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.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 FEV1%
predicted per year.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
FEV1 slopes. In most cohorts, the evaluation of
longitudinal lung function is based on prebronchodilator values of
FEV1 with bronchodilator withdrawal on the day of
testing.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 FEV1 variability, we calculated
slopes using at least 10 spirometry results, as persistent significant
bronchodilator response is a rare endotype of asthma
(5%).15 Moreover, Bui and colleagues have recently
shown that baseline asthma was associated with accelerated decline in
both pre- and post-bronchodilator
FEV1.16
The observation that children with better initial lung function at study
entry exhibited a loss of lung function is similar to other
studies.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 FEV1 and vital capacity compared
to normal blood eosinophils in the younger asthmatic subjects in
longitudinal studies.17 Overall, the inflammatory
phenotype in asthma has prognostic relevance since the annual decline in
FEV1 can also be predicted by the bronchial CD8+ cell
infiltrate.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.19
Recently, Denlinger and colleagues evaluated corticosteroid response
endotypes as longitudinal predictors of lung decline of adults in the
NHLBI Severe Asthma Research Program.11 The odds
ratios of BMI (for 5-unit decrease) and baseline FEV1%
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
FEV1/FVC z-score.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.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 FEV1 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 FEV1 after four
years in the CAMP study.22 Thus, occasional
FEV1 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.23Airflow limitation (after appropriate bronchodilator withhold
FEV1 <80% predicted, in the face of reduced
FEV1/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,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.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 of14), in which some children clearly exhibited a gain
in lung function during childhood or adolescence based on
prebronchodilator FEV1% 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
FEV1 z -scores.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.
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.