# Efficacy and Safety of Integrated Maxing Shigan Decoction and Azithromycin for Mycoplasma Pneumoniae Pneumonia in Children: A Systematic Review and Meta-Analysis

Authors: Qiong Huang; Qiong Zhang; Si Li
Journal: Journal of Clinical Pharmacy and Therapeutics
 (2023)

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## Abstract

Background. The primary objective of this study was to thoroughly assess the effectiveness of treating pediatric mycoplasma pneumoniae pneumonia (MPP) with Maxing Shigan decoction (MSD) and azithromycin. Materials and Methods. We comprehensively reviewed the literature for randomized controlled trials research on MPP treated by MSD combined with azithromycin in children in the databases of Medicine, Embase, ClinicalTrials.gov, Cochrane Library, PubMed, CNKI, WangFang, and VIP from inception to April 2021. dds ratio (OR) was used for dichotomous data, while the mean difference (MD) was adopted for continuous variables as effect size, both of which were demonstrated in effect size and 95% confidence intervals (CI). Results. A total of 49 studies with 5704 patients were included in the meta-analysis. The results showed that MSD combined with azithromycin significantly improved the clinical efficacy (OR = 5.31, 95% CI: (4.35, 6.49), and p<0.001) and reduced the chest X-rays recovery time (MD = −2.25, 95% CI: (−2.86, −1.65), and p<0.001), cough duration (MD = −2.53, 95% CI: (−2.93. −2.12), and p<0.001), CRP (MD = −7.84, 95% CI: (−9.51, −6.17), and p<0.001), fever duration (MD = −1.53, 95% CI: (−1.78, −1.28), and p<0.001), hospital days (MD = −2.70, 95% CI: (−3.35, −2.06), and p<0.001), moist rales duration (MD = −2.00, 95% CI: (−2.33, −1.68), and p<0.001), and adverse effects (OR = 0.55, 95% CI: (0.41, 0.75), and p<0.001) when compared with azithromycin alone in the treatment of MPP in children. Meta-regression analysis demonstrated that the course of disease and duration of medication contribute to the heterogeneity across studies when comparing outcomes between groups. Conclusion. MSD and azithromycin worked better when used in conjunction to treat MPP in young patients. These findings require confirmation by additional high-quality, big sample RCTs.


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## Body

## 1. Introduction

Mycoplasma pneumoniae pneumonia (MPP) is a kind of severe respiratory tract infection caused byMycoplasma pneumoniae [1]. The incidence rate of MPP in children is high and shows an upgraded trend, accounting for 10%∼40% of childhood community-acquired pneumonia [2–4]. Although the majority of instances have modest symptoms, some may have more serious conditions, such as myocarditis, nephritis, hemolytic anemia, and other multisystem functional impairment, which puts children’s lives in jeopardy [5]. At the moment, macrolide antibiotics are the first choice for the treatment of MPP in children, and azithromycin is a second-generation macrolide antibiotic with a longer half-life period and more significant clinical effects [6]. However, the management of MPP in children is becoming more challenging as a result of the rise in macrolide-resistant Mycoplasma pneumoniae strains [3, 7, 8].Integrated Chinese-Western therapy has emerged as a novel concept in recent years for the treatment of several illnesses, including MPP in children. Clinicians have given it a lot of attention due to its clear effects and few side effects. Maxing Shigan decoction (MSD) is a classic traditional Chinese medicine (TCM) formula, which is composed ofEphedra sinica Stapf (Mahuang), Amygdalus Communis Vas (Xingren), Gypsum (Sheng Shigao), and Glycyrrhiza uralensis Fisch. (Gancao) [9]. Accumulating evidence demonstrated that MSD or MSD combined with western medications effectively treated MPP in kids, with fewer side effects than western medications alone [10–12]. Studies found that the pharmacological ingredients of MSD mainly include ephedrine, amygdalin, glycyrrhizic acid, liquiritin, and glycyrrhizin [13, 14]. Recent research by Liu et al. sheds fresh light on the mechanism through which MSD counteracts MPP by reducing the amount of apoptosis that MPP causes [15].Despite the fact that clinical studies have demonstrated the effectiveness of using MSD and azithromycin together to treat MPP in children, the trial designs or small sample sizes in some of these studies have led to conflicting findings. There are currently no systematic reviews or meta-analyses that deal with this subject. In order to determine the therapeutic effectiveness of MSD in combination with azithromycin for the treatment of MPP in children, we conducted a thorough literature review and meta-analysis.


