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\begin{document}

\title{The predictive value of impulse oscillometry for asthma exacerbations in
childhood: a systematic review and meta-analyses}



\author[1]{Yongsheng Xu}%
\author[2]{Yaoyao Ling}%
\author[2]{Yufan  Niu}%
\author[2]{Yuqi Han}%
\affil[1]{Tianjin Children's Hospital}%
\affil[2]{Tianjin Medical University}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Several studies have explored the predictive value of
impulse oscillometry (IOS) for asthma exacerbations in childhood, but
its specific parameters are still unclear. Therefore, we designed this
meta-analysis to determine the related indicators of acute asthma
attacks. Methods: A comprehensive literature search was performed in
July 2020 based on Pubmed, Embase, and Web of science database. Weighted
mean differences (WMD) were calculated using Fixed-or random-effects
models. Results: A total of 615 patients from 6 trials were included in
this analysis. IOS may be a useful tool to predict asthma exacerbations.
And the results showed that R5 (WMD = - 1.21, 95\%CI: -1.55 to -0.87,
P<0.001), Fres (WMD = - 1.34, 95\%CI: -2.03 to -0.65,P=0.018) and AX
(WMD = - 7.35, 95\%CI: -9.94 to -4.76,P<0.001) had significant
correlation with asthma exacerbations. In addition, X5 may also predict
the acute attack of asthma (WMD =0.81, 95\%CI: 0.56 to 1.01, P<0.001).
Conclusion: R5, AX, Fres, and X5 may be able to identify the risk of an
acute attack of asthma. Besides, our research further demonstrated that
peripheral airway injury may play an important role in the acute attack
of asthma.%
\end{abstract}%



\sloppy


\textbf{1.Introduction}:

Asthma is the most common chronic lower respiratory disease in
childhood, characterized by airway inflammation and airway
hyper-responsiveness. Most cases of childhood asthma occur before the
age of 3 years, and pulmonary impairment often starts during the
preschool ages. Moreover, acute exacerbations are one of the main causes
of emergency department visits and may lead to long-term pulmonary
impairment children\textsuperscript{{[}1-3{]}}. Therefore, early
diagnosis and early treatment are of great significance to achieve full
control and reduce asthma exacerbations\textsuperscript{{[}4{]}}. Lung
function tests are a common detection method of asthma. Longitudinal
monitoring of respiratory parameters is helpful to early intervention
and improve prognosis.

Spirometry has traditionally been employed to evaluate lung function,
considered as the gold standard\textsuperscript{{[}4{]}}. However, young
children may be unable to perform the test, since it requires effort
dependent lung maneuvers. The effort dependent nature of the test
interferes with the reproducibility of the test. Besides, spirometry may
be limited when clinical conditions do not allow it to be carried out
safely\textsuperscript{{[}5{]}}.

For these reasons, impulse oscillometry (IOS), based on forced
oscillation technique (FOT), has been noticed to measure lung function
in young children(mainly over 3 years old)\textsuperscript{{[}6{]}}.
Compared with spirometry, IOS is a much simpler and noninvasive
technique for assessing airway impedance and responsiveness in children.
It is effort-independent that can be performed in tidal breathing and
requires minimal patient cooperation. Also, it can distinguish between
the degree of obstruction in central and peripheral
airways\textsuperscript{{[}7, 8{]}}. The main indicators of IOS are R5
(resistance at 5HZ), R20 (resistance at 20HZ), R5-20 (resistance at 5 Hz
minus resistance at 20 Hz), X5(reactance at 5Hz), AX(reactance area),
Fres(resonant frequency of reactance).

~In recent years, many studies have explored the predictive value of IOS
for asthma exacerbations in childhood, but its specific indicators are
still controversial. Therefore, we performed a systematic literature
review and meta-analysis to further investigate the issue and identify
potential sources of heterogeneity that might be confounders that have
affected some existing conclusions.

\textbf{2.Methods}

This meta-analysis strictly followed the recommendations of the
Preferred Reporting Items for Systematic Reviews and Meta-analyses
Statement\textsuperscript{{[}9{]}}. No ethical approval and patient
consent were required for this review as all data were already published
in peer-reviewed journals.

2.1 literature search and selection criteria

We conducted a comprehensive literature search of the PubMed, Embase,
and Web of Science databases up to July 2020 with the following search
algorithm: (asthma or asthmas or bronchial asthma or asthma, bronchial)
and impulse oscillometry. Besides, the reference lists of retrieved
articles and related reviews were examined to identify any potential
relevant research. There were no language or publication date
restrictions. The flow diagram was presented in Fig. 1.

The inclusion criteria were as follows: 1.study design was randomized
controlled trials (RCT); 2. participants were children ([?]14 years old)
with asthma exacerbations or poorly controlled asthma, which was
diagnosed according to the Global Initiative for Asthma or relevant
guidelines;3. participants used impulse oscillometry to evaluate lung
function;4. outcome measures included impulse oscillometry parameters.

