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\begin{document}

\title{ASSOCIATION OF ADENOTONSILLECTOMY WITH WHEEZING EPISODES IN CHILDHOOD: A
SECONDARY ANALYSIS OF THE CHILDHOOD ADENOTONSILLECTOMY TRIAL}



\author[1]{Jose A.   Castro Rodriguez }%
\author[1]{Andrea Beckhaus}%
\author[1]{Fiorella Biancardi}%
\author[2]{Ignacio Tapia}%
\affil[1]{Pontificia Universidad Catolica de Chile Escuela de Medicina}%
\affil[2]{University of Pennsylvania Perelman School of Medicine}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Background}: Observational studies suggest that asthma/wheezing
improve after adenotonsillectomy (AT). However, there is a paucity of
RCT specifically studying the effects of AT in asthma/wheezing.
Therefore, we conducted a post-hoc analysis of the Childhood
Adenotonsillectomy Trial, the largest RCT of AT in children with
obstructive sleep apnea (OSA) to test the hypothesis that AT would
result in fewer wheezing episodes. \textbf{Methods}: In the CHAT study,
464 children with OSA, aged 5 to 9 years, were randomized to early AT
(n=226) or watchful waiting with supportive care (WWSC) (n= 227). For
this post-hoc analysis children were categorized as having ``any
wheezing'' vs. ``no wheezing'' at baseline and at 7 months of follow-up.
A multivariate analysis was conducted to evaluate the association
between ``any wheezing'' at follow-up and treatment group after
controlling for several potential confounders. \textbf{Results}:
Children in the ``any wheezing'' group were predominantly black, had
more allergic rhinitis, eczema, second-hand smoke exposure, more
siblings and siblings with asthma, lower maternal education and family
income than those in the ``no wheezing group''. At baseline, wheezing
characteristics were similar between AT and WWSC arms. At follow-up (at
7 months of the intervention) those in the AT arm had significatively
less wheezing than those in the WWSC (22.4\% vs. 43.8\%, p=0.00001).
However, the multivariate analysis of ``any wheezing'' vs. ``no
wheezing'' at follow-up showed that the treatment arm was not associated
with wheezing. \textbf{Conclusion:} This study demonstrated that AT has
not effect on wheezing at 7 months of follow-up.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Adenotonsillectomy (AT) is one of the most common surgical procedures
performed in children. The most frequent indications for AT are
obstructive sleep apnea (OSA), refractory or recurrent sinusitis or
middle ear infections, and recurrent infection of the tonsils and/or
adenoids. Since birth to adolescence, several mucosal immune systems
develop in the upper and lower respiratory tract. The
nasopharyngeal-associated lymphoid tissues comprise the nasopharyngeal
adenoidal tissue nasopharyngeal, tubal, palatine, and lingual tonsils.
Hypertrophy or frequent episodes of inflammation can occur within
adenotonsillar tissues due to continuous exposure to antigens, such as
micro-organisms and allergens {[}1,2{]}.

Asthma is a common chronic disease in children and its association with
sleep-disordered breathing (SDB) has been observed by our group and
others {[}3-5{]}. Furthermore, SDB may affect asthma control {[}6{]}.
Although, causality has not been proven {[}4{]}.

Published evidence regarding the effect of AT on asthma in children is
controversial. Some observational studies have demonstrated that AT has
a positive effect on childhood asthma by reducing the effect of
stressors on the lower airway, leading to decreased inflammation and
improved asthma control {[}7-9{]}. In most of these studies,
adenotonsillar hypertrophy, and symptoms of sleep-disordered breathing,
were the commonest indications for AT. In contrast, one cohort study
showed that early-life adenoidectomy due to recurrent otitis media or
otitis media with effusion, may contribute to the subsequent development
of asthma in children {[}10{]}, and a recent South Korean cohort study
showed that the adjusted asthma hazard ratio was 2.25 in the AT vs.
non-AT groups {[}11{]}. However, the only randomized clinical trial
(RCT) that has analyzed the role of adenoidectomy in the development of
atopy and respiratory function changes characteristic of asthma in young
children, showed that adenoidectomy did not promote the occurrence of
asthma or allergy {[}12{]}. Since tonsils have an important function in
the differentiation of B lymphocytes to antibody-producing plasma cells
and were not removed in that RCT; results should be interpreted with
caution.