## 2. Method

### 2.1. Study Selection

Relevant studies were identified by searching eight databases, namely, Medicine, Embase, ClinicalTrials.gov, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journals Database, and PubMed, from their start date to April 20, 2022. We utilized the terms “Maxing Shigan decoction” and “mycoplasma pneumonia” as keywords and medical subject headings. Two researchers independently determined which studies were eligible after eliminating duplicate data using the titles and abstracts. The disputes among the reviewers were addressed by a third researcher. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria were used for this meta-analysis, and the PRISMA checklist was provided as supplementary material (TableS1).


### 2.2. Inclusion and Exclusion Criteria

Inclusion criteria were as follows: (1) The study was designed as a randomized controlled trial (RCT). (2) The patients were under 15 years old and suffered from MPP. (3) Patients in the treatment group received MSD therapy in addition to the baseline medication of azithromycin similar to the control group. The following criteria were excluded: (1) duplicate studies, retrospective studies, and literature without complete data; (2) animal experiments; (3) literature comprising reviews, letters, experiences, and case reports; (4) non-RCT studies.


### 2.3. Data Extraction and Quality Assessment

A predesigned data form was used to extract the relevant information, including the author, journal, year, sample size, country, interventions, and outcomes. Primary outcomes consisted of the clinical efficacy and the changes in five clinical symptoms, including chest X-rays recovery time, cough disappearance time, fever disappearance time, average hospitalization days, and moist rale disappearance time. The second outcome included changes in laboratory indicators, such as C-reaction protein (CRP). The Cochrane 5.1.0 assessment tool was adopted to evaluate the methodological quality of the RCTs. The data extraction and quality assessment were independently completed by two reviewers, and a third researcher resolved the disagreements that occurred between reviewers.


### 2.4. Meta-Analysis Methods

Statistical analysis was conducted by the Stata SE15.0 software (Stata, USA). The odds ratio (OR) was used for dichotomous variables, while continuous outcomes were presented as the mean difference (MD), both of which were demonstrated with effect size and 95% confidential interval (CI). The heterogeneity of studies was assessed by Chi-square andI2 test, and the random-effect model was used when I2 > 50% and p<0.01; otherwise, a fixed-effect model was used. A forest plot was generated as the number of studies over three. Begg and Egger’s tests were applied to detect potential publication bias in this study. The funnel plot of Begg’s test was also generated. Meta-regression analysis was performed to assess factors influencing heterogeneity.


## 2.1. Study Selection

Relevant studies were identified by searching eight databases, namely, Medicine, Embase, ClinicalTrials.gov, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journals Database, and PubMed, from their start date to April 20, 2022. We utilized the terms “Maxing Shigan decoction” and “mycoplasma pneumonia” as keywords and medical subject headings. Two researchers independently determined which studies were eligible after eliminating duplicate data using the titles and abstracts. The disputes among the reviewers were addressed by a third researcher. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria were used for this meta-analysis, and the PRISMA checklist was provided as supplementary material (TableS1).


## 2.2. Inclusion and Exclusion Criteria

Inclusion criteria were as follows: (1) The study was designed as a randomized controlled trial (RCT). (2) The patients were under 15 years old and suffered from MPP. (3) Patients in the treatment group received MSD therapy in addition to the baseline medication of azithromycin similar to the control group. The following criteria were excluded: (1) duplicate studies, retrospective studies, and literature without complete data; (2) animal experiments; (3) literature comprising reviews, letters, experiences, and case reports; (4) non-RCT studies.


## 2.3. Data Extraction and Quality Assessment

A predesigned data form was used to extract the relevant information, including the author, journal, year, sample size, country, interventions, and outcomes. Primary outcomes consisted of the clinical efficacy and the changes in five clinical symptoms, including chest X-rays recovery time, cough disappearance time, fever disappearance time, average hospitalization days, and moist rale disappearance time. The second outcome included changes in laboratory indicators, such as C-reaction protein (CRP). The Cochrane 5.1.0 assessment tool was adopted to evaluate the methodological quality of the RCTs. The data extraction and quality assessment were independently completed by two reviewers, and a third researcher resolved the disagreements that occurred between reviewers.


