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\begin{document}

\title{Lung Ultrasound in Pediatric Asthma - Characterizing Baseline Findings
Outside of Acute Exacerbations}



\author[1]{Noah Marzook}%
\author[2]{Francois Gagnon}%
\author[3]{Alexandre Deragon}%
\author[1]{David Zielinski}%
\author[4]{Adam Shapiro}%
\author[5]{Larry Lands}%
\author[6]{Alexander S. Dubrovsky}%
\affil[1]{McGill University}%
\affil[2]{University of Ottawa Department of Pediatrics}%
\affil[3]{McGill University Faculty of Medicine}%
\affil[4]{Montreal Children's Hospital, McGill University}%
\affil[5]{McGill University Health Centre}%
\affil[6]{McGill Univ}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
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\selectlanguage{english}
\begin{abstract}
Background: Lung ultrasound (LUS) has been shown to be an effective tool
to rapidly diagnose certain causes of pediatric respiratory distress in
the emergency department. However, very little is known about LUS
findings in pediatric asthma outside of acute exacerbations. Objectives:
The primary objective of this study was to characterize LUS findings in
a cohort of pediatric patients with a definitive diagnosis of asthma,
outside of an asthma exacerbation. Methods: Eligible patients, aged 6 to
17 years old and diagnosed with asthma, underwent LUS during an
outpatient visit. LUS was conducted using a six-zone scanning protocol.
A positive LUS was defined by one or more of the following: [?]3 B-lines
per intercostal space, pulmonary consolidation and/or pleural anomaly.
Images were interpreted by an expert sonographer blinded to patient
clinical characteristics. Results: 52 patients were included. 10/52
patients had a positive LUS (19.2\%, 95CI 8.3-30.1\%). Of those with
positive LUS findings, 8 had B lines, 7 had consolidations
\textless{}1cm, 1 had a pleural line abnormality and 1 had a
consolidation \textgreater{}1cm. Positive findings were seen in the
right anterior and lateral zones in 60\% of participants and were
limited to 1-2 intercostal spaces within one lung zone in 100\% of
participants. Conclusion: To our knowledge, this is the first report of
LUS findings in outpatient pediatric asthma. Positive LUS findings in
asthmatic children can be seen outside of acute exacerbations. Such
findings need to be taken into consideration when using LUS for the
acute evaluation of a pediatric patient with asthma.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Asthma represents one of the most common chronic conditions of
childhood\textsuperscript{1-4}. It is a leading cause for both pediatric
emergency department (PED) visits and hospital admissions amongst
children. Despite all of the investigational tools available to
physicians, it can sometimes be difficult to clinically discriminate
acute asthma from other diagnoses, including pulmonary infection, lobar
atelectasis and pneumothorax. Thus, the diagnosis of asthma often relies
on clinical features found through acquiring a thorough medical history,
and conducting a physical examination\textsuperscript{5,6}. Lung
ultrasound (LUS) has emerged as a rapid, bedside method of investigating
respiratory distress\textsuperscript{7}. It has proven to be both
sensitive and specific in diagnosing common pediatric respiratory
pathologies such as pneumonia, pneumothorax, pulmonary effusion and
neonatal lung diseases\textsuperscript{8-13}. Lung ultrasound has also
been compared to extent of parenchymal changes on CT scans in the
pediatric population and to extent of lung disease in different
pathologies for which lung ultrasound scoring systems have been
developed\textsuperscript{12,14-18}.

Previous studies have looked at LUS in pediatric patients with asthma
when presenting to the PED in respiratory
distress\textsuperscript{19,20}. A study by our group found that 45\% of
children presenting with an acute asthma exacerbation had a positive
LUS\textsuperscript{20}. The cause of these findings is uncertain. It
was hypothesized these findings were related to possible concomitant
respiratory infections, since viral upper respiratory tract infection is
the most common cause of asthma exacerbation in pediatric
patients\textsuperscript{21}. However, a more in-depth understanding of
the LUS findings in children with asthma is required for its routine
application in the acute PED setting.

The primary objective of this study was to characterize LUS findings in
a cohort of pediatric patients with a definitive diagnosis of asthma
(confirmed by spirometry or methacholine challenge test (MCT)) who were
not experiencing an asthma exacerbation and were at their baseline state
of health. The secondary objective was to compare the clinical
characteristics of participants with positive LUS to those with negative
LUS, in order to identify potential predictors of abnormal LUS findings.

