change (slope) for
prebronchodilator FEV\textsubscript{1} (percent predicted) was estimated
for each participant and three patterns were defined: significantly
positive slope, significantly negative slope, and null slope
(non-significant P-value in the Pearson test). The standard deviation
(SD) of each individual slope was recorded as a variability criterion of
FEV\textsubscript{1}.
\textbf{Results} : The median (25\textsuperscript{th} and
75\textsuperscript{th} percentile) age at inclusion and the last visit
was 8.5 (8.2, 9.3) and 15.4 (14.8, 16.0) years, respectively. Tracking
of function (null slope) was observed in 68.8\% of the children, while
27.8\% showed a loss of function (negative slope) and 3.4\% showed a
gain in function (positive slope). The children characterized by loss of
function depicted a better initial function and a lower
FEV\textsubscript{1} variability during their follow-up than children
with tracking or gain of lung function. At the last visit, these
children were characterized by a lower lung function than children with
tracking or gain of lung function.
\textbf{Conclusion} : Children with a better initial
FEV\textsubscript{1}value and less FEV\textsubscript{1} variability are
more prone to loss of lung function.
\textbf{Introduction}
As reported by Martinez,\textsuperscript{1} approximately 40\% of the
deficits in maximal expiratory flow observed at 6 to 7 years of age in
children with asthma were present at birth, whereas 60\% of the deficits
develop during the preschool years.\textsuperscript{2} A further decline
in FEV\textsubscript{1} occurs during the school years as part of the
natural history of asthma.\textsuperscript{3} Only one study has
demonstrated that asthmatic children can exhibit a loss of lung function
during childhood based on spirometry.\textsuperscript{4} In this study,
a reduction in postbronchodilator FEV\textsubscript{1}\% predicted was
observed in 25.7\% of children with mild to moderate asthma who were
enrolled in the Childhood Asthma Management Program
(CAMP).\textsuperscript{4} Factors associated with a reduction in
postbronchodilator FEV\textsubscript{1}\% predicted included a younger
age at enrollment, male sex, study site and higher postbronchodilator
FEV\textsubscript{1}\% predicted at baseline. As a consequence, the
results of Covar and colleagues should be confirmed (1) using a more
common asthma definition criteria, as hyperresponsiveness to
methacholine was an inclusion criterion in their
study,\textsuperscript{4} and (2) in an out-of-hospital series of
children that is more representative of childhood asthma than a cohort
included in a therapeutic trial involving children with mild to moderate
persistent asthma.
The objective of our prospective observational study was to assess
whether an abnormal decline in the trajectory of lung function by means
of serial FEV\textsubscript{1} monitoring can be identified in asthmatic
children participating in out-of-hospital follow-up.
\textbf{Materials and Methods}
Study design
This cohort study complied with STROBE guidelines and with the guidance
provided by the editors of respiratory, critical care, and sleep
journals.\textsuperscript{5}
The La Berma open cohort enrolls asthmatic children since 2009. This
open cohort is constituted of 7817 children with asthmatic symptoms
(with or without confirmed variable expiratory flow limitation). For
this study, selection was made in children with confirmed asthma:
suggestive symptoms and (1) a significant bronchodilator response
(either sRaw or FEV\textsubscript{1}, n=1152) or (2) by an asthma
exacerbation diagnosed and treated in a hospital Emergency Department
(n=1295) or (3) both (n=777). Preterm birth (gestational age
\textless{}37 weeks) was a non inclusion criterion as it is a well-known
risk factor for the development of persistent airflow
limitation.\textsuperscript{6} Only children who had at least 10
pulmonary function tests after 8 years of age were selected to ensure
the quality of spirometry, leaving 295 children with confirmed asthma.
The characteristics of each visit have been
standardized,\textsuperscript{7} as described in Table 1.
This cohort was registered to our regulatory agency for electronic data
collection (Commission Nationale Informatique et Libertés, no. 1408710).
Approval from the Ethics Committee of the French learned Society of
Pulmonology (SPLF) was obtained (CEPRO 2009/019). All children and
parents were informed of the prospective recording of clinical and
physiological data and could request to be exempted from the study in
accordance with French law regarding non-interventional research.
