Systematic Evaluation of Biyuan Tongqiao Granule in the Treatment of Chronic Sinusitis in Children Based on Meta-analysis

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1. Lunan Pharmaceutical Group Co., Ltd., Linyi 276006, China; 2. State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi 276006, China; 3. Center for New Drug Pharmacology of Lunan Pharmaceutical Group Co., Ltd., Linyi 273400, China

Abstract [Objectives] To make an evaluation of the efficacy and safety of Biyuan Tongqiao Granule in the treatment of chronic sinusitis in children, and provide evidence-based medical reference for clinical use. [Methods] Databases such as Chinese Biomedical Literature Service System (SinoMed), China Knowledge Infrastructure (CNKI), Wanfang Digital Journal Full-text Database (WF), VIP Database (VIP), EmBase, PubMed, Science Direct, and Cochrane Library were used to collect the clinical randomized controlled trials of Biyuan Tongqiao Granule in children with chronic sinusitis published since the creation of databases. The quality of the included literature was evaluated and the data were extracted. The data was analyzed using Review Manager 5.3 software for meta-analysis, and descriptive analysis was performed for studies that could not be combined. The GRADE method was applied to evaluate the quality of evidence. [Results] A total of 12 studies were included, including 1 645 cases of patients. The analysis results show that compared with the control group, Biyuan Tongqiao Granule has an excellent curative effect on children with chronic sinusitis and has a lower incidence of adverse reactions. The GRADE evidence level indicated that the sinus CT scan lesion score was intermediate evidence, and the visual analog score, endoscopic mucosal morphology score, and total effective rate were low-level evidence. [Conclusions] Biyuan Tongqiao Granule has a significant effect in treating chronic sinusitis in children and does not increase the incidence of adverse reactions, but its efficacy and safety need support of more high-quality studies.

Key words Biyuan Tongqiao Granule, Chronic sinusitis, Randomized controlled trial, Meta-analysis

1 Introduction

Sinusitis is a common disease in the ear, nose, and throat (ENT) department. It is a series of nasal cavity-sinus diseases characterized by mucosal inflammation. Sinusitis can be divided into acute and chronic sinusitis. Acute sinusitis is mainly caused by upper respiratory tract infections, including bacterial and viral infections. Chronic sinusitis is more common than acute sinusitis, often suffered from multiple sinuses at the same time. Sinusitis is prone to occur in all groups of people, but it is more common in young, old, and weak people. Sinusitis belongs to the category of "nasosinusitis" in traditional Chinese medicine. It is often accompanied by headache, nasal congestion, decreased sense of smell, and pain in the sinus area. If children with sinusitis are not treated in a timely manner, it will affect their physical and mental health. In severe cases, it may damage the hearing. It even can cause loss of appetite, mental depression, and memory loss. The pediatric sinus structure is not fully developed and the resistance is weak, surgical treatment may affect facial development, thus, conservative treatment with drugs is adopted[1]. Therefore, exploring a safe and effective treatment method is of great significance for the treatment of sinusitis.

Biyuan Tongqiao Granule, as a proprietary Chinese medicine preparation, has the effects of expelling wind and clearing away heat, and diffusing the lung to relieve the stuffy nose, and can be used for acute sinusitis (syndrome of lung infected by external pathogen), manifested as tenderness in the forehead or sacrum, nasal congestion, sticky white or yellow nasal mucus, or headache, or fever, thin yellow or white fur, and floating pulse[2]. Modern pharmacological studies have indicated that Biyuan Tongqiao Granule can play an anti-inflammatory effect by inhibiting the increase in capillary permeability and inhibiting inflammatory factors, and relieving the stuffy nose[3-4]. Clinically, Biyuan Tongqiao Granules are often used in the treatment or combined treatment of various rhinitis, sinusitis, and otitis media. Many clinical trials have demonstrated the effectiveness and safety of Biyuan Tongqiao Granule, but there is no systematic evaluation about the treatment of children with chronic sinusitis. In order to further sort out and explore the characteristics of the efficacy of Biyuan Tongqiao Granule in the treatment of children with chronic sinusitis, we systematically reviewed the literature both at home and abroad about the effectiveness and safety of Biyuan Tongqiao Granule in the treatment of children with chronic sinusitis, to provide evidence-based medical reference for its clinical use.

