<div>Small airway dysfunction is an independent dimension of wheezing disease
in preschool children</div><div>Plamen Bokov1, Donies Jallouli-Masmoudi2, Flore Amat3, Véronique
Houdouin4 and Christophe Delclaux1</div><div>Running title: Small airway dysfunction in wheezers</div><div>1: Université de Paris, AP-HP, Hôpital Robert Debré, Service de
Physiologie Pédiatrique-Centre du Sommeil, INSERM NeuroDiderot, F-75019
Paris, France</div><div>2: AP-HP, Hôpital Robert Debré, Service de Physiologie
Pédiatrique-Centre du Sommeil, F-75019 Paris, France</div><div>3: AP-HP, Hôpital Robert Debré, Service de Pneumopédiatrie, INSERM UMR S
1136, F-75019 Paris, France</div><div>4: AP-HP, Hôpital Robert Debré, Service de Pneumopédiatrie, INSERM UMR S
976, F-75019 Paris, France</div><div>Correspondence: Pr Christophe Delclaux</div><div>Service de Physiologie Pédiatrique</div><div>Hôpital Robert Debré</div><div>48, boulevard Sérurier</div><div>75019 Paris</div><div>Email : christophe.delclaux@aphp.fr</div><div>Word counts</div><div>Text : 2445; Abstract : 249</div><div>2 Tables, 2 Figures</div><div>Declarations of interest: none.</div><div>The study has not been founded</div><div>Abstract</div><div>Background. Whether small airway dysfunction (SAD), which is prevalent
in asthma, helps to characterize wheezing phenotypes is undetermined.
The objective was to assess whether SAD parameters obtained from
impedance measurement and asthma probability are linked.</div><div>Methods. One hundred and thirty-nine preschool children (mean age 4.7
years, 68% boys) suffering from recurrent wheeze underwent impulse
oscillometry that allowed calculating peripheral resistance and
compliance of the respiratory system (markers of SAD) using the extended
RIC model (central and peripheral Resistance, Inertance and peripheral
Compliance of the respiratory system). Children were classified using
the probability-based approach of GINA guidelines (few, some, most
having asthma). A principal component analysis (PCA) that determined the
dimensions of wheezing disease evaluated the links between SAD and
asthma probability.</div><div>Results. Forty-seven children belonged to the few, 28 to the some and 64
to the most having asthma groups. Whereas their anthropometrics and
measured parameters were similar, the most having asthma group exhibited
the lowest mean value of airway inertance after bronchodilator probably
due to airway inhomogeneities. PCA characterized nine independent
dimensions including a peripheral resistance (constituted by baseline
peripheral resistance, AX, R5-20Hz, X5Hz), a central resistance
(baseline central resistance, R20Hz) and an airway size dimension
(post-bronchodilator inertance and central resistance). PCA showed that
the SAD markers were independent from clinical dimensions (control and
asthma probability were two other dimensions) and did not help to define
wheezing phenotypes.</div><div>Conclusions. Lung function parameters obtained from impulse oscillometry
and asthma probability were belonging to independent dimensions of the
wheezing disease.</div><div>Key words: airway compliance; airway resistance; asthma; impulse
oscillometry; wheezing</div><div>Introduction</div><div>In a recent systematic review for the European Academy of Allergy and
Clinical Immunology, the clinical practice recommendations on
diagnostics of preschool wheeze stated that it is difficult to establish
guidelines for monitoring asthma in preschool children.(1) Lung function
measurement is an essential tool in the differential diagnosis of
preschool wheezing, although reliable lung function measurements are
challenging in this age group and the diagnosis value of functional
tests remains debated.(1) This issue is important given the possible
underestimation of asthma prevalence in preschool children.(2) On the
other hand, wheeze has been associated with prescriptions of asthma
medications in young children, which could lead to inappropriate and too
high prescription rate of inhaled corticosteroids.(3)</div><div>We recently showed that small airway dysfunction (SAD: increased
peripheral resistance and decreased peripheral compliance of the
respiratory system) was an almost constant finding in asthmatic children
with increased interrupter resistance.(4) One may hypothesize that SAD
markers obtained from a more sensitive method than spirometry, namely
impulse oscillometry,(5–7) could be linked to asthma probability.</div><div>Several wheezing phenotypes coexist at preschool age but not all
preschoolers with recurrent wheezing develop asthma at school-age; the
asthma diagnosis still needs to be based on clinical predicted models or
scores.(8) A probability-based approach, based on the pattern of
symptoms during and between viral respiratory infections, is given in
GINA guidelines that classifies the wheezing phenotypes of childhood.(9)
We thus evaluated the ability of IOS indices to differentiate these
wheezing phenotypes.</div><div>Methods</div><div>This cross-sectional study complied with The Strengthening the Reporting
of Observational studies in Epidemiology (STROBE) guidelines.