## 2.4. Meta-Analysis Methods

Statistical analysis was conducted by the Stata SE15.0 software (Stata, USA). The odds ratio (OR) was used for dichotomous variables, while continuous outcomes were presented as the mean difference (MD), both of which were demonstrated with effect size and 95% confidential interval (CI). The heterogeneity of studies was assessed by Chi-square andI2 test, and the random-effect model was used when I2 > 50% and p<0.01; otherwise, a fixed-effect model was used. A forest plot was generated as the number of studies over three. Begg and Egger’s tests were applied to detect potential publication bias in this study. The funnel plot of Begg’s test was also generated. Meta-regression analysis was performed to assess factors influencing heterogeneity.


## 3. Results

### 3.1. Characteristics of Eligible Study

The process of literature searching and screening were illustrated in Figure1. We obtained 253 pertinent studies in total from eight databases. After duplicate studies were eliminated, a total of 128 studies remained. Finally, 49 RCTs [10–12, 16–61] were included for the quality assessment and meta-analysis after studies were disqualified based on the title, abstract, and full-text. The detailed characteristics of the 49 RCTs are described in Table 1. All studies were conducted in China and published between 2007 and 2020. There are 5704 participants in the trials, 2845 of whom are in the treatment group and 2859 in the control group. More than 87.76% of the RCTs (43/49) reported the clinical effective rate. Fourteen RCTs (35.90%), 26 RCTs (53.06%), 10 RCTs (25.64%), 31 RCTs (63.27%), 10 RCTs (25.64%), and 27 RCTs (55.10%) reported disappearance time of pulmonary shadows in X‐ray, cough duration, C-reaction protein (CRP), fever duration, average hospitalization days, and the duration of moist rales, respectively. The result of the quality assessment was shown in Figure 2. It demonstrated that the majority of included studies had selection bias, which result from uncertain allocation concealment and random sequence generation.Figure 1
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart.Table 1
The characteristics of the included studies in the meta-analysis.
AuthorYearCountryNo. of case/controlInterventionOutcomesAdverse effectsExperimental groupControl groupAijun Mo2015China45/45TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 5, 3, 7, 6NAAling Liu2018China62/61TC + MSDOral intake of AZM 10 mg/kg/d for 1 d, and changed to oral intake of AZM 5 mg/kg/d1, 5, 3, 7, 4, 6, 8Gastrointestinal reactions, rash, and elevated transaminasesBaohua Chen2014China25/23TC + MSDOral intake of AZM 10 mg/kg/d at 1–3 and 8–10 d, max dose 0.5 g/d5, 3NAChang Liu2016China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d and stop for 4 d, then changed to oral intake of AZM for 3 d and stop for 4 d. Then oral intake of AZM for 3 d1, 5, 3, 7, 2NAChangru Wang2015China60/60TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 5, 3, 7, 6NAChenjia Qian2018China50/50TC + MSDIV AZM 10 mg/kg/d for 5 days, then stop for 4 days, changed to daily oral intake of AZM 10 mg/kg/d for 5 days5, 3, 7, 4NAChenwen Zhang2018China60/60TC + MSDIV AZM 10 mg/kg/d for 7 d1, 8Vomiting, diarrhea, abdominal discomfort, and nauseaCuiliu Liu2015China68/68TC + MSDIV AZM 10 mg/kg/d for 5 d, and changed to oral intake of AZM for 7 d1, 6NAGanlin Xu2020China40/40TC + MSDIV AZM 10 mg/kg/d for 7 d1, 5, 3, 7, 8Abdominal discomfort, nausea, and local rednessGuangchao Zhang2019China145/145TC + MSDIV AZM 10 mg/kg/d for 5 d1, 5, 3, 7NAGuiling Li2020China50/50TC + MSDIV AZM 10 mg/kg/d for 3 days, then stop for 4 days, changed to daily oral intake of AZM 10 mg/kg/d for 3 days1, 8Abdominal discomfort, vomiting, indigestion, and rashHai Zhang2016China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, and changed to oral intake of AZM for 3 d, stop for 4 d. Repeat for 3 times5, 7, 2NAHaizhu Zhan2020China48/48TC + MSDIV AZM 10 mg/kg/d for 3–5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3–5 d1, 5, 3, 7, 4, 2NAHongbo Wang2009China53/53TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 8Vomiting, diarrhea, and nauseaHua Jiang2014China100/100TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, and changed to oral intake of AZM for 3 d, stop for 4 d. Repeat for 3 times1NAHuihuan Guo2014China240/240TC + MSDIV AZM 10 mg/kg/d for 3 days, then stop for 3 days, changed to daily oral intake of AZM 10 mg/kg/d for 3 days and then stop for 2 days, continue oral AZM for 3 d1, 4, 6, 8UnspecifiedJiahong Wang2020China30/30TC + MSDOral intake of AZM 10 mg/kg/d for 1 d, changed to oral intake of AZM 5 mg/kg/d for 5 d and stopped for 2 days, repeat 1 time1, 5, 3NAJin Li2007China48/28TC + MSDIV AZM 10 mg/kg/d for 10 d1, 5, 3, 7, 2NAJin Yang2018China27/27TC + MSDIV AZM 10 mg/kg/d for 5 d1, 5, 3, 7, 4, 8UnspecifiedJinping Song2018China60/60TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d and changed to oral intake of AZM for 5 d, stop for 4 d5, 3, 7, 4, 8Gastrointestinal reaction and skin hypersensitivityJunwen Zeng2007China100/80TC + MSDIV AZM 5–10 mg/kg/d for 5–7 d, and changed to oral intake for 5–7 d1NAKeyan Sheng2013China60/60TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d and continue IV AZM for 5 d, then changed to oral intake of AZM 10 mg/kg/d for 3 d, stop for 4 d and continue oral intake for 3 d1, 8Nausea, vomiting, gastrointestinal reactions, and local vascular painLiangai Yao2014China40/40TC + MSDIV AZM 10 mg/kg/d for 3–5 d, changed to oral AZM intake of AZM for 4 d and stop for 3 d1, 5, 3, 6, 8Nausea, vomiting, rash, elevated transaminase, and enlarged lymph nodesLijun Fei2017China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d and stop for 4 d. Then repeated for 3 times1, 5, 7, 2NALijun Fei2017China42/42TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d, then repeated for 1 times1, 5, 3, 7, 2NALizhen Zhu2020China30/30TC + MSDOral intake of AZM 10 mg/kg/d for 3 days and stop for 4 d, then continue oral intake for 3 days1, 8Gastrointestinal reactionsLizhou Zhang2010China30/30TC + MSDIV AZM 10 mg/kg/d for 3 d and stopped for 4 d, repeat 3 times1NAMinfei Yang2019China30/30TC + MSDIV AZM 10 mg/kg/d for 5 d and stop for 3 d, changed to oral intake of AZM for 13 d1, 5, 3, 7NAMinhong Deng2015China20/20TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 5 d, stop for 4 d and then continued oral AZM for 3 d5NAPeicheng Wu2011China78/78TC + MSDIV AZM 10 mg/kg/d for 5–7 d, changed to oral intake of AZM1, 5, 3, 7, 2NAQifeng Chen2019China40/40TC + MSDIV AZM 10 mg/kg/d for 5–7 d (max dose 0.5 g/d), changed to daily oral intake of AZM 10 mg/kg/d on the first day, and changed to 5 mg/kg/d for 2–5 days1, 5, 3, 7, 4, 8Sore throat and mild nauseaQingsong Sun2017China42/42TC + MSDIV AZM 10 mg/kg/d for 5 d, changed to oral intake of AZM for 7 d1, 5, 3, 7, 6, 2, 8Nausea, vomiting, diarrhea, and elevated transaminaseRui Kong2017China115/115TC + MSDIV AZM 10 mg/kg/d for 5 d and stopped for 4 d, repeat 3 times1, 5, 3, 7, 6NAShuyuan Dong2019China45/45TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 4, 8Nausea, vomiting, and diarrheaShuzhi Yang2017China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d and stop for 4 d, then changed to oral intake of AZM for 3 d and stop for 4 d. Repeat for 3 times1, 5, 7, 2, 8UnspecifiedWeihong Yu2018China40/40TC + MSDIV AZM 10 mg/kg/d for 5 d, and changed to oral intake of AZM for 7 d1, 5, 3, 7, 2NAWen Hu2017China66/64TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 4NAXiaoyan Kong2018China45/45TC + MSDIV AZM or oral intake of AZM 10 mg/kg/d for 3–5 d, stop for 4 d. Repeat 2 times1NAXiaoyan Wang2017China55/55TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, then repeated for 3 times1, 5, 3, 7, 6NAXintan Bie2016China61/61TC + MSDIV AZM 10 mg/kg/d FOR 3–5 d, and changed to oral intake of AZM 10 mg/kg/d for 1 day and changed to oral intake of AZM 5 mg/kg/d1, 5, 3, 7, 2, 8Gastrointestinal reactionsXu Sun2019China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, repeat 2 times1, 5, 3, 7NAXuewen Wang2019China78/80TC + MSDIV AZM 10 mg/kg/d for 3 d and stop for 4 d, and changed to oral intake of AZM for 3 d1, 4NAYan Huang2016China70/130TC + MSDIV AZM 10 mg/kg/d for 5 days then changed to daily oral intake of AZM 5 mg/kg/d for 3 days, then changed to IV AZM 10 mg/kg/d for 3 d1, 5, 3, 7, 2, 8Liver function impairment, diarrhea, abdominal discomfort, nausea, and vomitingYanqiu Meng2018China14/14TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, repeat for 2 times1, 5, 3, 7, 2NAYaxiong Wan2020China210/210TC + MSDIV AZM 10 mg/kg/d6NAYinwei Liao2011China50/50TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d and changed to oral intake of AZM for 3 d, stop for 4 d and continue oral intake for 3 d1, 5, 3, 7, 2NAYuhong Liu2019China35/35TC + MSDIV AZM 10 mg/kg/d1, 8Nausea and vomitingZhaofan Qin2019China42/42TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1NAZhihua Wang2018China31/30TC + MSDIV AZM 10 mg/kg/d for 5 d1NATC, treatment of the control group; MSD, MAXING SHIGAN decoction; IV, intravenous; AZM, azithromycin. Notes: 1∼8 in outcomes column represents the clinical effective rate, chest X-ray recovery time, cough disappearance time, CRP, fever disappearance time, average hospitalization days, moist rale disappearance time, and adverse effects, respectively.Figure 2
The assessment of study quality using the Cochrane 5.1.0 assessment tool.