2 Data and methods

2.1LiteraturesearchstrategyWe searched databases such as Chinese Biomedical Literature Service System (SinoMed), China Knowledge Infrastructure (CNKI), Wanfang Digital Journal Full-text Database (WF), VIP Database (VIP), EmBase, PubMed, Science Direct, and Cochrane Library with the aid of computer, and collected randomized controlled trials (RCTs) of Biyuan Tongqiao Granule in the treatment of children with chronic sinusitis. Search words include: Biyuan, Biyuan Tongqiao, Biyuan Tongqiao Granule, sinusitis, chronic sinusitis (both in Chinese and English). The search time was from the creation of each database to December 1, 2019.

2.2Inclusioncriteria

2.2.1Type of study. The included literature is randomized controlled trials (RCTs) of Biyuan Tongqiao Granule for the treatment of children with chronic sinusitis. Other conditions such as blindness and loss of follow-up are not limited. The language of included literature is limited to Chinese and English.

2.2.2Object of studies. The included patients met the diagnostic criteria for children with chronic sinusitis[5-8]. Patients were below 16 years old and had a course of disease of more than one month, and there were no restrictions on the race and gender of the patient children.

2.2.3Intervention measures. The control group was treated with drugs or methods other than Biyuan Tongqiao Granule; the treatment group was treated with Biyuan Tongqiao Granule combined with the treatment methods for the control group. Both groups adopted the same the treatment course.

2.2.4Outcome indicators. The primary outcome indicators were visual analogue scale (VAS), endoscopic mucosal morphology score (Lund-Kennedy scale), sinus CT scan lesion scale, and the secondary outcome indicators were total clinical efficacy and other indicators. At the same time, adverse reactions were analyzed.

2.2.5Quality evaluation criteria. According to the quality evaluation criteria ofCochraneHandbook(Version 5.1.0)[9], for the random sequence generation, the concealment of the allocation scheme, the blindness of patients and researchers, the blindness of results evaluation, data integrity, selective reporting, and possible risk of bias of each literature were evaluated as low risk of bias, unclear risk of bias, and high risk of bias according to the report of each item. If all the above evaluation items are correctly and completely reported, the corresponding items would be evaluated as low risk of bias; if the content usage and reporting of the corresponding evaluation items are incorrect, the corresponding items would be evaluated as high risk of bias; if the information of the evaluation items is incomplete, and it is not possible to judge accurately, the corresponding item would be evaluated as unclear risk of bias. The chart for risk of bias was plotted with the aid of Review Manager 5.3. According to the factors affecting the evaluation of the quality of the evidence (the limitations of the study, the inconsistent results of the study, the uncertainty of direct evidence, insufficient accuracy or wide confidence intervals, and publication bias)[10], Grade of Recommendation, Assessment, Development, and Evaluation (GRADE) method was used to evaluate the quality of evidence of the included studies and evidences were divided into 4 levels: high-level evidence, intermediate-level evidence, low-level evidence, and very low-level evidence.

2.3ExclusioncriteriaIn case of any one of the following situations, the study would be excluded: (i) duplicate literature, literature that only provides abstracts, and information that cannot be extracted; (ii) obvious deficiencies or errors in the experimental design or no detailed information; (iii) literature with unclear diagnostic criteria and evaluation criteria; (iv) structural abnormalities in the nasal cavity, surgery correction combined with drug treatment.

2.4DiagnosticandevaluationcriteriaAccording to relevant diagnostic criteria (TextbookofTraditionalChineseMedicine/TCMCombinedwithWesternMedicineforPediatrics,ClinicalResearchGuidelinesforNewDrugsinTraditionalChineseMedicine,etc.), studies that diagnosed as chronic sinusitis through endoscopy or CT scan could be included.

The improvement of clinical symptoms of chronic sinusitis, nasal endoscopy, or CT scan results were used as the evaluation criteria. Total effective rate=(Total number of cases-Number of ineffective cases)/Total number of cases ×100%.

2.5DataextractionThe data of the included literature were extracted by the two reviewers separately according to the data extraction table and the results were checked with each other after completion of the extraction. The extracted data mainly include basic demographic information (such as the literature ID, number of included patients, gender, age, course of disease,etc.), methodological elements (random, blind method, outcome report, inclusion and exclusion criteria,etc.), intervention and control programs (drug name, dosage, frequency of treatment, duration of treatment), outcome indicators (total effective rate of clinical efficacy, visual analog score, endoscopic mucosal morphology score,etc.) and adverse reactions,etc. When uncertainties are encountered in the data checking process, agreement should be reached through discussion. If agreement fails to be reached, it should be determined by a third reviewer.

