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\begin{document}

\title{Oscillometry and spirometry are not interchangeable when assessing the
bronchodilator response in children and young adults born preterm}



\author[1]{Tiffany K. Bradshaw}%
\author[1]{Elizabeth Smith}%
\author[1]{Rhea C. Urs}%
\author[1]{Denby Evans}%
\author[1]{Naomi R. Hemy}%
\author[1]{Graham L. Hall}%
\author[1]{Andrew Wilson}%
\author[1]{Shannon Simpson}%
\affil[1]{Telethon Kids Institute}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} The European Respiratory Society Oscillometry
Taskforce identified that clinical correlates of bronchodilator
responses are needed to advance oscillometry in clinical practice. The
understanding of bronchodilator-induced oscillometry changes in preterm
lung disease is poor. Here we describe a comparison of bronchodilator
assessments performed using oscillometry and spirometry in a population
born very preterm and explore the relationship between
bronchodilator-induced changes in respiratory function and clinical
outcomes. \textbf{Methods:} Participants aged 6-23 born [?]32 (N=288; 132
with bronchopulmonary dysplasia) and [?]37 weeks' gestation (N=76,
term-born controls) performed spirometry and oscillometry. A significant
bronchodilator response (BDR) to 400mcg salbutamol was classified
according to published criteria. \textbf{Results:} A BDR was identified
in 30.9\% (n=85) of preterm-born individuals via spirometry and/or
oscillometry, with poor agreement between spirometry and oscillometry
definitions (k=0.26; 95\%CI 0.18 to 0.40, p\textless{}0.001). Those born
preterm with a BDR by oscillometry but not spirometry had increased
wheeze (33\% vs 11\%, p=0.010) and baseline resistance (Rrs
\textsubscript{5} z-score mean difference (MD)= 0.86, 95\%CI 0.07 to
1.65, p=0.025), but similar spirometry to the group without a BDR (FEV
\textsubscript{1} z-score MD= -0.01, 95\%CI -0.66 to 0.68,
p\textgreater{}0.999). Oscillometry was more feasible than spirometry
(95\% vs 85\% (FEV \textsubscript{1}), 69\% (FVC), p\textless{}0.001),
however being born preterm did not affect test feasibility.
\textbf{Conclusion:} In the preterm population, oscillometry is a
feasible and clinically useful supportive test to assess the airway
response to inhaled salbutamol. Changes measured by oscillometry reflect
related but distinct physiological changes to that measured by
spirometry and thus these tests should not be used interchangeably.%
\end{abstract}%



\sloppy


\emph{Title:}

\textbf{Oscillometry and spirometry are not interchangeable when
assessing the bronchodilator response in children and young adults born
preterm}

\textbf{Authors:} Elizabeth F. Smith\textsuperscript{1,2}, Tiffany K.
Bradshaw\textsuperscript{1}, Rhea C. Urs\textsuperscript{1,2}, Denby J.
Evans\textsuperscript{1,2}, Naomi R. Hemy\textsuperscript{1}, Graham L.
Hall\textsuperscript{1,2}, Andrew C.Wilson\textsuperscript{1,2,3}, and
Shannon J. Simpson\textsuperscript{1,2}

\textbf{Affiliations:}

\textsuperscript{1}Wal-Yan Respiratory Research Centre, Telethon Kids
Institute, Perth Children's Hospital, 15 Hospital Ave, Nedlands 6009,
Australia.

\textsuperscript{2}Curtin School of Allied Health, Faculty of Health
Sciences, Building 401 Curtin University, Kent St, Bentley 6102,
Australia.

\textsuperscript{3}Child and Adolescent Health Service, Perth Children's
Hospital, 15 Hospital Ave, Nedlands 6009, Australia.

\textbf{Corresponding author:}

Name: Dr Elizabeth Smith

Address: Children's Lung Health Team, Wal-Yan Respiratory Research
Centre, Telethon Kids Institute, Perth Children's Hospital, 15 Hospital
Ave, Nedlands 6009, Australia.

Email: elizabeth.smith@telethonkids.org.au

\textbf{Author contributions:} T. Bradshaw, E. Smith \& R. Urs wrote the
original draft. T. Bradshaw \& E. Smith conducted the data analysis
which was visualised and validated by S. Simpson. G. Hall, A. Wilson, S.
Simpson conceptualised the cohort studies, designed the methodology and
acquired funding. E. Smith conceptualised and designed the methodology
for the comparative analysis. T. Bradshaw, R. Urs, E. Smith, D. Evans
and N. Hemy undertook project administration and investigation
activities. All authors reviewed and edited the final manuscript.