\textbf{Method}

This prospective, cross-sectional study was conducted from December 2017
to June 2019 in the pediatric respiratory clinic of the McGill
University Health Centre. Approval for this study was granted by the
hospital's Institutional Research Ethics Board (Study 2018-3907).
Eligible patients were prospectively recruited in the pediatric
respirology clinic when a study sonographer was available. Written
informed assent and consent were obtained from participants and their
guardians.

The sample size was calculated on the basis of the previous study of
children presenting to the emergency room for an acute asthma
exacerbation, where approximately 20\% of the patients above 6 years of
age had a positive lung ultrasound\textsuperscript{20}. Assuming a
similar rate of lung ultrasound findings in our cohort and defining a
precision of \selectlanguage{ngerman}±10\% as clinically meaningful, a sample size of 52
patients would provide 90\% confidence that the true rate is within
these precision limits.

Patients were approached if they were 6 to 17 years old, and either
known asthmatics presenting for a routine visit with spirometry or
suspected asthmatics presenting for confirmatory methacholine challenge
test (MCT) in the pulmonary function lab. Patients were recruited if
they had a diagnosis of asthma with a positive spirometry or MCT result
consistent with a diagnosis of asthma. The reference values for
spirometry were obtained from the global lung function
initiative\textsuperscript{22}. A positive spirometry result was defined
as an FEV\textsubscript{1} \textless{}80\% predicted as well as an
FEV\textsubscript{1}/FVC \textless{}85 and 12\% increase in
FEV\textsubscript{1} after administration of a bronchodilator. A
positive MCT result was defined as PC20 less than 8mg/ml, where PC20
represents the provocative concentration that resulted in a 20\%
decrease in FEV\textsubscript{1}\textsuperscript{17,23}. We excluded
patients with history of viral illness in the previous 4 weeks.
Eligibility was determined through a combination of administered
questionnaires and review of the electronic medical record. At
enrollment, all participants and parents completed a pre-test
questionnaire (Appendix A) to record overall respiratory health and
medication compliance, the ISAAC Asthma Core Questionnaire, and the
Asthma Control Questionnaire.

Before the start of the study, all sonographers (AD, NM, FG) received
formal LUS training from an expert sonographer (ASD). An introductory
course on LUS was given by the latter followed by 5 proctored
ultrasounds. The principal investigator (ASD) is certified as an
independent practitioner by the Canadian Emergency Ultrasound Society
and has more than 10 years of experience with point of care ultrasound.

Using the z.one ultra ultrasound and the L14-3 linear transducer
(Mindray, Zonare Medical System, Mahwa, NJ), each LUS was completed by
one of three study sonographers. A six-zone scanning protocol was
performed, comparable to that described by Copetti and
Cattarossi\textsuperscript{24}. Settings included a depth of 6--8 cm at
a fundamental frequency (i.e., tissue harmonic imaging turned off) of 12
MHz. Ultrasound gel was layered on the probe and placed in a
longitudinal manner over 6 zones (right and left anterior, mid-axillary
and posterior chest zones). Six-second video clips were taken in each of
the six zones. The images were reviewed and interpreted by the expert
sonographer (ASD) who was blinded to all participant clinical
information.

The LUS findings were recorded as present or absent for each of the
following abnormal sonographic findings in each of the 6 lung zones, as
defined by the 2012 international evidence-based recommendations for
point-of-care ultrasound (POCUS)\textsuperscript{25}: lung slide,
multiple B lines, consolidation (defined as large if \selectlanguage{english}[?]1cm or small if
\textless{}1cm), pleural line abnormality and pleural effusion. A
negative lung ultrasound was defined by the absence of any of these
abnormal findings, the presence of normal lung sliding and a normal
A-line pattern in each zone. Asthma control was assessed via the Asthma
Control Questionnaire (ACQ). We defined asthma as being poorly
controlled if the ACQ score was \textgreater{}1.5\textsuperscript{26}.
We used the ISAAC Core Questionnaire to determine whether asthma was
more likely to be severe\textsuperscript{27}. The score is considered
positive if patients had \textgreater{}4 attacks of wheezing, or
\textgreater{}1 night per week sleep disturbance from wheeze or wheeze
affecting speech in the past 12 months. This definition is based on
previous ISAAC analyses showing a combination of these features
correlated more closely with asthma mortality and hospital
admissions\textsuperscript{28}.