Consecutive preschool children aged 3 to 6 years referred for the first
assessment of their wheezing disease were enrolled. These children were
suffering from persistent wheeze (symptoms began before the age of 3
years and continued) or late-onset wheeze (symptoms began after the age
of 3 years). The children were belonging to the “few” (&lt;3
episodes per year of symptoms [cough, wheeze, heavy breathing] for
&lt; 10 days during upper respiratory tract infections and no
symptoms between episodes) or “some” or “most” (&gt;3
episodes per year of symptoms [cough, wheeze, heavy breathing] for
&gt; 10 days during upper respiratory tract infections and
between episodes symptoms) having asthma patterns described in GINA
guidelines.(9) As compared to the group “some”, the group “most”
having asthma was defined by the presence of allergic sensitization or
family history of asthma. Therapeutic steps (1 to 4) and control
assessment were those defined in GINA guidelines.(9) Adequate withdrawal
of beta-agonist before testing was an additional inclusion criterion.
Severe exacerbation definition was defined by the need of at least three
days of oral steroid.</div><div>This study was approved by our local Ethics Committee (PHENOBS: N°
2018-430). The parents were informed of the collection of the
prospective data for research purposes and they could request that their
child to be exempted from this study in accordance with French law
(non-interventional observational research).</div><div>Pulmonary function tests</div><div>Interrupter resistance (Rint) was measured using SpiroDyn’R apparatus
(Dyn’R Ltd, Toulouse, France), as previously described.(4) Z-scores of
Rint were calculated according to Merkus et al.(10)</div><div>Impedance of the respiratory system was measured using an impulse
oscillatory system (IOS: Master Scope Body, Carefusion Technologies,
Yorba Linda, California, USA), as previously described.(4) We used the
following IOS variables: impedance at 5, 10, 15, 20, 25, 30 and 35 Hz,
resistance and reactance at 5 Hz and 20 Hz, fall in resistance between
R5 and R20 (R5-20Hz), area under the reactance curve (AX) and resonance
frequency (Fres). Z-scores of IOS variables were calculated according to
Gochicoa-Rangel et al.(11)</div><div>Rint and IOS measurements were obtained at baseline and after salbutamol
(400 µg) administration using an inhaler device.</div><div>We used two mechanistic models capable of accounting for significant
frequency dependence of the respiratory impedance, which have previously
been described.(4) Airway inertance Iaw is included in the RIC model as
compared to the simple RC circuit (Resistance of the airways and
Compliance of the alveoli). The RIC model with proximal shunting
describes the effect of cheeks (proximal compliance) that could affect
impedance measurement (measurement bias). In the extended RIC model,
eRIC, R is partitioned in central (Rc) and peripheral (Rp) resistance of
the respiratory system, while Cp is the peripheral compliance of the
respiratory system (including parenchymal and chest wall compliances).
Thus, SAD is characterized by Rp and Cp. The model was fitted to the
impedance data (5–35 Hz) and the minimization of a performance index
allowed the calculation of model parameters, as previously done.(4) To
determine the relative appropriateness of the various inverse model
topologies, we used the corrected Akaike information criterion, as
previously done.(4)</div><div>Statistical analyses</div><div>Principal component analysis (PCA) is a mathematical procedure that uses
an orthogonal transformation to convert a set of observations of
possibly correlated variables into a set of values of uncorrelated
variables called principal components (dimensions). We performed PCA of
27 variables (the minimal number of subjects providing usable data for
the analysis should be five times the number of variables being
analysed), using orthogonal varimax rotation. Results were expressed as
mean ± SD. Intergroup comparisons were made using t tests (two groups)
or ANOVA (three groups), before and after salbutamol conditions were
compared using paired t test. A P value &lt; 0.05 was deemed
significant. Statistical analyses were performed with StatView 5.0 (SAS