\textbf{Funding:} This project was funded by the National Health and
Medical Research Council (APP1138605 \& APP1140234), Telethon Kids
Institute and Curtin University.

\textbf{Abstract word count: 249 words}

\textbf{Manuscript word count: 3198}

\emph{Keywords} : preterm, bronchodilator response, respiratory
physiology

\emph{Take home message (256 characters)}

In the assessment of the airway response to salbutamol, oscillometry
reflects related but distinct physiological changes to spirometry in
preterm populations. Whilst oscillometry is a feasible and clinically
useful supportive test, it should not be used interchangeably with
spirometry.

\emph{Abstract:}

\textbf{Introduction:} The European Respiratory Society Oscillometry
Taskforce identified that clinical correlates of bronchodilator
responses are needed to advance oscillometry in clinical practice. The
understanding of bronchodilator-induced oscillometry changes in preterm
lung disease is poor. Here we describe a comparison of bronchodilator
assessments performed using oscillometry and spirometry in a population
born very preterm and explore the relationship between
bronchodilator-induced changes in respiratory function and clinical
outcomes.

\textbf{Methods:} Participants aged 6-23 born [?]32 (N=288; 132 with
bronchopulmonary dysplasia) and [?]37 weeks' gestation (N=76, term-born
controls) performed spirometry and oscillometry. A significant
bronchodilator response (BDR) to 400mcg salbutamol was classified
according to published criteria.

\textbf{Results:} A BDR was identified in 30.9\% (n=85) of preterm-born
individuals via spirometry and/or oscillometry, with poor agreement
between spirometry and oscillometry definitions (k=0.26; 95\%CI 0.18 to
0.40, p\textless{}0.001). Those born preterm with a BDR by oscillometry
but not spirometry had increased wheeze (33\% vs 11\%, p=0.010) and
baseline resistance (Rrs\textsubscript{5} z-score mean difference (MD)=
0.86, 95\%CI 0.07 to 1.65, p=0.025), but similar spirometry to the group
without a BDR (FEV\textsubscript{1} z-score MD= -0.01, 95\%CI -0.66 to
0.68, p\textgreater{}0.999). Oscillometry was more feasible than
spirometry (95\% vs 85\% (FEV\textsubscript{1}), 69\% (FVC),
p\textless{}0.001), however being born preterm did not affect test
feasibility.

\textbf{Conclusion:} In the preterm population, oscillometry is a
feasible and clinically useful supportive test to assess the airway
response to inhaled salbutamol. Changes measured by oscillometry reflect
related but distinct physiological changes to that measured by
spirometry and thus these tests should not be used interchangeably.

\emph{Introduction:}

The clinical review by members of the European Respiratory Society
Oscillometry Taskforce\textsuperscript{1} identified that oscillometry
may have a key role in the management of survivors of very preterm birth
(delivered \textless{}32 weeks completed
gestation).\textsuperscript{2}Over the lifespan, survivors of very
preterm birth report increased respiratory symptoms, including wheeze,
inhaled asthma medication use and re-hospitalization during early
childhood compared to their term-born counterparts.\textsuperscript{3}
Lung function deficits, including reduced FEV\textsubscript{1}, and
abnormal respiratory mechanics are reported throughout childhood and
into adulthood.\textsuperscript{4-7} By school-age,
\textasciitilde{}50\% of very preterm-born children are diagnosed with
asthma\textsuperscript{5}; up to five times increased odds than those
born at term.\textsuperscript{8} Despite the high prevalence of asthma
diagnoses in this patient group, preterm lung disease is typically
non-atopic\textsuperscript{9} with low exhaled nitric oxide
(FeNO)\textsuperscript{10}, contrary to childhood asthma. Additionally,
recent trials of inhaled corticosteroids (ICS) report only modest
improvements in lung function.\textsuperscript{11}

Even with ICS therapy a degree of airway reversibility exists for those
born \textless{}32 weeks gestation.\textsuperscript{11} A significant
bronchodilator response has been reported in about one third of those
born preterm\textsuperscript{12}, with the highest rates in those with a
neonatal diagnosis of chronic lung disease of prematurity,
bronchopulmonary dysplasia (BPD). Studies report 25-60\% of school aged
children with BPD respond to bronchodilators.
\textsuperscript{7,12-14}Despite this, there are reports of preterm-born
children being undertreated with bronchodilators, possibly due to the
belief that respiratory symptoms in this group are an inevitable
consequence of airway injury and remodelling.\textsuperscript{15}
Further, recent findings from our group indicate that those most likely
to respond to inhaled corticosteroids, display a degree of airway
reversibility.\textsuperscript{16} A thorough assessment of the efficacy
of short acting bronchodilators is likely to become key to optimal
patient management in this group.