### 3.2. Clinical Effective Rate

There were 43 trials that examined the clinical effectiveness of using azithromycin and MSD to treat MPP in children [10–12, 16–25, 27, 28, 31–44, 46, 48–58, 60, 61], and there was no heterogeneity across these studies (p=0.84, I2 = 0%). The results of the meta-analysis revealed that the clinical efficacy of MSD combined with azithromycin was significantly better than azithromycin alone for the treatment of pediatric MPP (OR = 5.31, 95% CI: (4.35, 6.49), and p<0.001) (Figure 3).Figure 3
Comparison of clinical effective rate between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


### 3.3. Chest X-Ray Recovery Time

Statistical analysis of 14 RCTs [11, 16, 21, 23, 27, 31, 32, 35, 39, 40, 43, 53, 56, 59] showed a high heterogeneity across studies when comparing the differences in chest X-ray recovery time between groups (p<0.001, I2 = 89%). The meta-analysis results showed that the chest X-rays recovery time of MSD combined with azithromycin was significantly better than azithromycin alone for the treatment of MPP in children (MD = −2.25, 95% CI: (−2.86, −1.65), and p<0.001) (Figure 4).Figure 4
Comparison of chest X-rays recovery time between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


### 3.4. Cough Disappearance Time

Statistical analysis of 27 RCTs [10, 11, 16, 18, 20, 21, 23, 25, 27, 29, 31, 35, 37, 39–41, 43–45, 47, 49–51, 53–55, 57] revealed a high between-study heterogeneity across studies when comparing the differences in cough disappearance time between groups (p<0.001, I2 = 96%). The meta-analysis results showed that the cough duration of MSD combined with azithromycin was significantly lower than azithromycin alone for the treatment of MPP in children (MD = −2.48, 95% CI: (−2.87, −2.08), and p<0.001) (Figure 5).Figure 5
Comparison of the cough disappearance time between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