To ensure accuracy, two authors chose the studies independently,
resolved their differences through discussion with the third author, and
selected the articles to be included by consensus.

2.2 quality assessment and data extraction

The Newcastle--Ottawa Scale (NOS) was applied to assess the quality of
included studies by two independent authors. NOS is a 9-star system,
which scores observational studies on 3 dimensions: selection (4 items),
comparability (1 item), and exposure/outcome (3 items). Except for
comparability (2 points), 1 point will be given for each item. A score
[?]of 7 was considered a high-quality article.

Two authors independently abstracted data and any discrepancy was

resolved by consensus. The following variables were collected from each
study: author, publication year, country, type of study, age of
baseline, sample size and number of cases, and measurements. The outcome
of interest was parameters of IOS that can predict asthma exacerbations
or loss of control.

2.3 Statistical analyses

For studies that reported separate effect size estimates of different
related indicators of IOS in acute asthma attacks, we combined these
risk estimates into each study, weighted by the inverse of the variance.
Subgroup analyses were performed based on different parameters of IOS
related to asthma exacerbations. Heterogeneity across included studies
was assessed with the Cochrane Q test (the level of significance was set
at 0.1)\textsuperscript{{[}10{]}}. The I\textsuperscript{2} score was
also used to determine the degree of heterogeneity
(I\textsuperscript{2}\textless{} 50\%, no obvious heterogeneity;
I\textsuperscript{2}\textgreater{}50\%, large or extreme
heterogeneity)\textsuperscript{{[}11{]}}. Galbraith
plot\textsuperscript{{[}12{]}} introduced to identify the studies that
contributed to the heterogeneity and meta-analysis was performed again
after removing these studies.

In the sensitivity analysis, the meta-analysis was repeated after each
study was omitted. Begg's test\textsuperscript{{[}13{]}} and Egger's
test \textsuperscript{{[}14{]}} were used to assess publication bias.
Meta-analysis was conducted using STATA 12.0.

\textbf{3.Results}

3.1Study searches and characteristics of the included studies

The detailed process of the literature search is shown in Fig. 1. A
total of 6 eligible studies\textsuperscript{{[}15-20{]}}, published
between 2016 and 2020, were enrolled in the present meta-analysis. The
studies were conducted in the following geographical
regions:USA(n=2),Germany(n=1), Turkey(n=1), China(n=2). All studies used
well-controlled asthma as the control group, and 4 studies also added
healthy people as the control group\textsuperscript{{[}15, 17, 18,
20{]}}. Our study focused on the role of IOS in predicting asthma
exacerbations or loss of control, so we did not include healthy people.
The sample size ranged from 54 to 192, including 615 children with an
average age of 3.65-11.20 years. They were all case-control studies. All
participants performed IOS. Meaningful pulse oscillation parameters
varied among the trials. The quality scores of these studies were
evaluated by the NOS ranging from 7 to 8. The characteristics of all
studies were summarized in Table1.

3.2Association between pulse oscillation parameters and asthma
exacerbations

The included six studies revealed that IOS may be able to identify the
risk of acute attack or loss of control of asthma. We further analyzed
the value of IOS common parameters in predicting the loss of asthma
control. In terms of resistance, we found that elevated levels of R5 may
indicate the risk of asthma exacerbations (WMD = - 1.21, 95\%CI: -1.55
to -0.87, P<0.001)(Fig.2a).However, as for R20(WMD = - 0.81, 95\%CI:
-1.95 to 0.32, P=0.161), R5-20 (WMD = - 0.68, 95\%CI: -1.61 to 0.25,
P=0.151), the results did not show a good correlation with the acute
attack of asthma (Fig.2b-2c). In terms of reactance, we found X5 (WMD
=0.81, 95\%CI: 0.56 to 1.01, P<0.001) were significantly related to the
loss of asthma control(Fig.2d). Moreover, the Fres (WMD = - 1.34,
95\%CI: -2.03 to -0.65,P=0.018) and AX (WMD = - 7.35, 95\%CI: -9.94 to
-4.76,P<0.001) can also identify the risk of acute attack or loss of
control of asthma(Fig.2e-2f).

3.3 Sensitivity analysis and publication bias

Sensitivity analysis confirmed that no individual study influenced the
overall results. There was no evidence of publication bias in this
meta-analysis indicated by Begg's funnel plot and Egger's tests (Fig3).

\textbf{4.Discussion}

To our knowledge, this is the first systematic review and meta-analysis
of IOS parameters to identify the risk of acute attack or loss of
control in children with asthma. Our research involved a total of 615
cases from 6 studies. We selected common IOS parameters and analyzed
them. The results showed that R5, X5, AX, and Fres may better predict
asthma exacerbations or loss of control.