Pulmonary function tests
Spirometry (MasterScreen Body; Jaeger, CareFusion, San Diego, CA, USA)
was performed without inhaled treatment (bronchodilator or LABA/ICS
association) on the day of measurement by the same operator
(BM),\textsuperscript{7} according to international
guidelines.\textsuperscript{8} Reference values were those of
GLI-2012,\textsuperscript{9} as recommended for describing the
progression of pulmonary function.\textsuperscript{10}
Classification of lung function patterns
The annualized rate of change (slope) for prebronchodilator
FEV\textsubscript{1} percent predicted was estimated for each
participant using standard least squares linear regression models, as
performed by others.\textsuperscript{11} Three patterns were defined. A
positive slope was defined by a significantly positive value of the
slope, whereas a negative slope was defined by a significantly negative
value of the slope according to the P-value obtained in the Pearson
test. When the P-value was not significant, the slope was considered
null. The standard deviation (SD) of each individual slope was recorded
as a criterion of FEV\textsubscript{1} variability.
Statistical analyses
The results were expressed as median (25\textsuperscript{th} and
75\textsuperscript{th} percentile) as some indices did not conform to a
normal distribution, and the positive slope group was small. Comparisons
of continuous variables between the three groups of children were
performed using the Kruskal-Wallis test, and subsequent intergroup
comparisons were performed using the Mann-Whitney U test. Categorical
variables were compared using the chi-square test or Fisher's exact test
where appropriate. A P-value \textless{}0.05 was deemed statistically
significant. All statistical analyses were performed with Statview 5.0
software (SAS institute, Cary, NC, USA).
\textbf{Results}
The clinical and functional characteristics of the 295 asthmatic
children are presented in Table 1. Three patterns were evident: tracking
of lung function (null slope of FEV\textsubscript{1}\% predicted change
over time) in 68.8\% of children (95\% confidence interval (CI)
{[}63.5\%, 74.1\%{]}), loss of lung function (negative slope) in 27.8\%
(95\% CI {[}22.7\%, 32.9\%{]}), and gain in lung function (positive
slope) in 3.4\% (95\% CI {[}1.3\%, 5.5\%{]}).
The children characterized by loss of lung function depicted a better
initial lung function (highest z-scores of FEV\textsubscript{1}, FVC and
FEV\textsubscript{1}/FVC) and a lower FEV\textsubscript{1} variability
(SD of the slope) during their follow-up than children with tracking or
gain of lung function. At the last visit, these children were
characterized by a lower lung function (lowest z-scores of
FEV\textsubscript{1}, FVC and FEV\textsubscript{1}/FVC) and lower BMI
than children with tracking or gain of lung function. At this last
visit, these children had a better level of asthma control than the
children with tracking of lung function, while receiving similar asthma
treatment.
Overall, the children characterized by a gain in lung function evolved
in an opposite way to those losing function. The Figure 1 shows changes
in FEV\textsubscript{1}\% predicted over time in the three different
groups based on individual slopes and the Figure 2 shows the
relationship between z-score of FEV\textsubscript{1} at inclusion and
individual FEV\textsubscript{1} slopes in the three different groups.
Finally, we determined the number of asthmatic children with severe
asthma (defined by airflow limitation): 45/295, 15\%, 95\% CI {[}11 to
19\%{]}, which was more frequent in children with a decline in lung
function than in children with tracking of function (see Table 1). As
compared to the 250 children without severe asthma, those with severe
asthma had a lower initial FEV\textsubscript{1} (87\% ±14 versus 95 ±14,
p\textless{}0.001), a lower initial z-score of FEV\textsubscript{1}/FVC
(-1.67 ±0.88 versus -1.10 ±0.97, p\textless{}0.001) and a higher ICS
dose at the last visit (423 \selectlanguage{greek}µ\selectlanguage{english}g \selectlanguage{ngerman}±223, n=34 versus 340 ±208, n=141;
p=0.0418); the exacerbation frequency of these two groups was not
different (p=0.367).
\textbf{Discussion}
The main result of our observationnal study is to confirm the result of
the CAMP study showing that about a quarter of asthmatic children
participating in out-of-hospital follow-up exhibited loss of lung
function during childhood and adolescence.