A post-hoc analysis was done on positive lung ultrasounds to quantify
abnormalities through a scoring system that we derived derived from
previous studies looking at respiratory pathology and extent of LUS
findings\textsuperscript{14,15,29}. This was done using the LUS
quantitative scoring system, (E-Appendix B). With a score of 0-2 for
each of the 6 lung zones (maximum score 12).

\textbf{Data analysis}

Descriptive statistics were calculated for continuous and categorical
variables, as medians with interquartile ranges and frequencies,
respectively. We assessed associations between LUS results and patient
characteristics (see Table 1) using univariate analysis (T-test for
continuous variables and Fisher's exact test for binary variables).
Because some of the participants were seen at the clinic for an MCT in
order to test for possible asthma, we felt they may have different
characteristics compared to patients who were seen in follow up for
their asthma control. Thus, we carried out a sub-analysis in both
groups, those known to be asthmatic and those who came for an MCT to
test for asthma.

P-values \textless{}0.05 were considered significant. Data were analyzed
with SPSS statistics (version 23; IBM, Armonk, NY).

\emph{Results}

76 patients were approached to participate in the study; 7 patients did
not complete the study due to non-cooperation with the LUS examination
(n=3) or poor LUS image quality (n=4). A total of 52 participants were
included in the final analysis (Figure 1). Clinical characteristics of
those who completed the study are presented in Table 1. The majority of
patients were male (66\%) with a median age of 11 years (IQR 8, 14).
Thirty-three (63\%) patients were diagnosed with asthma via positive
MCT, and the remainder had a positive spirometry diagnoses. A large
portion (42\%) of patients had asthma that was categorized as severe
following the ISAAC score, and 16\% had poorly controlled asthma on ACQ
questionnaires.

Ten of the 52 patients had a positive LUS (19.2\%, {[}95CI
8.3\%-30.1\%{]}). Of the patients with a positive LUS, 8 had \selectlanguage{english}[?]3 B lines
in an intercostal space, 7 had small subpleural consolidations
(\textless{}1cm), 1 had a larger consolidation (\textgreater{}1cm) and 1
had a pleural line abnormality (Table 2), (Figure 2). All the findings
were isolated within one to two intercostal spaces in all the
participants. There was a predilection for abnormalities to be in the
right side, primarily on the lateral and anterior LUS zones (6/10
positive LUS), (Figure 3).

For the 10 patients with a positive LUS, their median
FEV\textsubscript{1} score on the day of recruitment was 100\%
predicted, while 4 had severe asthma per the ISAAC definition.
Univariate analysis was performed to look at LUS positivity and the
relationship with various clinical asthma symptoms (Table 1), however
there were no significant associations. LUS positivity did not show an
association with asthma severity per the ISAAC criteria (\emph{p} =
0.579) or poorly controlled asthma per ACT score (\emph{p =} 0.557).
Further analysis looking at patients with reported wheeze in the past
week (4/10, \emph{p =} 0\emph{.} 478) or recent SABA use (8/10, \emph{p
=} 0.165) did not show an association with LUS either.

A subanalysis was carried out in participants who were already followed
at the clinic for asthma control and those who had a positive MCT result
on the day of the visit for asthma diagnosis. The results are shown in
Table 3. There were no significant associations found in the subanalysis
between having a positive LUS in each individual group and the different
variables. This analysis was only exploratory as it was not powered
appropriately. When comparing the two groups, there is a higher rate of
positive LUS in the known asthma group compared to those who presented
for a confirmatory MCT (6/19 vs 4/33). Analysis to look at different
variables between the two groups found that there was a significant
difference in the number of patients with lower FEV\textsubscript{1} (p
0.012), FEV\textsubscript{1}/FVC (p\textless{}0.001) and the use of
ICS/LABA (0.004) for maintenance therapy in the known asthmatic group
compared to patients who presented for an MCT to diagnose asthma.

Using the LUS quantitative scoring system, (E-Appendix B), 9/10 of the
patients had a score of 1, and only one patient had a score of 2
(patient with a \textgreater{}1cm consolidation).

\textbf{Discussion}

This is the first study characterizing LUS findings of pediatric asthma
patients at their baseline state of health. Our study showed that almost
20\% of children diagnosed with asthma had positive LUS findings when
well. The most frequent findings seen were small consolidations and
localized B-lines. These findings may be present at baseline and are not
to be attributed to, for example, a co-existing pneumonia or viral upper
respiratory tract infection.

