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\begin{document}

\title{Treatment strategy of cough variant asthma in children --A retrospective
longitudinal cohort study in China}



\author[1]{Nannan Lou}%
\author[1]{xiang ma}%
\author[2]{Qingxin Luo}%
\author[1]{Xiaoling Wei}%
\author[1]{Yun Zhang}%
\author[1]{Jing Guo}%
\author[1]{Jing Wang}%
\author[1]{Zhongtao Gai}%
\affil[1]{Children's Hospital Affiliated to Shandong University}%
\affil[2]{Shandong University Cheeloo College of Medicine}%


\vspace{-1em}



  
  \date{June 16, 2024}


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Treatment strategy of cough variant asthma in children

--A retrospective longitudinal cohort study in China

To the Editor,

Cough variant asthma (CVA) is the most common cause of chronic cough,
accounting for 41.95\% of the causes of chronic cough among Chinese
children, which greatly affects their learning, sleep, and quality of
life\textsuperscript{{[}1,2{]}}. About 40\%--50\% of CVA patients may
eventually develop wheezing symptoms and progress to typical asthma if
no appropriate and timely treatment is given \textsuperscript{{[}3{]}}.
However, the treatment plan and duration of children with CVA remain
unclear. To this end,~we performed retrospective longitudinal cohort
study to explore the best therapeutic regimen and treatment duration of
CVA in children.

The study was approved by the Ethics Committee of Children's Hospital
Affiliated to Shandong University (The ethics protocol number is
SDFE--IRB/T--2022075), which absolved the need for written informed
consent. A total of 314 children with CVA were assigned to receive
inhaled corticosteroid (ICS) combined with long-acting \selectlanguage{greek}β\selectlanguage{english}2-agonist (LABA)
group (group 1, n = 63), ICS combined with leukotriene receptor
antagonist (LTRA) group (group 2, n = 186), ICS monotherapy group (group
3, n = 30), and LTRA monotherapy group (group 4, n = 35). Based on the
causal diagram (Figure S1) model assumption, the marginal structure
model and the Cox proportional hazard regression model were fitted to
estimate the direct causal effect of the first medication on the
efficacy and safety outcomes based on inverse probability weighting.
Additional details on the methods are presented in the online
supplementary.

General Information of Children with CVA is shown in Table S1.
Distribution of the number of patients changed from 0 weeks to 60 weeks
with four treatment regimens is plotted in Figure S2. Results of
superiority analysis with group 1 as the control (Table 1): ICS + LABA
had the best effect within 8 weeks, followed by ICS + LTRA, whereas ICS
alone and LTRA alone had the worst efficacy. With the extension of
medication time, the efficacy of the ICS + LABA group was gradually
lower than other groups in the same period. ICS alone was predominant at
8 weeks and beyond, followed by LTRA alone, whereas ICS + LABA and ICS +
LTRA had the worst efficacy. Due to most of the guidelines recommend
that the CVA treatment is for at least 8 weeks, we divided it into two
parts with 8 weeks as the boundary\textsuperscript{{[}4-6{]}}. There was
no significant difference in therapeutic effects of the four treatment
regimens within 8 weeks of diagnosis of CVA (Table S2). And the efficacy
of ICS or LTRA alone was better than that of combination therapy after 8
weeks of diagnosis (Table S3).

Table 1. Comparison of four medication regimens for CVA children at
different courses.\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Treatment Duration & Efficacy Ranking\tabularnewline
\midrule
\endhead
2 weeks & ICS+LABA>ICS+LTRA>ICS>LTRA\tabularnewline
4 weeks & ICS+LABA>LTRA>ICS+LTRA>ICS\tabularnewline
8 weeks & ICS>ICS+LABA>ICS+LTRA>LTRA\tabularnewline
12 weeks & ICS>LTRA>ICS+LTRA>ICS+LABA\tabularnewline
16 weeks & ICS>LTRA>ICS+LABA>ICS+LTRA\tabularnewline
20 weeks & ICS>LTRA>ICS+LABA>ICS+LTRA\tabularnewline
28 weeks & ICS>LTRA>ICS+LABA>ICS+LTRA\tabularnewline
36 weeks & ICS>LTRA>ICS+LTRA>ICS+LABA\tabularnewline
\bottomrule
\end{longtable}

Notes: ICS: inhaled corticosteroids; LABA: ICS + long-acting
bete2-agonist; LTRA: Leukotriene receptor antagonists.