Therefore, our objective was to conduct a post-hoc analysis of CHAT
{[}13{]}, the largest RCT of AT in children with OSA to test the
hypothesis that AT would result in fewer wheezing episodes in children
randomized to AT vs watchful waiting.

\textbf{METHODS}

The Childhood Adenotonsillectomy Trial (CHAT) was a single-blind,
randomized, controlled trial at seven academic sleep centers
(ClinicalTrials.gov number, NCT00560859). Methodologic details have been
published previously {[}13{]}. Briefly, eligible children aged 5 to 9
years, with OSA syndrome (OSAS) without prolonged oxyhemoglobin
desaturation considered suitable candidates for AT were enrolled. OSAS
was defined as an obstructive apnea--hypopnea index (AHI) score of 2 or
more events per hour or an obstructive apnea index (OAI) score of 1 or
more events per hour. Children with an AHI score of more than 30 events
per hour, an OAI score of more than 20 events per hour, arterial
oxyhemoglobin saturation of less than 90\% for 2\% or more of the total
sleep time were not eligible, owing to the severity of the
polysomnographic findings. Exclusion criteria included recurrent
tonsillitis, a z score based on the body-mass index (the weight in
kilograms divided by the square of the height in meters) of 3 or more,
and medication for attention deficit-- hyperactivity disorder. Children
were randomly assigned to two arms of treatment: early AT within 4 weeks
after randomization or a strategy of watchful waiting with supportive
care (WWSC).

The primary outcome of this post-hoc analysis was wheezing at 7-months
of follow-up after AT. Wheezing was divided in two groups: ``no
wheezing'' and ``any wheezing''. The latter included rarely (less than
once a week), sometimes (1 to 2 times per week), frequently (3 to 4
times per week) and always or almost always (5 to 7 times per week).
``Any wheezing'' was further divided according to the severity of
wheezing in three groups: frequent wheezing (sometimes, frequent, and
always), rarely wheezing, and no wheezing.

\textbf{Statistical analysis:}

Bivariate analyses comparing baseline demographic and clinical
characteristics of children in the ``no wheezing'' vs. ``any wheezing''
groups were performed using Fisher's exact test or t tests as
appropriate. Also, bivariate analysis for wheezing characteristics at
baseline and at follow-up between the two treatment arms were conducted.
Multivariable analyses were then performed using logistic regression to
evaluate the association between wheezing characteristics at follow-up
and arm of treatment (AT vs. WWSC), conservatively adjusting for
variables with a p value \textless{} 0.10 in the bivariate analysis:
gender, race, rhinitis, eczema, second hand-smoke exposure, premature,
number of siblings, sibling with asthma, maternal level of education and
family income. In addition, a priori selected potential confounder
factors, such as age, BMI z-score, AHI, and parental asthma were also
included. These were retained in the final model if their coefficients
were significant, altered the significance of the wheezing
characteristics, or contributed significantly to the best model fit. A p
\textless{} .05 was considered statistically significant. The R version
4.1.3 \selectlanguage{ngerman}® software was used (www.r-project.org).

\textbf{RESULTS}

In the CHAT study, 464 children, aged 5 to 9 years, with the OSA
syndrome were randomized to AT (n=226) or WWSC (n= 227). Information for
wheezing characteristics at baseline was available for 216 children in
the AT and 216 in the WWSC. Baseline characteristics per study group
(any wheezing vs no wheezing) are shown on Table 1. Children in the
``any wheezing'' group were predominantly black and had more allergic
rhinitis, eczema, second-hand smoke exposure, more siblings and sibling
with asthma than the children in the no wheezing group. In contrast the
any wheezing group had lower maternal education and family income than
the no wheezing group. Nearly half the participants in both groups were
overweight or obese, and the AHI was similar between groups.

At baseline, wheezing characteristics were similar between AT and WWSC
(Table 2a). However, at the 7-month follow-up the AT arm had
significantly less wheezing (Table 2b). Upon dichotomization of the
wheezing variable between any vs. no wheezing, no difference by
treatment arms was present at baseline. However, children in the AT arm
had significatively less ``any wheezing'' than those in the WWSC arm
(22.4\% vs. 43.8\%, p=0.00001) at follow-up, (Figure 1). Results were
similar when the three different severities of wheezing groups were
analyzed according to the treatment arms (data not shown).