We have previously shown, in a retrospective study, that a significant
increase in prebronchodilator sRaw was observed in 17\% of the children
(mainly boys with a lower initial and higher final specific resistance)
who suffered from persistent asthma.\textsuperscript{12} Nevertheless,
the effect of lung growth (dysanaptic or isotropic, modifying sRaw via
thoracic gas volume) was identified as a potential source of bias. The
CAMP study used a predefined criterion of loss of lung function, which
was at least 1\% loss in postbronchodilator FEV\textsubscript{1}\%
predicted per year.\textsuperscript{4} Using a statistical definition of
the loss of lung function, we were able to confirm the results of the
CAMP study (25.7\% versus 27.8\%). It should be emphasized that our
three groups were differentiated based on prebronchodilator
FEV\textsubscript{1} slopes. In most cohorts, the evaluation of
longitudinal lung function is based on prebronchodilator values of
FEV\textsubscript{1} with bronchodilator withdrawal on the day of
testing.\textsuperscript{13,14} This may introduce a source of bias as
some asthmatic patients may occasionally exhibit some degree of airflow
limitation and a positive bronchodilator response. In order to reduce
the effect of occasional FEV\textsubscript{1} variability, we calculated
slopes using at least 10 spirometry results, as persistent significant
bronchodilator response is a rare endotype of asthma
(5\%).\textsuperscript{15} Moreover, Bui and colleagues have recently
shown that baseline asthma was associated with accelerated decline in
both pre- and post-bronchodilator
FEV\textsubscript{1}.\textsuperscript{16}
The observation that children with better initial lung function at study
entry exhibited a loss of lung function is similar to other
studies.\textsuperscript{4,7,11} Their frequency of severe exacerbation
leading to emergency department visit was not different, and they had a
better level of control at their last visit, than children with tracking
of lung function. Thus, asthma control does not seem to be a risk factor
of loss of lung function in our study. Among risk factors of loss of
lung function, elevated blood eosinophils have been associated with an
accelerated decline in FEV\textsubscript{1}~and vital capacity compared
to normal blood eosinophils in the younger asthmatic subjects in
longitudinal studies.\textsuperscript{17} Overall, the inflammatory
phenotype in asthma has prognostic relevance since~the annual decline in
FEV\textsubscript{1} can also be predicted by the bronchial CD8+ cell
infiltrate.\textsuperscript{18} In our study, sex, age at first symptoms
and atopy status were not significantly different in children exhibiting
loss of lung function while asthma severity was different, which seems
overall consistent with the overview made by Ulrik.\textsuperscript{19}
Recently, Denlinger and colleagues evaluated corticosteroid response
endotypes as longitudinal predictors of lung decline of adults in the
NHLBI Severe Asthma Research Program.\textsuperscript{11} The odds
ratios of BMI (for 5-unit decrease) and baseline FEV\textsubscript{1}\%
predicted (for a 10-unit increase) for predicting decline were of
borderline significance (1.06 {[}0.95, 1.19{]} and 1.07 {[}0.96,
1.19{]}, respectively), which may be consistent with our results. Of
note, the effect of BMI in these two studies may seem opposite to the
expected effect as overweight has been associated with reduced
FEV\textsubscript{1}/FVC z-score.\textsuperscript{20} Accordingly with
our results, Graff and colleagues recently showed that a lower BMI~is
associated with lung function decline and irreversible airflow
obstruction in adult asthma.\textsuperscript{21} Overall, why a better
initial lung function is a risk factor of subsequent loss of lung
function, which has consistently been found, remains unexplained but
cannot seem ascribable to regression toward the mean. This phenomenon
arises if a sample point of a random variable is extreme, a future point
is likely to be closer to the mean or average; thus, in our study the
slope criteria were defined a priori and were calculated based on at
least 10 measurements.
An original finding of the current study is that less variability in
prebronchodilator FEV\textsubscript{1} values over time is associated
with loss of lung function. Tantisira and colleagues showed that a
single higher bronchodilator response at inclusion was an independent
predictor of higher prebronchodilator FEV\textsubscript{1} after four
years in the CAMP study.\textsuperscript{22} Thus, occasional
FEV\textsubscript{1} variability could be associated with a better
prognosis, which may explain that absence of variability is associated
with a worst functional prognosis.