2.6StatisticalanalysisIn this paper, meta-analysis was performed with the aid of software Review Manager 5.3. First, the heterogeneity test between the results of each study was carried out (the test level was 0.05). If there is no heterogeneity between the results of the studies (P>0.1,I2<50%), a fixed effect model would be adopted. On the contrary, if statistical heterogeneity occurs between the results of each study (P≤0.1,I2≥50%), a random effect model would be used. Quantitative analysis was carried out for the potential publication bias using funnel plot, Egger’s test and Begg’s test. Binary variables used risk ratio (RR) as the measurement indicator, and continuous data (visual analogue scale, endoscopic mucosal morphology score) used weighted mean difference (MD), and all the results present 95% confidence interval (95% CI) . The quality level of outcome indicators was evaluated with the aid of the GRADE software.

3 Results

3.1QualityevaluationofincludedliteratureData were collected according to the retrieval strategy, and a total of 357 articles were obtained. After selection according to the inclusion and exclusion criteria, finally 12 articles were included[11-22], all of which were Chinese documents, including a total of 1 645 patients (852 cases in the experimental group and 793 cases in the control group). The literature selection process is shown in Fig.1.

Fig.1Flowdiagramofliteratureselection

The risk of bias for all included literature is shown in Fig.2. All the 12 articles mentioned the random grouping, 6 articles used random number method[12-13,16,20-22], and the rest of the articles did not state the method of random scheme generation. None of the articles mentioned the allocation concealment, the implementation of blind method of evaluators, selective reporting, and other biases. None of the articles mentioned the implementation of blind methods for experimenters and patients, but there is a possibility of breaking of the blindness.

Note: In each item, the color of green represents low risk of bias, the yellow represents unclear risk of bias, while the red represents high risk of bias.

Fig.2Summaryofriskofbias

3.2BasiccharacteristicsofincludedliteratureBasic characteristics of literature are shown in Table 1.

Table1Basiccharacteristicsofincludedliterature

IncludedliteratureGender(Male/Female)Age(years)BaselinecomparabilityNumber of cases(Observation group/Control group)Intervention measuresControl groupObservationgroupTreatmentcycleOutcomeindicatorsChen MM 201839/372-13Comparable76(38/38)Loratadine Tablets, Mometasone Furoate Aqueous Nasal SprayB+C6 weeks①④Chen NJ 201956/654-11Comparable121(60/61)ClarithromycinB+C4 weeks①②③④⑤Chen ZW 2016133/1434-12Comparable276(138/138)Amoxicillin/Clavulanate potassium, Ambr-oxol Hydrochloride GranulesB+C3 months④⑤Fan SC 2012153/1274-12Comparable280(148/132)Gelomyrtol for Children, nasal cavity nega-tive pressure replacementB+C6 weeks④Lin J 201454/562-11Comparable100(50/50)ClarithromycinB+C4 weeks①②④⑥Lin X 201749/514-11Comparable100(50/50)ClarithromycinB+C4 weeks①②③④⑥Liu J 2013-5-12Comparable150(97/53)Azithromycin, nasal cavity washingB+C4 weeks④Ma SM 201878/286-16Comparable106(53/53)Fluticasone Propionate Inhaled AerosolB+COne month④⑤Niu L 201476/646-14Comparable140(70/70)Nuotong Nasal Spray for ChildrenB+C15 d④⑥Xiang H 201749/313-12Comparable80(40/40)ClarithromycinB+C4 weeks①②③④⑥Xu ZY 201945/514-13Comparable96(48/48)Cefdinir Dispersible TabletB+COne month④Zhu HH 201469/514-12Comparable120(60/60)Amoxicillin/Clavulanate potassium, Ambr-oxol Hydrochloride Granules, Myrtol Stand-ardized Enteric CapsulesB+C6 weeks②④⑤

Note: ① visual analogue scale, ② endoscopic mucosal morphology score, ③ sinus CT scan lesion scale, ④ total effective rate, ⑤ others, ⑥ adverse reactions; "B+C" denotes "Biyuan Tongqiao Granule+Control group treatment".

3.3Meta-analysisresultsofclinicaleffect

3.3.1Visual analogue scale. Five studies mentioned VAS, involving a total of 477 children[11-12, 15-16, 20]. Heterogeneity analysis results showed that there was statistical heterogeneity between the studies (P<0.000 01,I2=90%). After one article[11]was excluded, the heterogeneity disappeared (P=0.29,I2=19%). Meta-analysis was performed using a random effects model, and the results showed that the difference between the two groups was statistically significant (P<0.000 01). Biyuan Tongqiao Granule was added to the children’s original treatment protocol. The VAS score of the observation group was significantly lower than the control group[MD=-7.02, 95% CI (-8.41, -5.63)], as shown in Fig.3.

