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\begin{document}

\title{Pediatric asthma control during the COVID-19 pandemic: a systematic
review and meta-analysis}



\author[1]{Ze Yang}%
\author[1]{Xiang Wang}%
\author[1]{Xigang Wan}%
\author[1]{Menglei Wang}%
\author[1]{Zonghua Qiu}%
\author[1]{Jiali Chen}%
\author[1]{Manhao Shi}%
\author[1]{Shiyi Zhang}%
\author[1]{Yongliang Xia}%
\affil[1]{Zhejiang Chinese Medical University}%


\vspace{-1em}



  
  \date{May 29, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: During the current ongoing COVID-19 pandemic, studies had
reported that patients with asthma would experience increased
asthma-associated morbidity because of the respiratory virus SARS-CoV-2
infection, based on experience with other respiratory viral infections.
However, some studies suggested that there was no apparent increase in
asthma related morbidity in children with asthma, it is even possible
that due to reduced exposures due to confinement, such children may have
improved outcomes. In order to understand the impact of Covid-19 on
asthma control in children, we performed this systematic review and
meta-analysis. Methods: We searched PubMed, Embase, and Cochrane Library
to find literature from December 2019 to June 2021 related to Covid-19
and children's asthma control, among which results such as abstracts,
comments, letters, reviews and case reports were excluded. The level of
asthma control during the COVID-19 pandemic was synthesized and
discussed. Results: A total of 20456 subjects were included in 7
studies. Random effect model is used to account for the data. Compared
to the same period before the COVID-19 pandemic, asthma exacerbation,
asthma admission, emergency room visit reduced a lot. The outcome of use
of inhaled corticosteroids and Beta-2 agonists shows no significant
difference. Conclusion: Compared to the same period before the COVID-19
pandemic and the measures in response to it, the level of asthma control
has been significantly improved. We need to understand the exact factors
leading to these improvements and find methods to sustain it.%
\end{abstract}%



\sloppy


\textbf{Title Page}

\textbf{Title:} Pediatric asthma control during the COVID-19 pandemic: a
systematic review and meta-analysis

\textbf{Authors:} Ze Yang\textsuperscript{1^}, Xiang
Wang\textsuperscript{1^}, Xi-gang Wan\textsuperscript{1}, Meng-lei
Wang\textsuperscript{2}, Zong-hua Qiu\textsuperscript{1}, Jia-li
Chen\textsuperscript{1}, Man-hao Shi\textsuperscript{1}, Shi-yi
Zhang\textsuperscript{1}, Yong-liang Xia\textsuperscript{3*}

\textbf{Affiliations:}

\textsuperscript{1}The First School of Clinical Medicine, Zhejiang
Traditional Chinese Medical University, Hangzhou 310006, China

\textsuperscript{2}The Third School of Clinical Medicine, Zhejiang
Traditional Chinese Medical University, Hangzhou 310006, China

\textsuperscript{3}*Correspondence Author: Yong-liang Xia, The First
Affiliated Hospital of Zhejiang Chinese Medical University (Chen Yi's
inheritance studio of national famous and old Chinese medicine experts
of Zhejiang Provincial Hospital of Traditional Chinese Medicine),
Hangzhou, 310006, Zhejiang, China. Tel: +86 13186968775, Email:
xiayongliang1@sina.com

^:co-first authors.

\textbf{E-mail:} Ze Yang\emph{995651045@qq.com}

Xiang Wang \emph{1013047386@qq.com}

Xi-gang Wan \emph{2416459264@qq.com}

Meng-lei Wang \emph{854577335@qq.com}

Zong-hua Qiu \emph{839020278@qq.com}

Jia-li Chen \emph{1164820856@qq.com}

Man-hao Shi \emph{1170516314@qq.com}

Shi-yi Zhang \emph{2878904995@qq.com}

Yong-liang Xia\emph{xiayongliang1@sina.com}



\textbf{Abstract}

\textbf{Background:} During the current ongoing COVID-19 pandemic,
studies had reported that patients with asthma would experience
increased asthma-associated morbidity because of the respiratory virus
SARS-CoV-2 infection, based on experience with other respiratory viral
infections. However, some studies suggested that there was no apparent
increase in asthma related morbidity in children with asthma, it is even
possible that due to reduced exposures due to confinement, such children
may have improved outcomes. In order to understand the impact of
Covid-19 on asthma control in children, we performed this systematic
review and meta-analysis.

\textbf{Methods:} We searched PubMed, Embase, and Cochrane Library to
find literature from December 2019 to June 2021 related to Covid-19 and
children's asthma control, among which results such as abstracts,
comments, letters, reviews and case reports were excluded. The level of
asthma control during the COVID-19 pandemic was synthesized and
discussed.