An important question to address is how our described findings may
impact the evaluation of an asthmatic patient with LUS. The findings we
have identified (mostly localized B-Lines in one intercostal space and
small consolidations less than 1cm) are similar to what was described in
previous studies, commonly seen in patients with mild bronchiolitis,
atelectasis and viral pneumonia\textsuperscript{12,18,30}. Therefore,
using LUS to try and differentiate these conditions from baseline asthma
findings is not possible.

The findings on LUS in our cohort of patients were objectively small and
often localized to one lung zone, effecting no more than 2 rib spaces.
LUS scores were also quite low (signifying mild changes) in most of the
positive LUS cases. Thus, more severe LUS findings including
consolidations \textgreater{}1cm and B-lines involving more than 2
intercostal spaces or effecting more than one lung zone, are atypical
for a pediatric asthmatic patient at baseline and should be considered
clinically significant, alerting the clinician to other possible lung
parenchyma changes outside of what is typically seen in pediatric
asthmatic patients.

Positive LUS findings in this study were more frequently observed on the
right anterior and lateral lung zones.(Figure 3). These findings may
correspond to the right middle lobe, where atelectasis is commonly seen
in asthmatic patients\textsuperscript{31}. We hypothesizese that these
LUS findings are from sub-segmental mucus plugging and atelectasis with
the known hypersecretory issues in asthma\textsuperscript{30,32-34}

As a secondary objective, we explored the association of having severe
or poorly controlled asthma with a positive LUS. The majority of our
population had relatively mild asthma with a median of 96\%, and only
17\% had an ACQ score that is considered elevated. There was no
significant association between having positive LUS and poor asthma
control, high ISAAC score, or FEV1 value. However, there was a trend
toward more frequent LUS abnormalities in patients already followed in
the respiratory clinic for asthma. These previously known asthmatics had
significantly lower spirometry FEV1\% predicted and were more likely to
be on maintenance therapy which included inhaled corticosteroid combined
and long-acting beta agonist than those who presented to the clinic for
asthma diagnosis with MCT (Table 3). Our LUS correlations with asthma
control or severity are only exploratory and further research should be
done explore these possible associations.

There are some limitations to this study. First, the sample size was
relatively small (yet adequately powered), and our recruited asthmatics
had overall mild disease. A larger and more severe asthma population may
detect significant relationships between different clinical variables
and likelihood of having a positive LUS. Second, sonographers attempted
to perform LUS before spirometry maneuvers, but some known asthmatics
had their scans completed after spirometry testing, which routinely
included the administration of Ventolin. This was not the case for any
of the MCT patients, as the scans were always done before the test. Both
spirometry maneuvers and beta agonists may have altered findings on LUS.
Three different sonographers performed the LUS evaluations, and
ultrasound images can often be influenced by operator specific
practices. However, the blinded interpretation by a single expert makes
this operator bias less of an issue, and prior studies show good
interrater reliability between sonographers and
interpreters\textsuperscript{19,20}. Four the ISAAC score was used in
our study as a surrogate measure to asthma severity, however it is not
in itself a true marker of severe asthma; the score was only used as a
proxy in an attempt to explore the association of LUS findings with more
severe asthma. Finally, reliance upon parental and patient
questionnaires to gauge asthma severity and control may have introduced
recall bias, as asthma symptoms and severity are often under-recognized
by patients and parents.

\textbf{Conclusion}

In conclusion, up to 20\% of patients with asthma may have positive LUS
findings when not experiencing an acute asthma exacerbation. Most of
these findings were on the right lateral or right anterior zone (60\%),
mild in severity, and limited to 1-2 intercostal spaces within one lung
zone. Such findings need to be taken into consideration when using LUS
for the evaluation of a pediatric patient with an acute asthma
exacerbation.

\textbf{Conflict of interests}

None.

\textbf{Author contribution statement}

ASD, AD, LL, AS and DZ conceived the study. ASD, NM and AD supervised
the conduct of the study and data collection. AD, NM and FG performed
LUS. The data, including quality control was managed by GA, FG, NM and
ASD. ER provided statistical advice. NM, FG and ASD analyzed the data.
NM drafted the manuscript.

\textbf{Acknowledgement}

The authors acknowledge Gregory Anderson, Raphael Freitas and Joanne
Ramil for their help and dedication to the project, as well as Emmanouil
Rampanakis for his support in statistical analysis.

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