The European Respiratory Society /American Thoracic Society guidelines
define severe asthma not only as asthma that remains uncontrolled
despite aggressive drug therapy, but also one that requires aggressive
therapy to prevent from becoming
uncontrolled.\textsuperscript{23}Airflow limitation (after appropriate
bronchodilator withhold FEV\textsubscript{1} \textless{}80\% predicted,
in the face of reduced FEV\textsubscript{1}/FVC defined as less than the
lower limit of normal) that is one of the four criteria of uncontrolled
asthma was quite frequent (15\%) and logically more frequent in children
with loss of function. Lung function may continue to decline in severe
asthmatics despite high-intensity treatment and improved asthma control
is not sufficient to prevent such progressive
deterioration,\textsuperscript{24} as suggested by our results. It
highlights that the future risks of severe asthma are poorly recognized
by both patients and physicians, may be because patients with loss of
function have the best initial lung functions. In the study of McGeachie
et al. including 684 study participants of the CAMP trial, (mean age,
26.0±1.8 years), a total of 23\% were classified as having reduced
growth without an early decline while 26\% were classified as having
reduced growth and an early decline.\textsuperscript{14} Therefore,
reduced growth (loss of lung function during childhood) may further
affect the prevalence of chronic obstructive pulmonary disease that is
an important message. Smoking prevention in these patients is mandatory.
An unexpected finding was the discovery of a small subset (3\%) of
asthmatic children who exhibited a gain in lung function. This result is
in line with individual data of the CAMP study (see appendix
of\textsuperscript{14}), in which some children clearly exhibited a gain
in lung function during childhood or adolescence based on
prebronchodilator FEV\textsubscript{1}\% predicted. This result is also
consistent with the pattern of early low, accelerated growth, normal
decline (8\% of participants) evidenced in the Tasmanian Longitudinal
Health Study (16\% of participants with ever asthma and 4\% with
persistent asthma) which modelled lung function trajectories measured at
7, 13, 18, 45, 50 and 53 years based on prebronchodilator
FEV\textsubscript{1} \emph{z} -scores.\textsuperscript{25}
Our study has some limitations, such as its monocenter design. The
children were in an open cohort; thus, there was a selection bias as
asthmatic children who were followed up for years were probably more
symptomatic. The percentage of children exhibiting loss of lung function
may have been overestimated. Nevertheless, this percentage was similar
to that observed in the CAMP study that included mild to moderate
persistent asthmatic children, which deserved to be confirmed in an
out-of-hospital setting.
In conclusion, we confirm the results of the CAMP study showing that a
significant proportion (27.8\%) of asthmatic children exhibits a loss of
lung function during childhood and adolescence, additionally a small
subset of asthmatic children exhibits a gain in lung function.
\textbf{Author Contributions:} Conceptualization: BM and CD2; Formal
analysis: PB, CD2; Investigation: BM; Methodology: PB, NB; Project
administration: CD2, NB; Supervision: CD2, NB; Validation: BM, CD2;
Roles/Writing - original draft: CD2; Writing - review \&editing: BM, PB,
NB.
\textbf{Key Message}
Only one study has demonstrated that asthmatic children can exhibit a
loss of lung function during childhood based on spirometry, in a
therapeutic trial (CAMP study). This result deserved to be confirmed in
an out-of-hospital setting. We show that tracking of function was
observed in 68.8\% of the children, while 27.8\% showed a loss of
function and 3.4\% showed a gain in function. We thus confirm the
results of the CAMP study.
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function trajectories and future COPD risk: a prospective cohort study
from the first to the sixth decade of life. 544 2018 Jul 1 {[}accessed
2020 Oct 19{]}. http://spiral.imperial.ac.uk/handle/10044/1/57288
26. Reddel HK, Taylor DR, Bateman ED, Boulet L-P, Boushey HA, Busse WW,
Casale TB, Chanez P, Enright PL, Gibson PG, et al. An official American
Thoracic Society/European Respiratory Society statement: asthma control
and exacerbations: standardizing endpoints for clinical asthma trials
and clinical practice. Am J Respir Crit Care Med 2009;180(1):59--99.