institute, Cary, North Carolina, USA) and OpenStat (version 5)
softwares. Due to the exploratory design of the study, no correction for
multiplicity of testing was done.(12)</div><div>Results</div><div>One hundred and sixty asthmatic children were enrolled of whom 12
children were excluded because the coherence of impedance measurements
was unsatisfactory (coherence 5Hz &lt; 0.60 or 20Hz
&lt;0.80) and 9 children were excluded because their impedance
spectra were better fitted by the RIC model with proximal (upper airway)
shunting. The remaining 139 children who were adequately fitted by the
extended RIC model are described in Table 1 (clinical characteristics)
and Table 2 (functional characteristics). The Figure 1 shows the
impedance spectra obtained by fitting the model. Whereas the results of
IOS measurements were similar (almost normal lung function after
bronchodilator), some modelled parameters were significantly different
after bronchodilation (inertance and peripheral compliance) between the
three groups. The most having asthma group exhibited both the highest
value of mean peripheral compliance and the lowest mean value of airway
inertance after bronchodilator. This group was also characterized by
more frequent recent severe exacerbations.</div><div>Bronchodilator response based on R5Hz decrease correlated weakly with
Rint response (r=0.20, p=0.002) and with Rp response (r=0.15, p=0.019),
and mainly with Rc response (r=0.63, p&lt;0.0001). All modelled
parameters, with the exception of Iaw, were significantly different
after bronchodilator: Rc, p=0.0001; Cp, p=0.0055; Rp, p=0.0096.</div><div>Twenty-nine children were premature (≤36 weeks of gestational age); they
were characterized by increased baseline z-score of Rint (2.05 ± 1.61
versus 1.50 ± 1.23, p=0.032), z-score of X5Hz (0.68 ± 2.51 versus -0.28
± 1.39, p=0.002) and Rp (1.04 ± 0.43 kPa.s/L versus 0.86 ± 0.28 kPa.s/L,
p=0.003) as compared to non-premature children. After bronchodilation,
the z-score of X5Hz (-0.55 ± 1.44 versus -1.43 ± 1.29, p=0.0008) and Rp
(0.95 ± 0.46 kPa.s/L versus 0.77 ± 0.43 kPa.s/L, p=0.042) remained
higher in premature children.</div><div>The Figure 2 shows the results of PCA using the 27 variables.
Communality of all variables was &gt; 60% (with the exception
of post-BD peripheral resistance) and 73.8% of the total variance was
explained by the factors (all factors had Eigenvalues &gt; 1).
The Kaiser-Meyer-Olkin measure of sampling adequacy was 0.651.</div><div>Nine dimensions were found, some groupings of variables were expected
such as anthropometrics (age, height: dimension 3), wheezing control
(controlled versus uncontrolled and recent severe exacerbation:
dimension 7) and asthma probability (wheezing patterns and therapeutic
steps: dimension 4). Markers of SAD (peripheral resistance and
compliance of the respiratory system) belonged to two different
dimensions (dimension 1 and 8, respectively) that were independent from
the clinical dimensions (wheezing control and asthma probability). A
peripheral resistance (constituted by baseline peripheral resistance,
AX, R5-20Hz, X5Hz and Rint, dimension 1), a central resistance (baseline
central resistance and R20Hz, dimension 2) and a post-bronchodilator
airway characterization (post-bronchodilator inertance, peripheral
compliance and central resistance, dimension 5) were evidenced. The
dimension 6 describes mainly full term boys, with elevated BMI z-score
and early wheezing. The dimension 8 is constituted of children born
prematurely of non-Caucasian origin.</div><div>Discussion</div><div>The main result of our cross-sectional study in preschool wheezers is to
show that lung function parameters obtained from impulse oscillometry
and asthma probability were belonging to independent dimensions of the
wheezing disease.</div><div>Previous classifications of wheezing phenotypes (such as episodic wheeze
and multiple-trigger wheeze) do not appear to identify stable
phenotypes,(13) and their clinical usefulness is uncertain, as stated in
GINA 2020 guidelines.(9) These guidelines recommend the use of a
probability-based approach.(9)</div><div>The studies evaluating the oscillometric technique’s ability to classify
lung function in wheezing and healthy children have been contradictory.