\textbf{Results:} A total of 20456 subjects were included in 7 studies.
Random effect model is used to account for the data. Compared to the
same period before the COVID-19 pandemic, asthma exacerbation, asthma
admission, emergency room visit reduced a lot. The outcome of use of
inhaled corticosteroids and Beta-2 agonists shows no significant
difference.

\textbf{Conclusion:} Compared to the same period before the COVID-19
pandemic and the measures in response to it, the level of asthma control
has been significantly improved. We need to understand the exact factors
leading to these improvements and find methods to sustain it.

\textbf{Keywords:} COVID-19, asthma control, children, systematic review
and meta-analysis



\textbf{1 Introduction}

The novel coronavirus disease (COVID-19), which is associated with
significant morbidity and medical complications induced by SARS- CoV-2,
has rapidly spread sparking alarm worldwide.\textsuperscript{1,2} In
June 2020 WHO declared COVID-19 as global pandemic which has made many
countries to shut down their borders\textsuperscript{3}. Asthma has
become the most common chronic respiratory disease in
children\textsuperscript{4-6}. As is well known to all for many decades,
respiratory infections trigger asthma exacerbations\textsuperscript{7}.
Studies had reported that patients with asthma would experience
increased asthma-associated morbidity because of the respiratory virus
SARS-CoV-2 infection, based on experience with other respiratory viral
infections\textsuperscript{8,9}. However, some studies suggested that
there was no apparent increase in asthma related morbidity in children
with asthma\textsuperscript{10}, it is even possible that due to reduced
exposures due to confinement, such children may have improved
outcomes\textsuperscript{11}.

The main objective of this study was to identify how is the asthma in
children during the COVID-19 pandemic controlled compared with the time
before it.

\textbf{2 Materials and Methods}

\textbf{2.1 Data Source}

We searched PubMed, Embase, and Cochrane Library for the update articles
published from the inception of each database to Jun 1, 2021. when
duplicate publications were identified, we chose the most complete and
recent trial . Two investigators (Z.Y. and X.W.) independently retrieved
all the related studies in the databases and excluded duplicate
publications. The combined text and medical subject heading (MeSH) terms
were cross-searched using MeSH and free word as follows: (
Asthma{[}Mesh{]} OR allergic asthma{[}Title/Abstract{]} OR Bronchial
Asthma{[}Title/Abstract{]}) AND Control{[}Title/Abstract{]}) AND
(COVID-19{[}Mesh{]} OR COVID-19 Virus Disease{[}Title/Abstract{]} OR
COVID-19 Virus Infection{[}Title/Abstract{]} OR 2019-nCoV
Infection{[}Title/Abstract{]} OR Coronavirus
Disease-19{[}Title/Abstract{]} OR 2019 Novel Coronavirus
Disease{[}Title/Abstract{]} OR 2019-nCoV Disease{[}Title/Abstract{]} OR
SARS Coronavirus 2 Infection{[}Title/Abstract{]} OR SARS-CoV-2
Infection{[}Title/Abstract{]} OR (COVID-19 Pandemic{[}Title/Abstract{]})
AND (Child{[}Mesh{]} OR Children{[}Title/Abstract{]}). We also reviewed
abstracts and presentations from major conference proceedings up to Jun
1, 2021 to ensure that no additional studies were overlooked.

\textbf{2.2 Inclusion and Exclusion Criteria}

Our meta-analysis is reported in line with the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) Statement and had been
registered at International Prospective Register of Systematic Reviews
(number:CRD42021266458)\textsuperscript{12}. Studies that met the
following criteria were included: (1) cross-sectional studies; (2)
children and adolescents aged \textless{} 19 years; (3) the population
are diagnosed as asthma; (4) the background of the study is COVID-19
pandemic.

However, articles had incomplete or unidentified data were excluded, as
well as abstracts, reviews, case reports, letters and duplicate
publications.

\textbf{2.3 Quality Assessment and Data Extraction}

Two independent investigators (Z.Y. and X.W.) evaluated the quality of
all studies according to 11-item checklist that was recommended by the
Agency for Healthcare Research and Quality
(AHRQ)\textsuperscript{13}subjectively. ``0'' will be scored if it was
answered No or Unclear and ``1'' will be given to the answer Yes.
Quality of articles was assessed as follows: ``0--3'' means low quality,
4--7 means moderate quality, 8--11 means high quality. The following
information was extracted: first author, publication time, study design,
source of population, mean age or age range, the sample size and
outcomes.

