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 FEV1 ≥12% and 200mL was present
in only 17.3% of asthmatics in a meta-analysis of 3 large population
studies (n=2,833).35 Spirometry can remain preserved
in symptomatic individuals until an advanced stage of lung disease,
whilst oscillometry is sensitive to changes in small airway
function36 and offers some advantages over spirometry
in the identification of individuals with poor asthma
control.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 ΔFEV1 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.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.2 In contrast, spirometry measures flow
and volume during a forced manoeuvre, and may be better able to
determine the function of larger airways.40 The lack
of sensitivity of oscillometry to detect a significant
FEV1 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 FEV1) 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.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
value41, 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
(ΔRrs5 ≤-40%, ΔXrs5 ≥50% or ΔAX
≤−80%) were developed from data from healthy
children1 and reports are emerging that these values
may be too stringent for the adult population.24,42Using 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 ΔFEV1% 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 R10insp-exp and
X10insp-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
R10insp-exp and X10insp-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 wheeze43 and
predicting lower respiratory tract infections44 in
infants and young children than spectral oscillometry, and in adults
with COPD.45 We observed no differences in
X10insp-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.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.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.40 That oscillometry
(intrabreath and spectral) is feasible in a preterm born population
reinforces its value in both a research and clinical context.