The response to inhaled bronchodilators is typically assessed using
spirometry, however the assessment of the bronchodilator response by
oscillometry may offer additional advantages in the evaluation of
preterm lung disease. As highlighted by the recent ERS
review\textsuperscript{5}, there is evidence that oscillometry may be a
useful tool in this patient group. At baseline, oscillometry outcomes
are abnormal in those born very premature, with the worst abnormalities
observed in those with bronchopulmonary dysplasia
(BPD).\textsuperscript{6,17,18} Additionally, in those born
\textless{}32 weeks gestation oscillometry outcomes correlate with
respiratory symptoms\textsuperscript{5,18} and are sensitive to changes
in lung function due to exposure to tobacco
smoke.\textsuperscript{19}High test feasibility may be of particular
value in this population where patients are young and developmental
delay is associated with severe respiratory disease.\textsuperscript{20}
Despite these advantages, the utility of oscillometry for the assessment
of bronchodilator responses in preterm lung disease has yet to be
explored.

Whilst few studies currently exist examining the bronchodilator response
by oscillometry in those born preterm,\textsuperscript{7,18} asthma
studies have reported that an oscillometry assessment of the
bronchodilator response may be better than spirometry at differentiating
asthmatic from healthy children\textsuperscript{21,22} and identifying
individuals with poor asthma control.\textsuperscript{23} Emerging
evidence suggests that intra-breath oscillometry may identify a
bronchodilator response in smokers and patients with COPD with greater
sensitivity than spirometry.\textsuperscript{24} Due to its ability to
detect changes in the small airways, it may be that oscillometry is a
more sensitive test in assessment of the bronchodilator response in
those born preterm, however this has yet to be determined.

This study aimed to assess the feasibility and sensitivity of detecting
a bronchodilator response by spirometry and oscillometry using published
cut-offs in a preterm population. To further our understanding of the
interpretation of these tests, we aimed to investigate the correlations
and agreement between reported outcomes, and their association with
clinical symptoms. We hypothesised that a greater response to
bronchodilators would be observed in those born preterm (by all
methods). We further hypothesised that there would be a correlation
between oscillometry and spirometry bronchodilator induced changes, but
that oscillometry outcomes would correlate with symptoms and identify
individuals with a bronchodilator response that would not have been
identified by spirometry alone.

\emph{Methods:}

\emph{Participants}

Preterm-born children and young adults, with and without a diagnosis of
BPD, and healthy term-born controls, were assessed between the ages of 6
and 23 years (data are collated from two distinct cohorts ages
6-12\textsuperscript{16} and 16-23 \textsuperscript{25}). Elements of
this lung function data have been presented in these publications.
Preterm-born participants were delivered at 32 weeks gestation or less,
hospitalised at King Edward Memorial Hospital (KEMH) in Perth, Western
Australia. Participants born preterm were classified as having
bronchopulmonary dysplasia if they received 28 days of oxygen
supplementation or more, as assessed at 36 weeks postmenstrual
age.\textsuperscript{26} Healthy term participants were born at 37 weeks
gestation or more and had no history of recurrent respiratory symptoms
or lung disease at the time of recruitment. Written informed consent was
obtained from participants over 18 years of age and from parents or
guardians for participants under 18 years. Ethical approval was obtained
from the Child and Adolescent Health Service Human Research Ethics
Committee (RGS367, RGS815).

\emph{History and Symptoms}

Neonatal and maternal health data was obtained from medical records and
the KEMH neonatal database. Respiratory symptoms history was obtained
using validated general and respiratory questionnaires adapted from the
International Study of Asthma and Allergies in Childhood (ISAAC)
questionnaires.\textsuperscript{27} Respiratory symptoms such as wheeze,
shortness of breath, cough and rattly chest in the 3 months prior to the
participant's study visit were parentally or self-reported, as
appropriate.