Table2GRADEevidencelevel

Biyuan Tongqiao Granule for chronic sinusitis in childrenPatient or population: patients with chronic sinusitisSettings:Intervention: Biyuan Tongqiao GranuleOutcomesIllustrative comparative risks∗ (95% CI)Assumed riskCorresponding riskControlBiyuan Tongqiao GranuleRelativeeffect(95% CI)No ofParticipants(studies)Quality of theevidence(GRADE)CommentsVASThe mean VAS ranged across control groups from 4.26 to 19.23 pointThe mean VAS in the intervention groups was 7.02 lower (8.41 to 5.63 lower)477(5 studies)⊕⊕ low1,2,3Lund-Kennedy scaleThe mean Lund-Kennedy scale ranged across control groups from 1.28 to 6.43 pointsThe mean Lund-Kennedy scale in the interven-tion groups was 2.7 lower (4.79 to 0.62 lower)477(5 studies)⊕very low2,3Sinus CT scan lesionscaleThe mean sinus CT scan lesion scale ranged across control groups from 4.42 to 9.77 pointsThe mean sinus CT scan lesion scale in the in-tervention groups was 5.25 lower (5.92 to 4.59 lower)301(3 studies)⊕⊕⊕moderate2Total efficacy772 per 1 000911 per 1 000 (872 to 949)RR 1.18(1.13 to 1.23)1 645(12 studies)⊕⊕low2,4∗The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence in-terval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidenceHigh quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.Very low quality: We are very uncertain about the estimate.1 Two of the included trials didnt mention the random sequence generation method.2 Allocation concealment, blinding of outcome assessment, selective reporting and other bias were not conducted in all trials.3 Heterogeneity is obvious based on I2 being more than 70%.4 There may be publication bias according to the qualitative and quantitative analysis.

Fig.3Meta-analysisofVAS

3.3.2Endoscopic mucosal morphology score. Five studies mentioned Lund-Kennedy, involving a total of 356 children[12, 15-16, 20]. Heterogeneity analysis results indicated that there was statistical heterogeneity between the studies (P<0.000 01,I2=99%), and there was greater heterogeneity in the scoring methods in each study. Meta-analysis was performed using a random effects model, and the results showed that the difference between the two groups was statistically significant (P=0.01). Biyuan Tongqiao Granule was added on the basis of the patient’s original treatment protocol. The Lund-Kennedy score of the observation group was significantly lower than that of the control group[MD=-2.70, 95% CI (-4.79, -0.62)], as shown in Fig.4.

3.3.3Sinus CT scan lesion scale. Three studies[12,16,20]mentioned changes in sinus CT scan lesion scores before and after treatment. There was no heterogeneity between the studies (P=0.99,I2=0%). Meta-analysis was carried out using a fixed effect model. The results indicated[MD=-5.25, 95% CI (-5.92, -4.59)]. The sinus CT scan lesion score of the observation group was lower than that of the control group, and there was a significant difference between the two groups (P<0.000 01), as shown in Fig.5.

3.3.4Total effective rate. All the 12 articles used the clinical total effective rate of chronic sinusitis as the outcome indicator. Among them, four articles[12,17-19]divided the curative effect evaluation criteria into three levels: cured, markedly effective, and ineffective, and the rest articles included four levels, namely, cured, markedly effective, effective, and ineffective. Based on this, subgroup analysis was carried out on 12 articles. When using

Fig.4Meta-analysisofLund-Kennedy

Fig.5Meta-analysisofsinusCTscanlesionscale

Biyuan Tongqiao Granule to treat children with chronic sinusitis, there was no heterogeneity between the studies (P=0.49,I2=0% andP=0.62,I2=0%), thus a fixed effect model was adopted. Through a combined analysis of all articles, there was no heterogeneity between the studies (P=0.68,I2=0%) and no heterogeneity between the two subgroups (P=0.45,I2=0%). Meta-analysis results showed that the total clinical effective rate of the experimental group using Biyuan Tongqiao Granule was higher than that of the control group, and the difference between the two groups was statistically significant[RR=1.18, 95% CI (1.13, 1.23),P<0.000 01 ], as shown in Fig.6.