Results of optimal course comparison with other groups not using the
drug as controls are plotted in Figure 1, the ICS + LABA group showed a
significant improvement in cough at an early stage, particularly in the
4th week, the symptoms significantly improved; meanwhile, the symptoms
of ICS+LTRA and ICS groups were significantly improved at 36 weeks. LTRA
alone showed a significant improvement at 20 weeks. The safety analysis
results with group 1 as the control are shown in Table S4, all four
treatment regimens could reduce the risk of CVA recurrence and
progression to typical asthma. The effect of the LTRA group was the most
significant, followed by ICS and ICS+LABA groups, and then the ICS+LTRA
group.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
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\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

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\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

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\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 1. Effective changed from 2 weeks to 36 weeks of ICS+LABA group
(A), ICS+LTRA group (B), ICS alone (C), and LTRA alone (D). ICS: inhaled
corticosteroids; LABA: ICS+ long-acting bete2-agonist; LTRA: Leukotriene
receptor antagonists.

In conclusion,~our results suggest that the four treatment regimens for
CVA children are effective. This article believes that ICS+LABA is the
first choice within 8 weeks of diagnosis, and ICS+LATR treatment can be
selected if the child cannot master the drug absorption technology well.
After 8 weeks, it can be reduced to ICS alone to control CVA for at
least 36 weeks based on the remission of symptoms in children.

\textbf{Acknowledgments}

We would like to thank all the study participants. This survey was
funded by the Clinical Science and Technology Innovation Plan in Jinan
(202134067,202225022), Jinan Key Laboratory of Respiratory Disease for
Children and Shandong Provincial Natural Science Program (ZR2021MH147).
All the funders had no role in the study design, data analysis, data
interpretation, and writing of the report.

\textbf{Conflict of interest}

All authors declare no conflict of interests

Nannan Lou\textsuperscript{1}, Xiang Ma\textsuperscript{1, 2*}, Qingxin
Luo\textsuperscript{3, 4}, Xiaoling Wei\textsuperscript{1, 2}, Yun
Zhang\textsuperscript{1, 2}, Jing Guo\textsuperscript{1, 2}, Jing
Wang\textsuperscript{1, 2}, Zhongtao Gai\textsuperscript{1, 2*}

1. Department of Respiratory Diseases, Children's Hospital Affiliated to
Shandong University (Jinan Children's Hospital), Jinan, Shandong,
250022, China.

2. Jinan Key Laboratory of Pediatric Respiratory diseases, Jinan
Children's Hospital, Jinan, Shandong, 250022, China.

3. Department of Biostatistics, School of Public Health, Cheeloo College
of Medicine, Shandong University, Jinan, 250000, People's Republic of
China.

4. Institute for Medical Dataology, Cheeloo College of Medicine,
Shandong University, Jinan, 250000, People's Republic of China.

* They are co-corresponding authors.

\textbf{Correspondence}

Xiang Ma, M.D, associate professor, Department of Respiratory Disease,
Children's Hospital affiliated to Shandong University (Jinan Children's
Hospital), Key Laboratory of Pediatric Respiratory Disease, Children's
Hospital affiliated to Shandong University (Jinan Children's Hospital),
Jinan, Shandong 250022, China, email:\emph{maxiang0176@163.com,} ORCID:
https://orcid.org/0000-0001-6139-4355

Zhongtao Gai, professor, Department of Respiratory Disease, Children's
Hospital affiliated to Shandong University (Jinan Children's
Hospital), Key Laboratory of Pediatric Respiratory Disease, Children's
Hospital affiliated to Shandong University (Jinan Children's Hospital),
Jinan, Shandong 250022, China, email:\emph{gaizhongtao@sina.com}.

They are co-corresponding authors.

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{[}3{]} Zugic V, Mujovic N, Hromis S, et al. Pattern of Response to
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{[}5{]} Asthma group of Chinese Throacic Society. Guidelines for
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{[}6{]} Asthma Group of Chinese Thoracic Society. Chinese national
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\textbf{Supporting information}

Additional supporting information can be found online in the Supporting
Information section at the end of this article

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