Asthma is a common disease in pediatrics. The goal of care is to
maximize the safety of treatment by achieving and maintaining the
control of disease at the lowest level and dose of inhaled
corticosteroids (ICS). Studies have shown that childhood asthma control
is closely related to adult asthma control, lung function, and chronic
obstructive pulmonary disease (COPD)\textsuperscript{{[}21{]}}. An acute
attack of asthma refers to the sudden occurrence of symptoms such as
wheezing, coughing, shortness of breath, chest tightness, or the acute
exacerbation of the original symptoms, which can even lead to dyspnea,
asphyxia and life-threatening. Therefore, timely and objective
indicators are needed for early identification and prevention. Pulmonary
ventilation function monitoring is an important means for future risk
assessment of asthma, but it has certain limitations. IOS has been
widely clinically studied because of its simple operation and its
ability to measure the impedance of the respiratory system, which
consists of reactance and resistance. Previous trials suggested that IOS
may be a reliable non-invasive method to assess asthma control in
children\textsuperscript{{[}22, 23{]}}.

Resistance can be conceptualized as the energy required for sound waves
to pass through the airways and inflate the lung. R5 represents the
total airway resistance. The included five trials found that R5
increased in asthma exacerbations\textsuperscript{{[}14-17, 19{]}}. Only
Smith et al did not report the difference in R5 between the two
groups\textsuperscript{{[}17, 19{]}}. Our study showed that R5 had a
good correlation with the acute attack of asthma. Besides, Galant et al
held that R5 increased significantly when peripheral airway obstruction
occurred\textsuperscript{{[}24{]}}. The reactance of the respiratory
system, expressed in Xrs, consists of the inert and elastic properties
of the respiratory system. X5 is defined as the peripheral elastic
resistance, providing important information about the peripheral
respiratory tract. When small airway obstruction and lung compliance
decrease, the negative value will increase
significantly\textsuperscript{{[}25{]}}. Our study found a good
correlation between X5 and asthma loss of control. Schulze et al found
that X5 represents hyperinflation\textsuperscript{{[}16{]}}.
Tirakitsoontorn et al also reported X5 may be well suited to identify
peripheral airway impairment phenotype in the clinical
setting\textsuperscript{{[}18{]}}. Galant et al further confirmed that
X5 decreased significantly in the uncontrolled asthma
group\textsuperscript{{[}26{]}}. Fres also known as resonant frequency
refers to the frequency when the elastic recoil of the airways and lungs
is equal and opposite to the inertance of the system, that is, the
reactance is zero. Moreover, based on the mechanical properties of
airways, Fres is the dividing point between large and small
airways\textsuperscript{{[}24{]}}. Our result revealed that Fres had a
certain significance in predicting the acute attack of asthma, but there
was large heterogeneity (I\textsuperscript{2}=85.1\%,p=0.000). This may
be contributed to the small number of trials and the large age span
between the trials. AX means the area under the reactance curve between
5 Hz (X5) and the Fres value, similar to X5, which also can provide
information about distal airway obstruction\textsuperscript{{[}27{]}}.
Our research found a significant correlation between AX and acute
asthma.

Peripheral airways have much smaller lumina than central (large)
airways, and inflammation/edema in the walls of peripheral airways can
be expected to have a proportionately larger effect on lumen size than
inflammation/edema in larger airways. The above indicators reveal that
peripheral airway impairment may be associated with uncontrolled asthma.
Besides, previous studies have also reported that peripheral airway
impairment is clinically related to asthma exacerbation, uncontrolled
asthma, loss of control, and asthma severity\textsuperscript{{[}22,
23{]}}. However, our study did not find the role of the R5-20 indicator
in predicting the loss of asthma control.R5-20 refers to the resistance
of the peripheral airways, which was also inconsistent with previous
research. This may be related to the age and height of the population
included in the study. When the peripheral airway was obstructed, R5 was
significantly elevated and R20 was not changed. However, R5 decreased
linearly with the growth of height\textsuperscript{{[}28{]}}.

Our meta-analysis had some limits. First, the severity of asthma

exacerbations or uncontrolled asthma and baseline treatment varied from
study to study, which may affect the results. In addition, other factors
like race, age, sex, height can also bring out the heterogeneity. These
indicate that a large number of randomized trials are still needed to
confirm the potential relationship between IOS parameters and acute
attack of asthma. Our research also had some advantages. For instance,
it is the first systematic review and meta-analysis about the predictive
value of the IOS common parameter in asthma exacerbations. And all
trials were of high quality.

\textbf{5.Conclusion:}

Overall, our results suggested that R5, X5, AX, Fres may be able to
predict acute attack or loss of control of asthma, while R20, R5-20
could not. Besides, our research further demonstrated that peripheral
airway injury had a good correlation with asthma exacerbations. It may
show that in clinical work, the role of peripheral airway injury should
be recognized, and timely identification and intervention should be made
to reduce the frequency of acute asthma attacks.

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interest.

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