\textbf{2.4 Statistical Analysis}

A random-effect model was used to estimate the asthma exacerbation,
asthma admissions, emergency room visits, use of inhaled corticosteroids
and Beta-2 agonists. Statistical heterogeneity was considered to be
present when p \textless{} 0.1 or I\textsuperscript{2} \textgreater{}
50\%. Publication bias was evaluated visually by funnel plots and
considered significant when p \textless{} 0.05 in either Begg's test or
Egger's test when the inclusion was more than 10 articles. STATA 15.0
software (Stata Corporation, College Station, TX, USA) was also used to
conduct different analyses and all statistical tests.

\textbf{3 Results}

\textbf{3.1 Search Results}

Our initial search yielded 73 articles in total, 17 of which were
removed for duplication. After screening titles and abstracts, further
22 items were taken away. Thirty-four articles were reviewed, among
which 7 were included in this meta-analysis\textsuperscript{14-19}. No
further study was identified by manual search. The flow diagram of
studies selection was shown in Figure 1.

\textbf{3.2 Study Characteristic}

Six cross-sectional studies and one prospective cohort study, with 20456
subjects were included for the final meta-analysis. The sample size of
the studies ranged from 16 to 18912. The age of participants ranged from
3 to 15 across all studies. Outcomes in the studies are showed as
follows: asthma exacerbation, asthma admissions, emergency room visits,
use of inhaled corticosteroids and use of Beta-2 agonists

The main characteristics of the 7 articles were summarized in Table 1.
AHRQ scores suggested that all studies scored at eight to nine as high
quality.

\textbf{3.3 Asthma exacerbation}

Three studies\textsuperscript{14,19,20} were included in this outcome,
with 751 cases during COVID-19 pandemic, and 889 cases before COVID-19
pandemic. Heterogeneity test analysis suggested that there was
heterogeneity (I\textsuperscript{2}=60\%, P=0.08), so the random effects
model was used. The meta-analysis demonstrated there was no significant
difference between two groups(OR =0.49, 95\%CI= {[}0.20,1.16{]}, Z=1.62,
P=0.11)(Figure 2).

\textbf{3.4 Asthma admission}

The meta-analysis showed that during COVID-19 pandemic, the asthma
admissions were lower than that before COVID-19 pandemic(OR =0.32,
95\%CI= {[}0.19,0.54{]}, Z=4.35 P<0.0001)(Figure 3). Heterogeneity test
analysis suggested there was no
heterogeneit(I\textsuperscript{2}=0\%,P=0.45).

\textbf{3.5 Emergency room visit}

Three studies\textsuperscript{14,18,20} were included in this outcome.
Heterogeneity test analysis suggested that there was no heterogeneity
(I\textsuperscript{2}=0\%, P=0.87). The meta-analysis demonstrated there
was significant difference between two groups(OR =0.11, 95\%CI=
{[}0.04,0.26{]}, Z=4.98, P<0.00001)(Figure 4), during COVID-19
pandemic, the emergency room visits of asthma were lower than that
before COVID-19 pandemic.

\textbf{3.6 Use of inhaled corticosteroids and Beta-2 agonists}

The meta-analysis showed that there was no significant difference
between two groups in the use of inhaled corticosteroids(OR=0.22,
95\%CI= {[}0.03,1.85{]}, Z=1.15, P=0.25)(Figure 5)and Beta-2 agonists(OR
=0.18, 95\%CI= {[}0.01,3.35{]}, Z=1.39, P=0.16)(Figure 6).Heterogeneity
test analysis suggested that there was heterogeneity in the two outcomes
(I\textsuperscript{2}=96\%, P<0.00001 of use of inhaled corticosteroids
and I\textsuperscript{2}=97\%, P<0.00001 of Beta-2 agonists), so the
random effects model was used.

\textbf{3.7 Publication bias}

We cannot use the funnel plot to reflect publication bias because of the
inclusion of fewer than 10 articles.

\textbf{4 Discussion}

The current systematic review provides a quantitative estimate of the
asthma control of the current ongoing COVID-19 pandemic in children. The
COVID-19 outbreak and the measures taken to it have had significant
influences on asthma control among children. We have shown for the first
time that the level of asthma control was significantly improved during
the COVID-19 pandemic compared to the same period before it, with a
reduction of asthma exacerbation, asthma admission and emergency room
visit. One reason of these results is probably associated with the
lockdown measures during COVID-19 pandemic, which limit viral disease
transmissions, reduce the possible exposure to asthma triggers, such as
viral infections, outdoor allergens, physical activities, and air
pollution\textsuperscript{21-23}. It might also be explained by
caregivers' afraid to bring children to hospital because of the risk of
exposure to SARS-Co-V2\textsuperscript{24}. And increased treatment
adherence is also an important factor. Caregivers are afraid of going to
hospital in the special time, so they pay more attention to their health
than that before the pandemic and treat their children's asthma in time,
and take the treatment actively, thus the times of visits to the
hospital has decreased and the frequency of asthma exacerbation has also
decreased. Anyway, these results mean less medication and healthcare
resources are used in the control of children's asthma.