Fig.6Meta-analysisforestmapofthetotaleffectiverateforchronicsinusitis

3.3.5Others outcome indicators. One article[18]mentioned that Fluticasone Propionate Inhaled Aerosol combined with Biyuan Tongqiao Granule could reduce the incidence of orbital complications and upper respiratory complications in children with chronic sinusitis. Two articles mentioned[12-13]that compared with the control group, the application of Biyuan Tongqiao Granule could improve the nasal mucosal cilia transport rate and nasal mucociliary clearance rate. Three articles[12-13, 22]reported the effects of drugs on the levels of interleukin-2 (IL-2) and other blood biochemical indicators in children with chronic sinusitis. However, IL-6 detection methods or standards were not consistent, thus quantitative analysis was not carried out. In two studies, the levels of IL-6 in the blood of children in the experimental group were lower than those before the treatment, and higher than before treatment in one study[13]. The biological effects of the drug on IL-6 need more clinical data to prove. Between three studies, the reports of IL-2 levels were not heterogeneous (P=0.66,I2=0%), so meta-analysis was performed using a fixed effect model. The results showed that[MD=-5.60, 95% CI (-6.41,-4.78)], the content of IL-2 in the blood of the children in the observation group was lower than that in the control group, showing a significant difference (P<0.000 01), as shown in Fig.7.

Fig.7Meta-analysisofIL-2

3.4SafetyevaluationFour articles[15-16, 19-20]reported the occurrence of adverse reactions. In each article, neither the control group nor the observation group showed significant adverse reactions, indicating that taking Biyuan Tongqiao Granule would not increase the risk of adverse reactions.

3.5AnalysisofpublicationbiasA "funnel chart" analysis was carried out for the total effective rate. The results showed an asymmetric distribution, suggesting that there might be publication bias. Then, a test was carried out with the aid of Stata 12.0 software. Egger’s test results:[P=0.001, 95% CI (1.04, 2.86)] and Begg’s test results (Z=2.67,P=0.007), also suggesting a publication bias, as shown in Fig.8.

Fig.8Funnelchartofthetotaleffectiverate

3.6GRADEevidenceThe GRADE software was used to evaluate the main outcome indicators and total effective rate. The results showed that GRADE evidence levels of visual analog score, endoscopic mucosal morphology score, sinus CT scan lesion score, and total effective were "low" (weak recommendation), "very low" (weak recommendation), "moderate" (moderate recommendation), and "low" (weak recommendation), as indicated in Table 2.

4 Discussions

Sinusitis is a complex inflammatory disease. Its pathogenesis is complicated and may be related to various factors such as allergic reactions, bacterial and fungal infections, immune dysfunction, impaired defense function of the epithelium, and environmental exposure[23]. Sinusitis is divided into acute and chronic sinusitis. Chronic sinusitis is usually caused by acute sinusitis that has not been completely cured and then developed after repeated episodes. Pathological changes include decreased nasal ciliary transmission, sinus mucosal hyperemia, and swelling. For sinusitis in children, macrolides can significantly improve the life quality of children with chronic sinusitis, improve ciliary clearance, reduce inflammatory cytokine levels, and reduce recurrence[24].

Sinusitis belongs to the category of "nasosinusitis" in traditional Chinese medicine. Its basic pathogenesis is qi stagnation, so the treatment of qi stagnation syndrome should focus on regulating qi, and mainly removing qi stagnation. Biyuan Tongqiao Granule was developed on the basis of Fructus Xanthii Powder inPrescriptionsforRescuingLivescompiled by Yan Yong in Song Dynasty, with addition of Herba Ephedrae and Ligustici Rhizoma Et Radix. It can quickly improve nasal congestion, reduce nasal secretions, eliminate turbinate swelling, improve or restore olfactory function, relieve headache, dizziness and other symptoms; it is effective for bacterial infection and viral infection; it is widely applied in nasal diseases of children, adults, the elderly. According to its instructions, Biyuan Tongqiao Granule is mainly used for acute sinusitis. However, through analyzing a randomized controlled study of Biyuan Tongqiao Granule combined with conventional treatment in children with chronic sinusitis, the results show that compared with conventional treatment methods, Biyuan Tongqiao Granule has better effects in visual analog scores, sinus CT scan lesions, endoscopic mucosal morphology, and total clinical effective rate. Therefore, regardless of acute or chronic sinusitis, children with wind evil lungs can be treated with Biyuan Tongqiao Granule and the effect is better than conventional treatment methods.

In this meta-analysis, the sample size of the included literature is small and the overall quality is low, it increases the risk of bias in the conclusions of this systematic evaluation. Thus, more large samples and high-quality clinical trials are needed to confirm the efficacy and safety of Biyuan Tongqiao Granule in the treatment of children with acute and chronic sinusitis.