\emph{Lung function assessment}

Participants attended Perth Children's Hospital for lung function
assessment. Respiratory mechanics were assessed using the TremoFlo C-100
(Thorasys Inc. Montreal, Canada). Spectral oscillometry was performed
across 5-37Hz and intrabreath oscillometry was performed using a single
10Hz frequency. Spirometry was performed using the using the Medisoft
Hypair or BodyBox 5500 (Medisoft Corporation, Sorinnes, Belgium). All
tests were carried out according to American Thoracic Society/European
Respiratory Society (ATS/ERS) guidelines.\textsuperscript{1,28,29}

Spirometry outcomes were expressed as z-scores according to the Global
Lung Function Initiative equations.\textsuperscript{30} Spectral
oscillometry outcomes including respiratory resistance at 5Hz
(Rrs\textsubscript{5),} resonant frequency (Fres), area under the
reactance curve (AX) and respiratory system reactance at 5Hz
(Xrs\textsubscript{5}) were expressed as z-scores according to the
reference equations published by Calogero \emph{et al} (6-12 year
data,\textsuperscript{31}) and Oostveen \emph{et al} , (16-23 year
data,\textsuperscript{32}). Rrs\textsubscript{5-20}, and intra-breath
oscillometry measures were expressed as raw values and absolute
difference.\textsuperscript{33}

Oscillometry and spirometry were performed before and after
administration of 400\selectlanguage{greek}µ\selectlanguage{english}g salbutamol via a spacer. A bronchodilator
response by spirometry was defined according to ATS/ERS guidelines as an
increase of [?]200mls and 12\% in FEV\textsubscript{1} or
FVC\textsuperscript{29} (the 200ml rule was omitted for children [?]12
years). A bronchodilator response by spectral oscillometry was defined
according to ERS guidelines as a change of [?]-40\% in
Rrs\textsubscript{5}, [?]50\% in Xrs\textsubscript{5} or [?]-80\% in AX
across all age groups.\textsuperscript{1}

\emph{Statistics}

Data was analysed using IBM SPSS Statistics for Windows, Version 27.0
and GraphPad Prism 9.4.0. Normally distributed data are presented as
means and standard deviations. Non-normally distributed data are
presented as medians and interquartile ranges. Differences between two
groups were analysed by independent samples t-test or Mann-Whitney U
test depending on normality of the data. To compare three or more
groups, the one-way ANOVA with Bonferroni Post-Hoc or the Kruskal Wallis
test with pairwise comparisons was performed, as appropriate. For
categorical data, the chi-squared test was used. Agreement between
spirometric and oscillometric BDRs was assessed using kappa statistics,
where Cohen's kappa coefficient (k) of \textgreater{}0.75 represented
excellent agreement, 0.40--0.75 represented a fair to good agreement,
and \textless{}0.40 was indicative of poor
agreement.\textsuperscript{34}

\emph{Results:}

\emph{Study participants}

Included in the study were 364 participants (76 term; 288 preterm) at a
median (IQR) age of 12.9 years (9.8, 19.0), assessed at a single time
point. There were no anthropometric differences between the preterm and
term cohorts (Table 1). Those born [?]32 weeks gestation had a high burden
of respiratory symptoms, with 39\% having received an asthma diagnosis
during their lifetime.

\emph{Baseline lung function}

Preterm participants had a lower FEV\textsubscript{1} (MD= -0.87; 95\%
CI -0.56, -1.17; p\textless{}0.001) and FEV\textsubscript{1}/FVC z-score
(MD= -0.85; 95\% CI -0.57, -1.14; p\textless{}0.001), but not FVC
z-score (Table 2) compared to term-born participants. Obstructive
spirometry (defined as FEV\textsubscript{1} or FEV\textsubscript{1}/FVC
[?]-1\selectlanguage{ngerman}·64 z-scores) was seen in 31.4\% of preterm participants, compared to
8.6\% of term born controls (X\textsuperscript{2}= 14.8,
p\textless{}0.001).

Preterm-born participants also had abnormal respiratory mechanics as
assessed by oscillometry. Spectral oscillometry z-scores revealed
significant differences in reactance at 5Hz (Xrs\textsubscript{5}) (MD=
-0.52; 95\% CI -0.26 to -0.79; p\textless{}0.001), area under the
reactance curve (AX) (MD= 0.67; 95\% CI 0.40 to 0.94; p\textless{}0.001)
and resonant frequency (Fres) (MD= 0.62; 95\% CI 0.33 to 0.91;
p\textless{}0.001) for those born preterm, compared to term. Z-scores
for respiratory resistance at 5Hz (Rrs\textsubscript{5}) were not
different between term and preterm groups (Table 2,
p\textgreater{}0.05), however the difference between respiratory
resistance at 5 and 20 Hz (Rrs\textsubscript{5-20}) was greater in the
preterm group (Table 2, p\textless{}0.001).

