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\begin{document}

\title{Reactance Inversion in persistent asthma: artifact or airway narrowing
marker?}



\author[1]{Alberto Vidal Grell}%
\author[2]{Ramiro González Vera}%
\author[3]{Jose Castro-Rodriguez}%
\author[1]{Alejandra Méndez Yarur}%
\affil[1]{Clinica MEDS}%
\affil[2]{Clinica Las Condes}%
\affil[3]{Pontificia Universidad Catolica de Chile Escuela de Medicina}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\textbf{Reactance Inversion in persistent asthma: artifact or airway
narrowing marker?}

\selectlanguage{ngerman}\textbf{Ramiro González Vera MD\textsuperscript{1}, Alberto Vidal Grell
MD\textsuperscript{2}, Jose A. Castro-Rodríguez MD,
PhD\textsuperscript{3}, Alejandra Méndez Yarur RT\textsuperscript{2}}

\begin{enumerate}
\tightlist
\item
  Department of Pediatric Pulmonology, Clínica Las Condes, Santiago
  Chile
\item
  Department of Pediatric Pulmonology Clínica MEDS, Santiago Chile
\item
  Department of Pediatric Pulmonology, School of Medicine, Pontificia
  Universidad Católica de Chile, Santiago, Chile
\end{enumerate}

To the Editor,

Recently Tsukahara et al. published a study of impulse oscillometry
(IOS) in a cohort of 22 school\selectlanguage{english}-age former preterm children at high risk
of bronchopulmonary dysplasia in which reactance inversion (RI) was
found in 7 (32\%) children. And reported significant differences between
inspiratory and expiratory resistance (R) and reactance (X) parameters
in children with RI compared to those without RI. They postulated that
RI may have a possible pathophysiological cause as tracheobronchomalacia
or since it occurs at low oscillatory frequency it may be an artifactual
component produced by high respiratory rates (1).

However, R and X are derived exclusively from the impulse test signal.
If the technical standards for acceptability and reproducibility are
met, ventilatory rate should not influence these parameters. Tsukahara
et al. (1) showed only R and X at 10 Hz, but values at 5Hz and other IOS
parameters reflecting peripheral airway function like reactance area
(AX), resonance frequency (Fres), difference between respiratory R at 5
and 20 Hz (R5-R20), spirometry, and bronchodilator response (BDR) were
not included. Therefore, information on lung function in these patients
is limited. Notice that the R10 had highest values in the RI group,
suggesting more obstructive compromise.

Our group, previously described that RI in children with moderate to
severe persistent asthma (n=507, aged 3-18 years) was more frequent in
younger children with greater peripheral airway obstruction. In those
with RI, the X5 value was highest than expected, the correction X5c,
done automatically by Sentry Suite software, correlated better with
other IOS parameters reflecting peripheral small airways disfunction
(2).

Therefore, to expand these findings, we performed a pilot study on RI in
children with persistent moderate and severe asthma. Our hypothesis is
that RI occurs mostly in children with narrow or prone to collapse
airway as occurs in asthma and especially if they were premature or with
low birth weight. The aim of this study was to compare pulmonary
function among asthmatic children with and without RI, and between those
in whom the RI disappeared versus persisted after the bronchodilator
test.

\textbf{Methods}

In the present study we enrolled children with persistent moderate to
severe asthma who attended at Clinica Las Condes, Santiago and had
pulmonary function tests: oscillometry followed by spirometry performed
with a Vyaire Vyntus model v\selectlanguage{english}-176430 spirometer-oscillometer and
according to ATS/ERS guidelines (3, 4). A systematic medical history on
birth weight, gestational age, history of of maternal asthma, and pre
and post-natal maternal smoking was obtained. The differences between
groups were calculated with the ANOVA test and the post hoc analysis
with the Tukey test. The study was approved by the Ethics Committee of
the institution; and informed consent was applied to the
parents/guardians, and assent to the patients.

\textbf{Results}

We enrolled 57 patients with a mean age of 8.4 years, 59.6\% were male.
We identified 3 groups of children according with the presence of RI.
Group 1 corresponded to 17 (29.8\%) patients without RI, group 2 to 17
(29.8\%) children in whom RI did not persist after the bronchodilator
test, and group 3 to 23 (40.4\%) children who had RI before and after
the bronchodilator test. The demographic characteristics of the three
groups were shown in Table 1. Groups 2 and 3 had lower birth weight and
gestational age than group 1; although it was significantly between
group 2 vs. 1. No significant differences were found in history of
maternal asthma, prenatal or postnatal maternal smoking among groups.
Lung function measured by spirometry and IOS was more altered in groups
2 and 3 than in the group 1. VEF1 and FEF25-75 were significantly lower
in groups 2 and 3 than in group 1, and FVC was lower in the group 3 vs
1. In the IOS, R5, AX, Fres and DR5-R20 were significantly lower in the
group 1 vs. 3. Also, R5 and DR5-R20 were lower in the group 2 vs. 3. In
contrast, X5c was significantly higher in the groups 1 and 2 vs. 3, and
in the group 2 vs. 3. Finally, RBD in X5c and D5-20 were significant
lower in the group 1 vs. 2, and in group 2 vs 3 (Table 2).

\textbf{Discussion}

In this moderate to severe asthmatic schoolchildren, RI was found in a
high proportion of the sample (70\%). This percentage is similar that we
found in a previously published study with high number of participants
(2). Results of both studies are concordant and confirm that RI is
frequent in schoolchildren with moderate to severe asthma and represents
a real peripheral airway condition and not a technical artefact.