Depending on the patient selection, both significant differences(14) and
lack of differences(15,16) have been reported. Subtle changes have been
observed in the small airway indexes of IOS among children with mild to
moderate recurrent wheezing.(17) Several studies have suggested that IOS
parameters could be more sensitive than spirometry to diagnose asthma in
children.(5,6) Finally, we recently showed that SAD was almost constant
in young asthmatics exhibiting an increased interrupter resistance.(4)
Based on this background, one may have supposed that IOS and additional
modelling of SAD markers may have differentiated the three groups of
wheezers defined on asthma-probability.</div><div>Among the three groups of wheezers, the most having asthma group was
characterized by more recent severe exacerbations requiring oral
steroid, which may seem expected in a group mainly constituted of
asthmatic children. This group depicted the lower baseline interrupter
resistance, which could be related to the higher proportion of
asthmatics, responding to inhaled corticosteroid treatment (high dose
for 59/64 children). IOS parameters were similar among the three groups,
showing a slight mean basal impairment (for instance, mean z-score of
R5Hz value of +1.46 in the whole population, with a mean z-score of
post-bronchodilator of +0.12, almost normal). Thus, in contradiction
with our hypothesis, conventional IOS parameters were not able to
differentiate these three wheezer groups, which may be related to the
presence of asthmatic children into the three groups. Malmberg and
colleagues showed better results for R5Hz and its bronchodilator
response in identifying preschool children with probable asthma, but
their groups were different from ours (treated asthma, probable asthma,
chronic cough and healthy children).(15) By contrast, some parameters
obtained from the eRIC model were significantly different among the
three groups. Inertance is proportional to the length and inversely
proportional to the cross-sectional area of the airways. The group with
the highest probability of asthma had the smaller post-bronchodilator
inertance; this result may seem counterintuitive since asthma has been
associated with reduced peripheral airway caliber. This observation
could be explained by the virtual decrease of inertance due to augmented
airway inhomogeneities.(18) This group also had a higher compliance of
the peripheral respiratory system that may favor ventilation
inhomogeneity, a finding that has previously been evidenced in wheezing
children having had a recent exacerbation.(19) This higher respiratory
system compliance may have been related to either increased airway(20)
or tissue compliance(21) that have been evidenced in asthma.</div><div>Reduced lung function in early infancy is predictive of persistent
asthma in young adults and a persistent reduction in lung function,
suggesting abnormal lung development and growth in utero or very early
in life.(22) Preterm birth is associated with increased risks of asthma
symptoms in childhood. The underlying mechanism seems to include
persistently higher airway resistance.(23) We thus evaluated IOS
measurements in premature versus non-premature children, showing that
even after bronchodilation, the respiratory reactance and peripheral
resistance remained higher in premature children, which further validate
the parameters obtained from the eRIC model.</div><div>The main findings of our study are evidenced in Figure 2. We first
confirm that AX, R5-20Hz and X5Hz are related to SAD since these
parameters belonged to the same dimension than peripheral resistance of
the respiratory system. Rint belonged to this dimension also, which is
consistent with our previous results(4) and the previously reported high
sensitivity of Rint in asthmatic children.(24) A proximal resistance
dimension was also evidenced that included R20Hz and central resistance.
Proximal and distal resistances were independent dimensions of wheezing
disease. As previously evidenced in childhood asthma,(25) control,
severity (treatment) and lung function were independent dimensions of
the wheezing disease also. The ATLANTIS study showed that SAD is present
across adult patients with all severities of asthma.(26) In this latter
study, the levels of statistical correlations between IOS parameters and
severity or control were mild (maximum r value of 0.25 and 0.23 for the
number of exacerbations and GINA score, respectively).(26) Thus, our
results in wheezing children are in agreement with those obtained in
adult asthmatics. Asthma probability was an independent dimension of
wheezing disease, which may explain the difficulty to predict asthma in
this population.(8,9) Importantly, SAD markers were not linked to this
asthma probability.</div><div>One may have hypothesized that an increased airway tone (reduced