At 10Hz, inspiratory and expiratory resistance was higher and reactance
was lower in the preterm group (Table 2), however the magnitude of the
difference between inspiratory and expiratory reactance values
(X10\textsubscript{insp-exp}) was not different in those born preterm
compared to term born controls (Table 2, p\textgreater{}0.05).

\emph{Assessment of the bronchodilator response}

Oscillometry was more feasible than spirometry, with 95\% of overall
participants obtaining acceptable measures pre- and post-bronchodilator
with oscillometry, compared to 85\% for
FEV\textsubscript{1}(p\textless{}0.001) and 69\% for FVC
(p\textless{}0.001). However, the feasibility of achieving a successful
bronchodilator assessment with either test was similar in term and
preterm groups (p\textgreater{}0.05, Table 3).

A greater bronchodilator response was observed in the preterm group
compared to the term group via both spirometry and oscillometry (Table
3). A small but significant improvement in FEV\textsubscript{1,} but not
FVC, was observed, relative to term born controls with a mean difference
of 3.5\% (95\% CI 2.0 to 4.9; p\textless{}0.001). Similarly,
improvements were observed in the oscillometry measures
\selectlanguage{greek}Δ\selectlanguage{english}Rrs\textsubscript{5} (MD= -4.9\%, 95\% CI -8.7 to -1.0, p=0.013),
\selectlanguage{greek}Δ\selectlanguage{english}Rrs\textsubscript{5-20} (MD= -0.39, 95\% CI -0.56 to -0.23,
p\textless{}0.001), \selectlanguage{greek}Δ\selectlanguage{english}Xrs\textsubscript{5} (MD= 11.4\%, 95\% CI 5.8 to
17.0, p\textless{}0.001) and \selectlanguage{greek}Δ\selectlanguage{english}AX (MD= -14.1\%, 95\% CI -22.6 to -5.7,
p=0.001).

Using published cut-offs, we observed a bronchodilator response in
24.1\% of those born [?]32 weeks gestation by spirometry compared to 7.6\%
of term-born controls (p=0.003). Oscillometry detected a bronchodilator
response in 16.4\% of those born preterm, compared to 4.3\% of term-born
controls (p=0.009).

Intrabreath oscillometry revealed that the magnitude of the change in
inspiratory reactance (X10\textsubscript{insp}) and expiratory reactance
(X10\textsubscript{exp}) following bronchodilator was greater in those
born preterm (Table 3). The magnitude of this change was however
proportional across the breath cycle, with negligible within breath
differences in reactance (X10\textsubscript{insp-exp}) (MD= -0.01, 95\%
CI -0.1208 to 0.101, p=0.861) (Table 3). No significant bronchodilator
induced decrease in inspiratory or expiratory resistance were observed
in the preterm group, relative to the term-control group (Table 3).

\emph{Agreement between oscillometry and spirometry outcomes}

Bronchodilator induced FEV\textsubscript{1}\% change and change in
oscillometry outcomes were correlated (Figure 1), however these
correlations were weak (R\textsuperscript{2} \textless{}0.16, data not
shown).

Of the 85 preterm individuals identified with a BDR (using published
cut-offs), 76 had acceptable spirometry and oscillometry. Of these
individuals, only 19 (25\%) showed an agreement between tests; 38 (50\%)
were identified by spirometry only and 19 (25\%) by oscillometry only
(Figure 2). In the preterm group, agreement between tests was poor (k=
0.26; 95\% CI 0.18 to 0.40, p\textless{}0.001). Similarly, in the term
group, the agreement was extremely poor, with no overlap between tests
(k= -0.06; 95\% CI -0.10 to -0.01, p=0.641).

Oscillometry identified an additional 7 preterm-born individuals with a
BDR that could not otherwise complete acceptable spirometry. Conversely,
spirometry identified 2 preterm individuals with a BDR and no acceptable
oscillometry measures.