Interestingly, there were asthmatic (group 2) in whom RI disappeared
after the bronchodilator test, indicating that in these cases it is due
to reversible bronchial obstruction; while in others asthmatic (40\% of
the patients) the RI persisted after the bronchodilator test (group 3).
These last group of patients could have a compromised peripheral airway
function for different causes, such as increased inflammation,
remodeling, or diminished lung function present from birth.

There were also another differences in lung function between these three
groups. Patients in group 1 with no prematurity or low birth weight
record, had better values in spirometry and in IOS parameters reflecting
the peripheral airway function even in X5c. In contrast, lung function
was lower in groups 2 and 3. Resistance was increased and the parameters
reflecting peripheral airway obstruction were higher in children from
groups 2 and 3 than in group 1. Group 3 had highest total airway
resistance (R5) and greater small airway compromise (X5c and DR5-R20)
than group 2. Besides, group 3 had a lower RBD average in X5c and
DR5-R20 than in group 2, which could indicate that group 3 corresponds
to asthmatics with a narrow and/or a more collapsible airway associated
with prematurity that it persisted until school age.

It has been described that the increase in expiratory resistance and
reactance compared to inspiratory may be useful to differentiate
asthmatic children from healthy ones or premature children from those
born at term and reflects the narrowing of the airways during expiration
(5,6). In real life, both conditions may or may not coexist, and in this
situation the evaluation of the clinical history, and spirometry becomes
important. In the study by Tsukahara et al. (1), the clinical history
was not reported, nor spirometry was performed; and an alternative
explanation for their finding could be that children with RI were also
asthmatic.

Finally, it is important to highlight that in the lung, not only a
series resonant structure, but a parallel resonant structure is
incorporated. The parallel resonant effect exists in every subject. In
children with obstructive disease, the accessed lung chamber becomes so
small that a superimposed parallel resonance is seen. The greater the
degree of obstruction, the smaller the pulmonary chamber accessed and
the higher the specific parallel resonance frequency. At low frequencies
(5 Hz), this will cause the RI phenomenon. In young patients with
moderate to severe asthma, obstruction and small peripheral airway may
explain why RI occurs. In these cases, the X5 reactance is no longer
representative; and the use of ''X5 c'' would be the most indicated (2).
This was also seen in the present study where the basal alterations and
bronchodilator response were significant with X5c and not with X5Hz.

\textbf{Conclusion}

RI is a frequent phenomenon exist in moderate to severe persistent
asthma children with a history of prematurity or low birth weight, and
it is an indicator of alterations in lung function, especially in the
parameters that evaluate the function of the peripheral airway. In
asthmatics with RI by IOS, it was possible to identify a subgroup with
greater peripheral airway obstruction and less bronchodilator response
than the group in which the RI disappeared after the bronchodilator
test. More studies should be done to confirm these findings.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Tsukahara K, Scully T, McDonough J, Boas H, DeMauro SB, Ren CL, Allen
  J. Reactance inversion in a cohort of former preterms: Physiology or
  artifact? Pediatr Pulmonol. 2023. doi: 10.1002/ppul.26553. Epub ahead
  of print. PMID: 37341587.
\item
  Gonzalez Vera R, Vidal Grell A, Yarur AM, Meneses CO, Castro-Rodriguez
  JA. ''Reactance inversion'' at low frequencies during lung function
  measurement by impulse oscillometry in children with persistent
  asthma. J Asthma. 2022;59(8):1597-1603.
  doi:10.1080/02770903.2021.1955376
\item
  King GG, Bates J, Berger KI, Calverley P, de Melo PL, Dellaca RL,
  Farre R, Hall GL, Ioan I, Irvin CG et al. Technical standards for
  respiratory oscillometry. Eur Respir J. 2020;55(2):1900753.
  doi:10.1183/ 13993003.00753-2019
\item
  Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG,
  Hall GL, Hallstrand TS, Kaminsky DA, McCarthy K, McCormack MC et al.
  Standardization of spirometry 2019 update. An official American
  Thoracic Society and European Respiratory Society technical statement.
  Am J Respir Crit Care Med. 2019;200(8):e70\selectlanguage{english}-e88.
  doi:10.1164/rccm.201908-1590ST
\item
  Sol IS, Kim YH, Kim S, Kim JD, Choi SH, Kim KW, Sohn MH. Assessment of
  within-breath impulse oscillometry parameters in children with asthma.
  Pediatr Pulmonol. 2019 ;54(2):117-124. doi: 10.1002/ppul.24201
\item
  Accorsi BF, Friedrich FO, Corso AL, Rosa JPD, Jones MH. Intra-breath
  oscillometry for the evaluation of lung function in children and
  adolescents with a history of preterm birth. J Bras Pneumol. 2022
  ;48(1):e20210290. doi: 10.36416/1806-3756/e20210290.
\end{enumerate}

\textbf{Hosted file}

\verb`Table 2 Reactance inversion in persistent asthma artifact or airway narrowing marker.docx`  available at \url{https://authorea.com/users/482667/articles/659639-reactance-inversion-in-persistent-asthma-artifact-or-airway-narrowing-marker}

\textbf{Hosted file}

\verb`Tables 1 Reactance Inversion in persistent asthma artifact or airway narrowing marker.docx`  available at \url{https://authorea.com/users/482667/articles/659639-reactance-inversion-in-persistent-asthma-artifact-or-airway-narrowing-marker}

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