\textbf{Table 1.} Characteristics of the 295 asthmatic children
according to the three groups of FEV\textsubscript{1} \% predicted
slope.\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Characteristics} \textbf{N (\% population)}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Positive slope} \textbf{10 (3.4)}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Null slope} \textbf{203 (68.8)}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Negative slope} \textbf{82 (27.8)}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
P value\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Intergroup comparisons\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Sex, male (\%) Atopic dermatitis, n Early wheezing, n Age at first
symptoms, years Atopy status negative skin prick tests, n\\
one positive prick test, n\\
more than one positive prick test, n Parental atopy, n Parental asthma,
n \textbf{Longitudinal PFT characteristics} Duration of follow-up,
years\\
ED Hospitalization frequency*\\
Number of PFT\\
Best sRaw reversibility in the past\\
Best FEV\textsubscript{1} reversibility in the past\\
\textbf{FEV\textsubscript{1} slope, \% per year}\\
SD of FEV\textsubscript{1} slope\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5 (50) 5 3 0 {[}0; 3{]} 1 1 8 5 4 5.9 {[}5.0; 6.7{]} 0.000 {[}0.000;
0.071{]} 12 {[}12; 14{]} 56 {[}49; 65{]} 25 {[}16; 31{]} \textbf{+3.58
{[}+2.17; +4.52{]}} 1.05 {[}0.83; 1.51{]}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
135 (67) 89 88 1 {[}0; 4{]} 22 46 135 102 82 6.4 {[}5.6; 7.2{]} 0.066
{[}0.000; 0.200{]} 12 {[}11; 14{]} 55 {[}47; 62{]} 21 {[}15; 31{]}
\textbf{-0.46 {[}-1.51; +0.45{]}} 1.15 {[}0.85; 1.52{]}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
59 (72) 38 38 0 {[}0; 3{]} 7 15 60 40 32 6.9 {[}6.1; 7.6{]} 0.071
{[}0.000; 0.166{]} 13 {[}11; 15{]} 53 {[}47; 61{]} 20 {[}14; 26{]}
\textbf{-2.77 {[}-3.51; -2.11{]}} 0.79 {[}0.64; 0.98{]}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.3284 0.8767 0.6049 0.3989 0.8442 0.4897 0.4038 0.9752 0.9774 0.0098
0.5088 0.1240 0.5478 0.4196 ND \textless{}0.0001\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1,2\textless{}3 1,2\textgreater{}3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Spirometry at inclusion} Age, years FEV\textsubscript{1}, L\\
FEV\textsubscript{1}, \% predicted\\
FEV\textsubscript{1}, z-score\\
FVC, L\\
FVC, z-score\\
FEV\textsubscript{1}/FVC\\
FEV\textsubscript{1}/FVC, z-score\\
Obstructive defect, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9.3 {[}8.6; 11.9{]} 1.50 {[}1.42; 1.64{]} 84 {[}76; 88{]} -1.40
{[}-1.98; -1.04{]} 2.09{[}1.92; 2.25{]} -0.30 {[}-0.87; +0.28{]} 0.75
{[}0.71; 0.76{]} -2.04 {[}-2.31; -1.65{]} 7 (70)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
8.5 {[}8.2; 9.4{]} 1.61 {[}1.41; 1.76{]} 93 {[}83; 102{]} -0.58
{[}-1.42; +0.15{]} 2.04 {[}1.79; 2.29{]} +0.27 {[}-0.49; +0.99{]} 0.79
{[}0.73; 0.84{]} -1.34 {[}-2.08; -0.76{]} 82 (40)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
8.4 {[}8.2; 8.9{]} 1.62 {[}1.48; 1.78{]} 99 {[}90; 109{]} -0.09
{[}-0.83; +0.74{]} 2.01 {[}1.83; 2.25{]} +0.66 {[}-0.23; +1.23{]} 0.82
{[}0.77; 0.87{]} -1.07 {[}-1.73; -0.28{]} 24 (29)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.0187 0.2506 \textless{}0.0001 \textless{}0.0001 0.8246 0.0198 0.0020
0.0024 0.0240\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1\textgreater{}2,3 1\textless{}2\textless{}3 1\textless{}2\textless{}3
1,2\textless{}3 1,2\textless{}3 1,2\textless{}3 1\textgreater{}3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Spirometry at last follow-up} FEV\textsubscript{1}, L\\
FEV\textsubscript{1}, \% predicted\\
FEV\textsubscript{1}, z-score\\
FVC, L\\
FVC, z-score\\
FEV\textsubscript{1}/FVC\\
FEV\textsubscript{1}/FVC, z-score\\
Obstructive defect\textsuperscript{\#}, n (\%)\\
Severe asthma, (\%)\selectlanguage{ngerman}\textsuperscript{§}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.82 {[}3.06; 4.28{]} 101 {[}95; 105{]} +0.06 {[}-0.44; +0.40{]} 5.07
{[}3.59; 5.38{]} +0.31 {[}-0.10; +0.63{]} 0.82 {[}0.81; 0.83{]} -0.81
{[}-0.96; -0.64{]} 1 (10) 1 (10)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.30 {[}2.77; 3.75{]} 91 {[}84; 100{]} -0.76; -1.38; -0.01{]} 4.21