compliance) would have been associated with reduced airway caliber
(increased resistance). Nevertheless, peripheral compliance and
resistance belonged to two independent dimensions (dimensions 8 and 1,
respectively). Peripheral resistance is related to both airway anatomy
and smooth muscle contraction, which may explain the absence of
correlation. Reduced peripheral airway caliber in asthmatics is well
known.(27) Moreover, both a decrease and an increase in airway
distensibility have been described in asthma.(20,28) It has to be
highlighted that peripheral compliance of the respiratory system is
related to airway but also tissue compliance. Increased pulmonary
compliance has recently been described in some asthmatic children that
is associated with increased static volumes.(21)</div><div>The other dimensions that were evidenced further suggest the validity of
the PCA. Gestational age was linked to ethnicity in the ninth dimension,
a fact that is well demonstrated.(29) The sixth dimension regrouped sex,
z-score of BMI and persistent wheezing that could be in agreement with
the ”fat happy wheezer” phenotype in boys.(30)</div><div>Our study has some limitations. The included children were unable to
perform spirometry, whether the children with abnormal Rint or IOS
parameters had normal or abnormal spirometry cannot be assessed. Given
the absence of follow-up of the children, asthma diagnosis cannot be
assessed confidently since bronchodilator reversibility may be observed
in other children during their follow-up. Nevertheless, our study was
designed to assess the usefulness of the cross-sectional assessment by
IOS parameters, which belonged to other dimensions than the clinical
ones.</div><div>In conclusion, the characterization of SAD by IOS gives parameters
independent from clinical dimensions in wheezing preschool children that
does not help to define wheezing phenotypes of Global Initiative for
Asthma guidelines in a cross-sectional design.</div><div>Acknowledgments</div><div>The authors thank the nurses of the Respiratory physiology unit of
Robert Debré hospital for expert technical assistance.</div><div>Impact statement, Key Message</div><div>Impulse oscillometry does not help to predict asthma in wheezing
preschool children. Lung function is an independent dimension of
wheezing disease, as shown in asthma.</div><div>Author Contributions</div><div>Conceptualization: PB and CD2; Formal analysis: PB, CD2; Investigation:
PB, DM; Methodology: PB, FA, VH; Project administration: CD2, FA, VH;
Supervision: CD2, FA, VH; Validation: PB, CD2; Roles/Writing - original
draft: PB, CD2; Writing - review &amp;editing: DM, FA, VH.</div><div>References</div><div>1. Elenius V, Chawes B, Malmberg PL et al. Lung function testing and
inflammation markers for wheezing preschool children: A systematic
review for the EAACI Clinical Practice Recommendations on Diagnostics of
Preschool Wheeze. Pediatr Allergy Immunol Published Online First: 22
November 2020. doi:10.1111/pai.13418</div><div>2. Lawson JA, Brozek G, Shpakou A et al. An international comparison of
asthma, wheeze, and breathing medication use among children. Respir Med
2017: 133:22–28.</div><div>3. Mikalsen IB, Dalen I, Karlstad Ø et al. Airway symptoms and atopy in
young children prescribed asthma medications: A large-scale cohort
study. Pediatr Pulmonol 2019: 54:1557–1566.</div><div>4. Bokov P, Bafunyembaka G, Medjahdi N et al. Cross-sectional
phenotyping of small airway dysfunction in preschool asthma using the
impulse oscillometry system. J Asthma 2020: :1–13.</div><div>5. Marotta A, Klinnert MD, Price MR et al. Impulse oscillometry provides
an effective measure of lung dysfunction in 4-year-old children at risk
for persistent asthma. J Allergy Clin Immunol 2003: 112:317–322.</div><div>6. Komarow HD, Skinner J, Young M et al. A study of the use of impulse
oscillometry in the evaluation of children with asthma: analysis of lung
parameters, order effect, and utility compared with spirometry. Pediatr
Pulmonol 2012: 47:18–26.</div><div>7. Song TW, Kim KW, Kim ES et al. Utility of impulse oscillometry in
young children with asthma. Pediatr Allergy Immunol Off Publ Eur Soc
Pediatr Allergy Immunol 2008: 19:763–768.</div><div>8. Castro-Rodriguez JA, Cifuentes L, Martinez FD. Predicting Asthma
Using Clinical Indexes. Front Pediatr 2019: 7:320.</div><div>9. Reports. Glob. Initiat. Asthma - GINA. https://ginasthma.org/reports/
(accessed 11 Sep2020).</div><div>10. Merkus PJFM, Stocks J, Beydon N et al. Reference ranges for
interrupter resistance technique: the Asthma. UK Initiat Eur Respir J
2010: 36:157–163.</div><div>11. Gochicoa-Rangel L, Del Río-Hidalgo R, Hernández-Ruiz J et al.
Validating Reference Equations for Impulse Oscillometry in Healthy
Mexican Children. Respir Care 2017: 62:1156–1165.</div><div>12. Rothman KJ. No adjustments are needed for multiple comparisons.