### 3.5. CRP

Severe heterogeneity was observed across 10 RCTs [11, 20, 22, 24, 33, 34, 41, 45, 47] when comparing differences in CRP between groups (p<0.001, I2 = 100%). The results of the meta-analysis showed that the CRP level in the MSD combined with azithromycin was significantly lower than azithromycin alone for the treatment of MPP in children (MD = −7.84, 95% CI: (−9.51, −6.17), and p<0.001) (Figure 6).Figure 6
Comparison of CRP between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


### 3.6. Fever Disappearance Time

We observed a high heterogeneity across 31 RCTs [10–12, 16, 18, 20, 21, 23, 25, 27, 29–32, 35, 37, 39–41, 43–45, 47, 49, 51, 53–57, 59] when comparing the differences in fever disappearance time between groups (p<0.001, I2 = 95%). The pooled results demonstrated that the fever disappearance time of MSD combined with azithromycin was significantly lower than azithromycin alone for the treatment of MPP in children (MD = −1.53, 95% CI: (−1.78, −1.28), and p<0.001) (Figure 7).Figure 7
Comparison of fever disappearance time between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


### 3.7. Average Hospitalization Days

Ten trials mentioned this outcome, and the random-effect model was used owing to the heterogeneity across 10 studies (p<0.001, I2 = 92%) [17, 21, 26, 33, 37, 41, 44, 49, 51, 57]. The pooled results showed that the hospitalization days of MSD combined with azithromycin were significantly lower than azithromycin alone for the treatment of MPP in children (MD = −2.70, 95% CI: (−3.35, −2.06), and p<0.001) (Figure 8).Figure 8
Comparison of average hospitalization days between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


### 3.8. Moist Rale Disappearance Time

Twenty-seven studies reported the efficacy of shortening moist rale time between two groups [10, 11, 16, 18, 20, 21, 23, 25, 27, 31, 32, 35, 37, 39–41, 43–45, 47, 49, 51, 53–56, 59], and the random-effect model was applied due to the heterogeneity among the trials (p<0.001, I2 = 90%). The results of the meta-analysis demonstrated that the moist rale disappearance time of the integrated group was significantly lower than that of azithromycin alone for the treatment of MPP in children (MD = −2.00, 95% CI: (−2.33, −1.68), and p<0.001) (Figure 9).Figure 9
Comparison of moist rale disappearance time between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


### 3.9. Adverse Effects

Eighteen trials reported the adverse effects and provided sufficient data to compare the differences between the experiment and control groups (Figure10). The most common side effects include nausea, vomiting, and diarrhea. Moreover, rash, elevated transaminase, enlarged lymph nodes, and indigestion were also reported. No heterogeneity was observed across studies, and thus, the fixed-effect model was applied (p=0.834, I2 = 0.0%). The pooled results demonstrated that the adverse effects of the integrated group were significantly lower than that of the group treated with azithromycin alone (OR = 0.55, 95% CI: (0.41, 0.75), and p<0.001).Figure 10
Comparison of adverse effects between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


### 3.10. Publication Bias

As shown in Figure11, the funnel plots for fever disappearance time, cough disappearance time, moist rale disappearance time, CRP, average hospitalization days, and Chest X-rays recovery time were basically asymmetric, whereas the funnel plots for average hospitalization days, adverse effects, and clinical effective rate were basically symmetrical. In addition, the results of Begg and Egger’s tests are shown in Table 2, which demonstrated the potential publication bias across studies when evaluating the following outcomes: fever disappearance time, cough disappearance time, moist rale disappearance time, CRP, and chest X-rays recovery time. Taken together, our data suggested that this study might have a relatively high degree of publication bias.Figure 11
Funnel plots of fever disappearance time (a), cough disappearance time (b), moist rale disappearance time (c), CRP (d), average hospitalization days (e), chest X-rays recovery time (f), adverse effects (g), and clinical efficacy (h).
(a)(b)(c)(d)(e)(f)(g)(h)Table 2
The results of the publication bias detected by Begg’s and Egger’s test.
OutcomesBeggEggerZptpClinical effective rate1.8900.0580.6900.493Fever disappearance time−1.5600.118−3.7600.001Cough disappearance time−1.4800.139−4.810≤0.001Moist rale disappearance time0.0001.000−2.7500.011CRP−2.4100.016−5.750≤0.001Average hospitalization days−1.3400.180−1.2800.238Chest X-rays recovery time1.3100.1892.5600.025Adverse effects−0.7200.472−0.6400.532CRP, C-reactive protein. The bold values were statistical significant and we sought to highlight these values in the table.