{[}3.54; 4.88{]} +0.14 {[}-0.59; +0.86{]} 0.78 {[}0.73; 0.84{]} -1.33
{[}-1.97; -0.75{]} 72 (35) 23 (11)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2.91 {[}2.67; 3.44{]} 82 {[}74; 88{]} -1.46 {[}-2.14; -1.00{]} 4.00
{[}3.56; 4.47{]} -0.49 {[}-1.11; +0.31{]} 0.74 {[}0.70; 0.80{]} -1.88
{[}-2.35; -1.09{]} 46 (55) 21 (26)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.0017 \textless{}0.0001 \textless{}0.0001 0.1465 0.0006 0.0003 0.0004
0.0008 0.0089\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1,2\textgreater{}3 1\textgreater{}2\textgreater{}3
1\textgreater{}2\textgreater{}3 1,2\textgreater{}3 1,2\textgreater{}3
1,2\textgreater{}3 1,2\textless{}3 2\textless{}3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Clinical characteristics at last follow-up} Age, years BMI,
kg.m\textsuperscript{-2} SABA on demand, n ICS, n ICS dose, BED \selectlanguage{greek}µ\selectlanguage{english}g/day
LABA, n Partially or uncontrolled last 3 months, n Days, symptoms within
last 3 months Severe exacerbation\textsuperscript{\$} within last 3
months, n\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
15.6 {[}15.3; 17.1{]} 21.1 {[}18.8; 23.4{]} 5 5 400 {[}325; 620{]} 3 4 0
{[}0; 5{]} 0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
15.3 {[}14.6; 16.0{]} 20.2 {[}18.8; 22.0{]} 80 123 400 {[}200; 400{]}
114 94 1 {[}0; 7{]} 21\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
15.5 {[}14.9; 16.0{]} 18.9 {[}17.8; 20.7{]} 35 47 400 {[}200; 400{]} 46
25 0 {[}0; 3{]} 4\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.1262 0.0044 0.7290 0.7290 0.4971 0.2631 0.0492 0.0351 0.2010\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1,2\textgreater{}3 2\textgreater{}3 2\textgreater{}3\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}
*: frequency per year of hospitalization in a hospital Emergency
Department (ED) for severe asthmatic exacerbation, calculated since two
years of age
\#: an obstructive defect is defined by a z-score of
FEV\textsubscript{1}/FVC \textless{} -1.645.
BMI denotes body mass index, SABA denotes short-acting beta agonist
treatment, ICS denotes inhaled corticosteroid, BED denotes
beclomethasone-equivalent daily dose, LABA denotes long-acting beta
agonist
\textsuperscript{\$}: severe exacerbation is defined according to Reddel
et al.\textsuperscript{26}
\selectlanguage{ngerman}\textsuperscript{§}: Severe asthma defined by
FEV\textsubscript{1}\textless{} 80\% predicted and a z-score of
FEV\textsubscript{1}/FVC \textless{} -1.645, according to international
recommendations\textsuperscript{23}
\textbf{Figure legends}
\textbf{Figure 1.} Lung function trajectories of the 295 asthmatic
children.
As stated in the Methods, participants were classified into three slope
categories, namely loss of function (significant negative slope), gain
of lung function (significant positive slope) and null slope
(non-significant slope). The lines are the individual
FEV\textsubscript{1} \% predicted slopes over age (either positive, n=10
or negative, n=82). X axis is the age (8 to 18 years old) and Y axis is
FEV\textsubscript{1} \% predicted (50 to 130\%).
\textbf{Figure 2.} Relationship between z-score of
FEV\textsubscript{1}at inclusion and individual FEV\textsubscript{1}
slopes.
The annualized rate of change (slope) for prebronchodilator
FEV\textsubscript{1} percent predicted was estimated for each
participant and is described according to the z-score of
FEV\textsubscript{1} at inclusion for the three groups of slopes
(negative, null or positive). A positive slope was defined by a
significantly positive value of the slope, whereas a negative slope was
defined by a significantly negative value of the slope according to the
P-value obtained in the Pearson test. When the P-value was not
significant, the slope was considered null.
A significant linear relationship between FEV\textsubscript{1} at
inclusion and the subsequent slope is evidenced using the Pearson test
(R= -0.36, p\textless{}0.0001).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1/Figure1}
\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure2/Figure2}
\end{center}
\end{figure}
\selectlanguage{english}
\FloatBarrier
\end{document}