Epidemiology 1990: 1:43–46.</div><div>13. Raaymakers MJA, Brand PLP, Landstra AM et al. Episodic viral wheeze
and multiple-trigger wheeze in preschool children are neither distinct
nor constant patterns. A prospective multicenter cohort study in
secondary care. Pediatr Pulmonol 2019: 54:1439–1446.</div><div>14. Oostveen E, Dom S, Desager K et al. Lung function and bronchodilator
response in 4-year-old children with different wheezing phenotypes. Eur
Respir J 2010: 35:865–872.</div><div>15. Malmberg LP, Pelkonen AS, Haahtela T et al. Exhaled nitric oxide
rather than lung function distinguishes preschool children with probable
asthma. Thorax 2003: 58:494–499.</div><div>16. Cuijpers CE, Wesseling GJ, Kessels AG et al. Low diagnostic value of
respiratory impedance measurements in children. Eur Respir J 1997:
10:88–93.</div><div>17. Knihtilä H, Kotaniemi-Syrjänen A, Pelkonen AS et al. Small airway
function in children with mild to moderate asthmatic symptoms. Ann
Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol 2018:
121:451–457.</div><div>18. Lutchen KR, Hantos Z, Peták F et al. Airway inhomogeneities
contribute to apparent lung tissue mechanics during constriction. J Appl
Physiol Bethesda Md 1985 1996: 80:1841–1849.</div><div>19. Kowalik K, Dai R, Safavi S et al. Persistent ventilation
inhomogeneity after an acute exacerbation in preschool children with
recurrent wheezing. Pediatr Allergy Immunol Off Publ Eur Soc Pediatr
Allergy Immunol 2020: 31:608–615.</div><div>20. Al-Alwan A, Bates JHT, Chapman DG et al. The nonallergic asthma of
obesity. A matter of distal lung compliance. Am J Respir Crit Care Med
2014: 189:1494–1502.</div><div>21. Comberiati P, Spahn JD, Paull K et al. Lung mechanical properties
distinguish children with asthma with normal and diminished lung
function. Clin Exp Allergy J Br Soc Allergy Clin Immunol 2020:
50:453–462.</div><div>22. Owens L, Laing IA, Zhang G et al. Infant lung function predicts
asthma persistence and remission in young adults. Respirol Carlton Vic
2017: 22:289–294.</div><div>23. Sonnenschein-van der Voort AMM, Gaillard R, de Jongste JC et al.
Foetal and infant growth patterns, airway resistance and school-age
asthma. Respirol Carlton Vic 2016: 21:674–682.</div><div>24. Merkus PJ, Mijnsbergen JY, Hop WC et al. Interrupter resistance in
preschool children: measurement characteristics and reference values. Am
J Respir Crit Care Med 2001: 163:1350–1355.</div><div>25. Mahut B, Peyrard S, Delclaux C. Exhaled nitric oxide and clinical
phenotypes of childhood asthma. Respir Res 2011: 12:65.</div><div>26. Postma DS, Brightling C, Baldi S et al. Exploring the relevance and
extent of small airways dysfunction in asthma (ATLANTIS): baseline data
from a prospective cohort study. Lancet Respir Med 2019: 7:402–416.</div><div>27. Martinez FD. Early-Life Origins of Chronic Obstructive Pulmonary
Disease. N Engl J Med 2016: 375:871–878.</div><div>28. Kelly VJ, Brown NJ, Sands SA et al. Effect of airway smooth muscle
tone on airway distensibility measured by the forced oscillation
technique in adults with asthma. J Appl Physiol Bethesda Md 1985 2012:
112:1494–1503.</div><div>29. Manuck TA. Racial and ethnic differences in preterm birth: A
complex, multifactorial problem. Semin Perinatol 2017: 41:511–518.</div><div>30. Turner S, Zhang G, Young S et al. Associations between postnatal
weight gain, change in postnatal pulmonary function, formula feeding and
early asthma. Thorax 2008: 63:234–239.</div><div>Table 1. Clinical characteristics of the wheezing children.</div><div>Characteristics Whole population Few having asthma Some having asthma
