Effects of cinnamaldehyde on anti-respiratory syncytial virus

Abstract Background: Previous reports found that cinnamaldehyde has effects on anti-respiratory syncytial virus (ARSV). However, their results are still contradictory. Therefore, this study will systematically address the effects of cinnamaldehyde on ARSV. Methods: The following electronic bibliographic databases will be retrieved from their outset to the March 31, 2020: MEDLINE, EMBASE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Technology Periodical Database, China Biology Medicine, and China National Knowledge Infrastructure. No language and publication time limitations will be exerted in this study. All relevant case-controlled studies or randomized controlled studies exploring the effects of cinnamaldehyde on ARSV will be included. Study quality of case-controlled studies will be assessed by Newcastle–Ottawa scale, and that of randomized controlled studies will be identified by Cochrane risk of bias tool. All data pooling and analysis will be performed using RevMan 5.3 software. Results: This study will summarize the up-to-date high-quality evidence to synthesize outcome data on the effects of cinnamaldehyde on ARSV. Conclusion: Findings of this study may provide beneficial evidence for both clinicians and future studies regarding the effects of cinnamaldehyde on ARSV. Systematic review registration: INPLASY202040074.


Introduction
Respiratory syncytial virus is one of the most leading causes that lead to lower respiratory tract disease in infants and young children. [1][2][3][4][5] It mostly occurs in infants of 2 to 3 months old with high morbidity and mortality. [6][7][8] The major risk factors are prematurity, bronchopulmonary dysplasia, and congenital heart disease. [9,10] Previous study reported that it accounts for more than 75% of all childhood bronchiolitis, and 40% of all children pneumonias. [11] Thus, anti-respiratory syncytial virus (ARSV) intervention is very urgent to manage such condition. [12][13][14][15][16] Several studies have reported that cinnamaldehyde has effects on ARSV. [17][18][19][20] However, there is a lack of supportive evidence on the effects of cinnamaldehyde on ARSV. Therefore, this study aims to conduct a systematic review and meta-analysis of casecontrolled studies (CCSs) or randomized controlled studies (RCSs) on the effects of cinnamaldehyde on ARSV.

Study registration
This study has been registered on INPLASY202040074. It has been conducted according to the preferred reporting items for systematic reviews and meta-analysis protocol statement guidelines. [21,22] 2.2. Eligibility criteria 2.2.1. Types of trials. We will only include potential CCSs or RCSs exploring the effects of cinnamaldehyde on ARSV.

2.2.2.
Types of subjects. This study will include respiratory syncytial virus infects host HeLa cells as its research targets.
LF and JL contributed equally to this study.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Types of interventions.
In the experimental group, all studies utilized cinnamaldehyde alone for the treatment of ARSV.
In the control group, studies used any comparators will be included, such as no treatment. However, we will not include studies using cinnamaldehyde.

Types of outcome measurements.
Primary outcome is apoptotic host HeLa cells, as detected by flow cytometry.

Information sources and search strategy
This study will search MEDLINE, EMBASE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Technology Periodical Database, China Biology Medicine, and China National Knowledge Infrastructure from their outset to the March 31, 2020 without restrictions of language and publication time. We will consider all potential CCSs or RCSs that examined the effects of cinnamaldehyde on ARSV for inclusion. A detailed search strategy for MEDLINE is summarized (Table 1). Identical search strategies with specifics will be adapted and applied to the other electronic databases. We will also search other resources, such as relevant conference proceedings, and reference lists of included studies.

Study selection
Two researchers will independently identify studies for inclusion in 2 steps. At the first step, we will examine the titles and abstracts for potentially relevant citations; and duplicates and unrelated studies will be eliminated. At the second step, we will obtain fulltext of potential papers and will carefully read them based on the all eligibility criteria. Divergences will be solved by discussion with a third researcher involved. Details of entire study selection process will be presented in a preferred reporting items for systematic reviews and meta-analysis flow diagram.

Data extraction and management
Two researchers will independently extract data using a previous designed data extraction template. It consists of study characteristics (title, first author, journal, etc), information of targeted Host cell Hela, study design (types of study, sample size, etc), intervention and control details (types of treatments, dosage, etc), outcomes, results, findings, and other related information. In case of unclear or missing data, we will contact primary authors to obtain it. Any uncertainties will be solved by discussion with a third researcher involved.

Study quality assessment
Two researchers will independently assess study quality for each included study. The study quality of CCSs will be evaluated by Newcastle-Ottawa scale, and study quality of RCSs will be appraised by the Cochrane risk of bias tool. Any divergences will be resolved by discussion with the help of a third researchers invited.

Statistical analysis
Statistical analyses will be undertaken by RevMan 5.3 software. We will use risk ratio and 95% confidence intervals to calculate dichotomous data, and will utilize mean difference or standardized mean difference and 95% confidence intervals to present continuous data. We will check heterogeneity using I 2 test. I 2 50% means homogeneity and fixed-effects model will be employed. If possible, we will conduct a meta-analysis. I 2 > 50% indicates remarkable heterogeneity, and we will utilize a random-effects model. In addition, we will perform a subgroup analysis to examine the possible sources of obvious heterogeneity.
2.8. Additional analysis 2.8.1. Subgroup analysis. We will perform a subgroup analysis based on the types of studies, different intervention and controls, and outcomes.
2.8.2. Sensitivity analysis. We will carry out a sensitivity analysis to test the stability of study findings by removing low methodological quality studies.

Reporting bias.
All reporting bias will be examined by a funnel plot and Egger regression test if over 10 eligible studies are included.

Dissemination and ethics
This study will not employ any individual patient information, thus, no ethical approval is needed. We will plan to publish this study on a peer-reviewed journal or conference presentation.

Discussion
Published studies reported the effects of cinnamaldehyde on ARSV. However, there is not a systematic review to explore this issue. Thus, this study will firstly provide concise literature sources of the present evidence of cinnamaldehyde on the effect of ARSV. Its results will supply helpful reference for clinicians, Table 1 Detailed search strategy of MEDLINE.

Number
Search terms Cinnamon oil 13 Or 10-12 14 Case-controlled studies 15 Randomized controlled studies 16 Case-controlled 17 Controlled study 18 Random 19 Randomly 20 Case studies 21 Or 14-20 22 9 and 13 and 21 Feng et al. Medicine (2020) 99:20 Medicine policy makers, stakeholders, and researchers. In addition, its findings may help to investigate the research gaps and opportunities for the future researchers.