\emph{Clinical characteristics by bronchodilator response status}

In the preterm group, those with a BDR by either test were more likely
to have abnormal baseline lung function (Table 4). Those with a
spirometry BDR had the lowest pre-bronchodilator spirometry; this
relationship was non-linear (R\textsuperscript{2}=0.44,
p\textless{}0.001. Supplementary Figure E1). Similarly, those with an
oscillometry BDR had the worst pre-bronchodilator oscillometry (Table
4), Whilst a BDR was more likely in those with lower baseline lung
function, spirometry was not reduced in the group with a BDR by
oscillometry alone, relative to the group without a BDR
(FEV\textsubscript{1} z-score MD= -0.01, 95\%CI -0.66 to 0.68,
p\textgreater{}0.999). However, in the group that had a BDR by
oscillometry but not spirometry, airway resistance was increased
(Rrs\textsubscript{5} z-score MD= 0.86, 95\%CI 0.07 to 1.65, p=0.025) as
was wheeze (33\% vs 11\%, p=0.010), compared to those without a BDR.

Baseline lung function (oscillometry and spirometry) was lowest in those
with a BDR detected by both tests (e.g., FEV\textsubscript{1} z-score
MD= -2.14, 95\%CI -2.89 to -1.39, p\textless{}0.001), compared to those
without a BDR.

\emph{Discussion:}

Here we describe the first comparison of bronchodilator assessments
performed using oscillometry and spirometry in a preterm-born
population. Both oscillometry and spirometry demonstrate that those in
the preterm group have a greater response to salbutamol, however the
magnitude of the change measured by spirometry and oscillometry was only
weakly correlated. Similarly, when a response was defined as
`significant' using published thresholds, there was a poor agreement
between tests.

Spirometry is the ``gold-standard'' with which to assess the
bronchodilator response, however, we show that oscillometry provides
additional information especially in preterm individuals with normal
spirometry and respiratory symptoms (wheeze). Spirometry may not detect
mild disease that presents as `normal' between exacerbations, for
example, an increase in FEV\textsubscript{1} [?]12\% and 200mL was present
in only 17.3\% of asthmatics in a meta-analysis of 3 large population
studies (n=2,833).\textsuperscript{35} Spirometry can remain preserved
in symptomatic individuals until an advanced stage of lung disease,
whilst oscillometry is sensitive to changes in small airway
function\textsuperscript{36} and offers some advantages over spirometry
in the identification of individuals with poor asthma
control.\textsuperscript{37,38} ~Our finding that preterm individuals
with an oscillometry BDR only had increased respiratory symptoms, but
normal spirometry, suggests that oscillometry has clinical value as a
supplement to-, rather than surrogate for- assessing the bronchodilator
response in this population.

Oscillometry is not a suitable surrogate for spirometry due to poor
agreement between oscillometry and spirometry detected BDRs, and a weak
correlation between \selectlanguage{greek}Δ\selectlanguage{english}FEV\textsubscript{1} and oscillometry outcome
measures. This has been reported previously in a retrospective review of
592 children with asthma or suspected asthma; 18\% had a BDR by
spirometry only, 9\% by oscillometry only, and only 8\% had a BDR by
both tests.\textsuperscript{39} Oscillometry and spirometry have
different measurement techniques (tidal breathing vs forced manoeuvres)
which likely partially explains this discrepancy. Performed during tidal
breathing, oscillometry is perceived as a sensitive measure of small
airway disease.\textsuperscript{2} In contrast, spirometry measures flow
and volume during a forced manoeuvre, and may be better able to
determine the function of larger airways.\textsuperscript{40} The lack
of sensitivity of oscillometry to detect a significant
FEV\textsubscript{1} change raises concerns surrounding the ability of
oscillometry to detect more global changes in airway resistive forces.
Notwithstanding, it may be that oscillometry has value in discriminating
disease isolated to the small airways in those born preterm.