The outcome of use of inhaled corticosteroids and Beta-2 agonists shows
no significant difference. In fact, on one hand, a lot of children
reduced their maintenance therapy (use of inhaled corticosteroids and
Beta-2 agonists), it is likely because of the good level of disease
control, in the study of Ullmann et al.\textsuperscript{18} showed the
significant reduction of respiratory symptoms, which meant there was a
real improvement in asthma control. On the other hand, there are some
children stepped up their therapy during the lockdown. It was not only
because of symptoms or the fear and anxiety related to the spreading of
the COVID-19 pandemic\textsuperscript{25-27}. Also, studies have
suggested that inhaled corticosteroids may enhance innate immunity to
viral infections\textsuperscript{28,29}, reduce susceptibility to severe
respiratory viral infections and can downregulate virus
angiotensin-converting enzyme-2 receptor expression in the airways in
the case of SARS-CoV-2\textsuperscript{30}.

The outcome of c-ACT scores were not analyzed, though many articles
included it. It was mainly because of the different manifestations used.
For example, Papadopoulos et al.\textsuperscript{17} use number of
people to show improved scores. Jia et al.\textsuperscript{16} use the
number of people whose scores were greater or equal to 20 which means
good control. Ullmann et al.\textsuperscript{18} use the exact scores
directly. Yucel et al.\textsuperscript{19} use the ratio of score less
than 20. So it is hard to unite these outcomes. This is a problem that
needs to be unified in the follow-up studies.

Although the current meta-analysis results show that the control of
asthma in children has been improved during pandemic, we are still
concerned about the question that will childhood asthma worsen if the
lockdown continues for a very long time? The asthma control of patients
with indoor allergen sensitization might be worse. Confounding factors
such as increased exposure to indoor allergens, such as HDMs, molds, pet
allergens, and decreased exposure to seasonal outdoor allergens such as
pollens may have both negative and positive effects respectively on
asthma. Further researches are needed.

After the COVID-19 disappearing, children suffering from asthma and
their caregivers should still reduce exposure to asthma triggers like
viral infections, outdoor allergens, and air pollution, at the same time
increase treatment adherence, just do what they underwent in the
pandemic, thus to restore, maintain and promote effective asthma
management for children, this is the meaning of our writing this
article.

Our review has several limitations. First, the sample size of this
meta-analysis was relatively small. As a result, the unknown risk of
bias caused by incomplete data could constrain our results. Second, our
results are based on observational studies, which are susceptible to
design bias, selection bias and residual confounding. Third, in this
study was that heterogeneity across the studies was substantial, which
could be attributed to different definition of severity used or sample
size. Despite these limitations, this meta-analysis provides information
on the association between children's asthma control and COVID-19
pandemic.

\textbf{5 Conclusion}

In summary, compared to the same period before the COVID-19 pandemic and
the measures in response to it, the level of asthma control has been
significantly improved. we need to understand the exact factors leading
to these improvements and find methods to sustain it. This meta-analysis
can guide children and their caregivers to restore, maintain and promote
effective asthma management during, and more important, after the
pandemic.



\textbf{Acknowledgments}

The authors thank Hai-yong Ye for helping to revise this manuscript.

\textbf{Conflict of interests}

The authors declare that there are no conflicts of interests.

\textbf{Author contributions}

Study design: Ze Yang, Xiang Wang, Xi-gang Wan, Zong-hua Qiu, and
Yong-liang Xia.~Data collection: Ze Yang, Xiang Wang, Xi-gang Wan,
Jia-li Chen, Man-hao Shi, and Shi-yi Zhang.~Analysis: Ze Yang and Xiang
Wang.~Manuscript drafting, editing, and approval: All authors.

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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1} PRISMA flow diagram of the study selection process.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2} Forest plots for comparison of asthma exacerbation
between COVID-19 pandemic and before it.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3} Forest plots for comparison of asthma admission
between COVID-19 pandemic and before it.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Figure 4} Forest plots for comparison of emergency room visit
between COVID-19 pandemic and before it.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Figure 5} Forest plots for comparison of use of inhaled
corticosteroid between COVID-19 pandemic and before it.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Figure 6} Forest plots for comparison of use of Beta-2 agonists
between COVID-19 pandemic and before it.

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/427123/articles/531377-pediatric-asthma-control-during-the-covid-19-pandemic-a-systematic-review-and-meta-analysis}

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