Importantly, the multivariate analysis of ``any wheezing'' vs. ``no
wheezing'' at follow-up as a dependent variable, showed that treatment
arm was not associated with `any wheezing''. Only paternal asthma.
maternal education and BMI z-score were significantly associated with
``any wheezing'' (Table 3). Using the three groups of wheezing
severities as dependent variable, the results were similar (data not
shown).

\textbf{DISCUSION}

This secondary analysis of the CHAT data aimed at investigating the
effect of AT on recurrent wheezing in children with OSAS at the 7-month
follow up visit. Results showed that recurrent wheezing was no different
in children randomized to AT compared to those randomized to WWSC after
controlling for the following confounders: age, gender, race, parents
and siblings with asthma, exposure tobacco, siblings, AHI, BMI z-score,
maternal education, and family income.

The results of the present study, which is the first RCT of AT, were
similar to an adenoidectomy RCT previously conducted by Mattila et al.
in Finland {[}12{]}. They analyzed 166 children (aged 12--48 months)
with recurrent or persistent otitis media who were followed for 3 years
after randomization to undergo insertion of tympanostomy tubes with or
without adenoidectomy and showed that adenoidectomy did not influence
baseline lung function, exercise-induced bronchoconstriction, exhaled
nitric oxide concentration, the development of positive skin prick
tests, or physician-diagnosed asthma {[}12{]}.

Those results were in contrast with several observational studies
performed in US. Saito et al. {[}7{]} found in 25 asthmatic children
that 88\% of them improved their symptoms and reduced or eliminated the
need for asthma medications after AT. Busino et al. {[}8{]} compared 93
children with asthma and 372 without asthma who underwent AT mainly for
OSA/adenotonsillar hypertrophy and showed that the Asthma Control Test
(ACT) scores significantly improved 12 months following AT. Levin et al.
{[}9{]} conducted a retrospective cohort analysis of 66 children with
asthma and 64 controls and showed 6 months after AT that improvement in
the ACT in 85\% of the asthmatic children. In a prospective cohort, 52
out of 92 children with poorly controlled asthma had OSA and after
1-year follow-up of 35 children who underwent AT due to OSA decreased
annual frequency of asthma exacerbation, rescue inhalers use, and asthma
symptoms compared to no changes in the group without OSA {[}14{]}. Also,
a large longitudinal cohort comparing asthma outcomes one year preceding
vs. one year following AT, showed that AT was associated with
significant reductions in asthma exacerbation, status and emergency
visits, hospitalization rate and asthma prescription, but no information
was available for race and obesity status {[}15{]}. Finally, a
systematic review suggested an overall reduction in asthma severity
following AT e.g., decline in the use of respiratory medications,
reduction in the frequency of asthma exacerbations, decrease in asthma
symptoms and in medication use and emergency department visits for
severe distress {[}16{]}. However, since several biases could affect
observational studies, we considered important to further analyze RCT
data. Both RCTs done in Finland {[}12{]} and CHAT showed no effect of
adenoidectomy or AT on asthma or wheezing, respectively.

This study has some limitations. First, the diagnosis of asthma was
assessed by questionnaires, and the available baseline and follow up
outcome were wheezing episodes. However, results did not change by
wheezing severity. Second, no pulmonary function tests, respiratory
medications use, decrease in asthma symptoms and emergency department
visits for severe distress were assessed and atopic markers were not
performed. Finally, follow up was limited to 7 months and since asthma
is a chronic condition, a larger follow up time may be required.
Nonetheless, CHAT is the largest AT RCT to date, most patients (more
than 90\%) completed the study, and the effect of AT on wheezing was
controlled for several potential confounders.

Conclusions. This post-hoc analysis of the largest AT RCT demonstrated
that AT has not effect on wheezing at 7 months of follow-up.

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\textbf{Hosted file}

\verb`Figure 1.docx`  available at \url{https://authorea.com/users/489715/articles/573330-association-of-adenotonsillectomy-with-wheezing-episodes-in-childhood-a-secondary-analysis-of-the-childhood-adenotonsillectomy-trial}

\textbf{Hosted file}

\verb`Tables 1,2,3.docx`  available at \url{https://authorea.com/users/489715/articles/573330-association-of-adenotonsillectomy-with-wheezing-episodes-in-childhood-a-secondary-analysis-of-the-childhood-adenotonsillectomy-trial}

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