This poor agreement between oscillometry and spirometry BDR detection is
likely exacerbated by the current published definitions of a BDR using
both tests. Fixed cut-offs are typically recommended (e.g., [?]12\%
improvement and 200ml in FEV\textsubscript{1}) and hence used here,
however the response to a bronchodilator is inversely proportional to
baseline lung function and therefore also dependant on age, height, and
sex.\textsuperscript{41} Whilst the recently published ATS/ERS
guidelines have gone someway to addressing this in spirometry,
recommending that the magnitude of the change should be normalised to an
individual's predicted value, rather than their baseline
value\textsuperscript{41}, this had little influence on our results
(supplementary tables E1 and E2). In oscillometry, there has been debate
as to whether a BDR should be expressed as absolute, relative or z-score
change, with the latest ERS technical standards advocating for relative
change, until there are sufficiently robust healthy data for
oscillometry to permit a z-score approach. The published cut-offs
(\selectlanguage{greek}Δ\selectlanguage{english}Rrs\textsubscript{5} [?]-40\%, \selectlanguage{greek}Δ\selectlanguage{english}Xrs\textsubscript{5} [?]50\% or \selectlanguage{greek}Δ\selectlanguage{english}AX
[?]-80\%) were developed from data from healthy
children\textsuperscript{1} and reports are emerging that these values
may be too stringent for the adult
population.\textsuperscript{24,42}Using a z-score change that
incorporates the variability of the reference data set may be a suitable
way to address this limitation, however reference values for
oscillometry are currently limited and, in part, device specific. There
is currently no recommendation for cut-offs for the intrabreath
oscillometry measures. Nevertheless, whilst the published cut-offs may
be problematic, the weak correlation observed between
\selectlanguage{greek}Δ\selectlanguage{english}FEV\textsubscript{1}\% and oscillometry outcomes supports that the poor
agreement is more likely reflective of the differences in airway
physiology that these tests represent, rather the purely an issue of
classification.

Ours is the first study to report within-breath changes with
single-frequency oscillometry with R10\textsubscript{insp-exp} and
X10\textsubscript{insp-exp} measures pre- and post-bronchodilator in
preterm-born children. Our findings suggest these within-breath measures
may be less useful than spirometry and conventional spectral
oscillometry when assessing the bronchodilator response in this
population. We observed no difference in the magnitude of the
R10\textsubscript{insp-exp} and X10\textsubscript{insp-exp} response to
a bronchodilator, rather changes were proportional across the breath
cycle, and reflected global changes in resistance and reactance at 10
Hz. Recent studies have suggested that intra-breath oscillometry
measures may be more useful in detecting wheeze\textsuperscript{43} and
predicting lower respiratory tract infections\textsuperscript{44} in
infants and young children than spectral oscillometry, and in adults
with COPD.\textsuperscript{45} We observed no differences in
X10\textsubscript{insp-exp} measures between preterm and healthy
participants at baseline, or in response to a bronchodilator, meaning
that airway inhomogeneity is likely not the primary driver of airway
obstruction in preterm-born individuals. Indeed, small studies measuring
ventilation inhomogeneity using multiple breath washout report no
differences between preterm and term-born
infants.\textsuperscript{46-48} Airway obstruction in preterm-born
individuals may instead be more attributable to reduced compliance as
suggested by our spectral oscillometry outcomes. As the literature
around within-breath oscillometry is limited, there are no references
for `normal' measures and the physiology behind within-breath outcomes
remains somewhat speculative. Further work is needed to explore the
physiology of within-breath changes and its implications in individuals
born preterm.

Consistent with previous findings we show that, whilst oscillometry is a
more feasible test, being born 32 weeks gestation or less did not
influence feasibility.\textsuperscript{40} It should be noted that those
with severe impairment were excluded at the time of recruitment, however
our results show that for most survivors of preterm birth, similar test
success rates should be expected for those born at term in the age range
studied. It should be noted that these measurements were made during a
research appointment, which is not subject to the same time constraints
as a clinical service, however reviews of routine clinical testing
reveal similar findings.\textsuperscript{40} That oscillometry
(intrabreath and spectral) is feasible in a preterm born population
reinforces its value in both a research and clinical context.

\emph{Conclusions:}

In the preterm population, oscillometry is a feasible and clinically
useful supportive test for those unable to perform spirometry or where
bronchial hyperresponsiveness is suspected in the presence of normal
spirometry results. A bronchodilator response by spirometry and
oscillometry reflects related but distinct physiological changes in the
airways of those born preterm, and these tests should not be used
interchangeably. Our observations that the response to a bronchodilator
as measured by oscillometry and spirometry may reflect different aspects
of airway physiology warrants further investigation to advance our
understanding of preterm lung disease.

\textbf{Acknowledgments}

We would like to acknowledge all the families and participants who have
taken part in this research, to improve the care of the next generation
of those born too soon. We would also like to thank the Preterm
Community Reference Group for their ongoing support and guidance on
everything that we do from the perspective of those with lived
experience.

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