Most having asthma P value Intergroup</div><div>comparisons</div><div>Number of children 139 47 28 64</div><div>ethnicity, C / B / A / M 90/37/6/6 32/13/1/1 16/9/1/2 42/15/4/3 0.797</div><div>gestational age, weeks 38 ± 3 38 ± 3 38 ± 4 38 ± 2 0.500</div><div>sex (male, %) 94 (68) 34 (72) 18 (64) 42 (66) 0.692</div><div>age, years 4.7 ± 0.8 4.7 ± 0.8 4.7 ± 0.8 4.7 ± 0.8 0.926</div><div>height, cm 108.3 ± 7.4 108.7 ± 8.3 107.7 ± 5.8 108.2 ± 7.4 0.700</div><div>weight, kg 19.3 ± 3.9 19.6 ± 4.4 18.7 ± 3.3 19.3 ± 3.9 0.584</div><div>BMI z-score 0.40 ± 1.33 0.44 ± 1.42 0.18 ± 1.48 0.47 ± 1.20 0.542</div><div>persistent wheeze, n (%) 101 (73) 32 (68) 23 (82) 46 (72) 0.410</div><div>personal atopy (positive skin prick test) , (n tested) 53 (120) 13 (33)
0 40 (59) ND</div><div>rhinitis, n (n available) 45 (129) 12 (43) 5 (28) 28 (58) 0.011
1,2&lt;3</div><div>eczema, n (n available) 49 (124) 17 (40) 4 (28) 28 (56) 0.006
2&lt;1,3</div><div>parental asthma, n (n available) 50 (130) 12 (41) 0 38 (61) ND</div><div>parental atopy, n (n available) 58 (114) 12 (37) 12 (27) 34 (50) 0.003
1,2&lt;3</div><div>Asthma control</div><div>GINA score, 0 / 1 / 2 / 3 / 4 (past month) 64/20/24/17/14 22/8/5/6/6
16/4/4/3/1 26/8/15/8/7 0.655</div><div>controlled / uncontrolled, n 64/75 22/25 16/12 26/38 0.340</div><div>severe exacerbation within last three months, n (%) 39 (28) 10 (21) 4
(14) 25 (39) 0.023</div><div>Asthma treatment</div><div>beta-agonist on demand only (inhaled treatment), n 48 41 1 0 ND 2=3</div><div>low ICS dose, n 2 0 1 1 ND 2=3</div><div>medium ICS dose, n 7 0 3 4 ND 2=3</div><div>high ICS dose, n 82 0 23 59 ND 2=3</div><div>LABA, n 42 0 11 31 ND 2=3</div><div>LTRA, n 24 0 10 14 ND 2=3</div><div>Therapeutic steps</div><div>1 / 2 / 3 / 4 47/6/47/39 47/0/0/0 0/2/17/9 0/4/30/30 ND</div><div>BMI denotes body mass index, BD denotes bronchodilator, ICS notes
inhaled corticosteroid, LABA denotes long-acting beta-agonist, LTRA
denotes leukotriene receptor antagonist</div><div>Ethnicity: C denotes Caucasian, B denotes African-American, A denotes
Asian and M denotes mixed</div><div>Results are provided as mean ± SD or absolute number with percentage
(%)</div><div>Table 2. Functional characteristics of the wheezing children.</div><div>Characteristics Whole population Few having asthma Some having asthma
Most having asthma P value Intergroup</div><div>comparisons</div><div>Number of children 139 47 28 64</div><div>Resistance and impedance measurements</div><div>Rint, z-score before BD 1.49 ± 1.30 1.83 ± 1.36 1.69 ± 1.36 1.14 ± 1.16
0.033 1,2&gt;3</div><div>Rint, z-score after BD 0.06 ± 1.10 0.24 ± 1.15 0.39 ± 1.24 -0.21 ± 0.93
0.054</div><div>Coherence 5Hz, before BD 0.76 ± 0.08 0.78 ± 0.09 0.75 ± 0.08 0.75 ± 0.07
0.141</div><div>Coherence 20Hz, before BD 0.94 ± 0.04 0.94 ± 0.05 0.94 ± 0.04 0.94 ±
0.04 0.977</div><div>Coherence 5Hz, after BD 0.73 ± 0.07 0.74 ± 0.08 0.72 ± 0.08 0.72 ± 0.07
0.444</div><div>Coherence 20Hz, after BD 0.92 ± 0.04 0.92 ± 0.04 0.92 ± 0.04 0.92 ± 0.04
0.846</div><div>R20Hz, z-score before BD 1.08 ± 1.65 0.92 ± 1.28 1.21 ± 1.91 1.215± 1.78
0.706</div><div>R20Hz, z-score after BD 0.39 ± 1.52 0.20 ± 1.69 0.59 ± 1.61 0.45 ± 1.35
0.517</div><div>R5Hz, z-score before BD 1.46 ± 2.13 1.16 ± 1.83 1.93 ± 2.72 1.47 ± 2.04
0.245</div><div>R5Hz, z-score after BD 0.12 ± 1.60 -0.07 ± 1.68 0.54 ± 1.72 0.08 ± 1.48
0.269</div><div>R5-20Hz, z-score before BD 1.01 ± 2.31 0.75 ± 2.08 1.54 ± 2.85 0.96 ±
2.21 0.261</div><div>R5-20Hz, z-score after BD -0.24 ± 1.45 -0.33 ± 1.36 0.17 ± 1.50 -0.37 ±
1.48 0.234</div><div>X5Hz, z-score before BD -0.28 ± 1.58 -0.12 ± 1.46 -0.22 ± 1.66 -0.41 ±
1.63 0.838</div><div>X5Hz, z-score after BD -1.60 ± 1.29 -1.52 ± 1.55 -1.45 ± 1.22 -1.74 ±
1.10 0.525</div><div>AX, z-score before BD 0.78 ± 2.31 0.73 ± 2.54 0.79 ± 1.82 0.81 ± 2.36
0.722</div><div>AX, z-score after BD -0.87 ± 1.44 -0.85 ± 1.55 -0.43 ± 1.37 -1.09 ± 1.37
0.136</div><div>Fres, z-score before BD 0.10 ± 1.80 -0.12 ± 1.40 -0.06 ± 2.06 0.33 ±
1.94 0.144</div><div>Fres, z-score after BD -0.91 ± 1.29 -0.99 ± 1.23 -0.45 ± 1.46 -1.06 ±
1.24 0.102</div><div>eRIC model indices</div><div>Performance Index before BD 0.045 ± 0.056 0.046 ± 0.062 0.061 ± 0.071
0.037± 0.042 0.169</div><div>corrected AIC before BD -70 ± 11 -70 ± 11 -66 ± 12 -72 ± 11 0.066</div><div>Performance Index after BD 0.041 ± 0.054 0.033 ± 0.024 0.042 ± 0.045
0.047 ± 0.071 0.439</div><div>corrected AIC after BD -72 ± 12 -72 ± 9 -70 ± 11 -72 ± 14 0.752</div><div>Rc, kPa.s/L before BD 0.75 ± 0.16 0.74 ± 0.14 0.76 ± 0.16 0.75 ± 0.17
0.872</div><div>Rc, kPa.s/L after BD 0.70 ± 0.16 0.69 ± 0.17 0.70 ± 0.14 0.71 ± 0.16
0.738</div><div>Iaw, cPa.s2/L before BD 111 ± 42 110 ± 41 112 ± 46 112 ± 41 0.986</div><div>Iaw, cPa.s2/L after BD 116 ± 36 124 ± 32 122 ± 33 108 ± 40 0.044
1,2&gt;3</div><div>Cp, mL/kPa before BD 84 ± 135 91 ± 151 87 ± 129 75 ± 113 0.769</div><div>Cp, mL/kPa after BD 108 ± 147 74 ± 72 90 ± 156 141 ± 185 0.040
1,2&lt;3</div><div>Rp, kPa.s/L before BD 0.93 ± 0.29 0.98 ± 0.29 0.93 ± 0.29 0.90 ± 0.28
0.363</div><div>Rp, kPa.s/L after BD 0.81 ± 0.53 0.79 ± 0.45 0.87 ± 0.52 0.80 ± 0.60
0.829</div><div>Bronchodilator response, %</div><div>R5Hz decrease, % baseline 14 ± 15 14 ± 16 13 ± 13 15 ± 16 0.606</div><div>Results are provided as mean ± SD. BD denotes bronchodilator. AIC
denotes Akaike Information Criterion</div><div>Results in italic are quality criteria of impedance measurement or model
fitting</div><div>Figure legends</div><div>Figure 1. The impedance spectra obtained by fitting the model.</div><div>Respiratory system resistance (A) and reactance (B) obtained by fitting
the model (thick solid lines) to the prebronchodilator data of the
experimental measurements represented by the median values and the 25th
and 75th percentiles for each frequency.</div><div>Figure 2. Results of the principal component analysis.</div><div>PCA shows factors which have very high (red to brown, positive values or
blue colors, negative values) or very low (green color) loadings for the
original variables and thus simplifies the interpretation of the
resulting factors. Each single dimension is characterized by the
variables with high loadings (red and blue colors).</div><div>The 27 variables were: 1 ethnicity (0 Caucasian), 2 age, 3 sex (0
female), 4 height, 5 z-score of BMI, 6 gestational age, 7 persistent
wheezing (0 absent, 1 present), 8 severe exacerbation within previous 3
months (0 absent, 1 present), 9 GINA therapeutic steps (1 to 4), 10
probability (1 few, 2 some, 3 most having asthma), 11 control (0
controlled versus 1 uncontrolled based on GINA score), 12 baseline Rint,
13 baseline Fres, 14 baseline AX, 15 baseline R5Hz, 16 baseline X5Hz, 17
baseline R20Hz, 18 baseline R5-20Hz, 19 baseline Rc, 20 baseline Iaw, 21
baseline Cp, 22 baseline Rp, 23 post-BD Rc, 24 post-BD Iaw, 25 post-BD
Cp, 26 post-BD Rp, 27 BD response based on R5Hz. Raw values of pulmonary
function parameters were used in the PCA.</div><div>SAD denotes small airway dysfunction, BD denotes bronchodilator.</div>