### 3.11. Meta-Regression Analysis

Due to the observation of severe heterogeneity when comparing several outcomes, meta-regression analysis was conducted to reveal possible factors influencing heterogeneity. We assessed the influence of age, course of disease, male/female ratio, and duration of medication. The results are shown in Table3 and demonstrated that CRP, fever disappearance time, and cough disappearance time were significantly associated with several included variables. Specifically, the course of disease was revealed to be associated with CRP (t = −3.1, p=0.027), fever disappearance time (t = 2.39, p=0.026), and cough disappearance time (t = −2.17, p=0.043). Meanwhile, fever disappearance time was also associated with the duration of medication (t = 2.47, p=0.02).Table 3
Meta-regression analysis of the outcomes according to characteristics of the cohort.
OutcomesCovariatesNumber of obstpCoeff.Average hospitalization daysAge8−1.430.202−0.307Cod5−1.870.1580.027Mfr90.170.867−0.136Duration90.120.9060.027Chest X-rays recovery timeAge8−0.830.438−0.212Cod110.510.622−0.557Mfr11−0.610.5580.316Duration130.610.5570.012CRPAge80.760.4750.655Cod7−3.100.027−0.693Mfr90.630.5516.286Duration10−1.440.188−0.390Fever disappearance timeAge24−1.110.277−0.090Cod232.390.0260.052Mfr28−1.390.175−0.164Duration302.470.020.046Cough disappearance timeAge21−0.210.837−0.040Cod20−2.170.043−0.112Mfr24−0.110.915−0.024Duration26−0.990.333−0.048Moist rale disappearance timeAge21−1.330.200−0.124Cod220.890.3840.026Mfr24−1.360.189−0.183Duration260.310.7560.007Side effectsAge13−1.000.341−0.146Cod101.450.1850.071Mfr161.050.3110.741Duration16−0.620.547−0.015Clinical effective rateAge32−0.950.349−0.063Cod251.580.1270.043Mfr39−0.280.778−0.031Duration410.950.3490.017Cod, course of disease; Mfr, male/female ratio; Coeff., coefficient; CRP, C-reactive protein. The bold values were statistical significant and we sought to highlight these values in the table.


## 3.1. Characteristics of Eligible Study

The process of literature searching and screening were illustrated in Figure1. We obtained 253 pertinent studies in total from eight databases. After duplicate studies were eliminated, a total of 128 studies remained. Finally, 49 RCTs [10–12, 16–61] were included for the quality assessment and meta-analysis after studies were disqualified based on the title, abstract, and full-text. The detailed characteristics of the 49 RCTs are described in Table 1. All studies were conducted in China and published between 2007 and 2020. There are 5704 participants in the trials, 2845 of whom are in the treatment group and 2859 in the control group. More than 87.76% of the RCTs (43/49) reported the clinical effective rate. Fourteen RCTs (35.90%), 26 RCTs (53.06%), 10 RCTs (25.64%), 31 RCTs (63.27%), 10 RCTs (25.64%), and 27 RCTs (55.10%) reported disappearance time of pulmonary shadows in X‐ray, cough duration, C-reaction protein (CRP), fever duration, average hospitalization days, and the duration of moist rales, respectively. The result of the quality assessment was shown in Figure 2. It demonstrated that the majority of included studies had selection bias, which result from uncertain allocation concealment and random sequence generation.Figure 1
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart.Table 1
The characteristics of the included studies in the meta-analysis.
AuthorYearCountryNo. of case/controlInterventionOutcomesAdverse effectsExperimental groupControl groupAijun Mo2015China45/45TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 5, 3, 7, 6NAAling Liu2018China62/61TC + MSDOral intake of AZM 10 mg/kg/d for 1 d, and changed to oral intake of AZM 5 mg/kg/d1, 5, 3, 7, 4, 6, 8Gastrointestinal reactions, rash, and elevated transaminasesBaohua Chen2014China25/23TC + MSDOral intake of AZM 10 mg/kg/d at 1–3 and 8–10 d, max dose 0.5 g/d5, 3NAChang Liu2016China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d and stop for 4 d, then changed to oral intake of AZM for 3 d and stop for 4 d. Then oral intake of AZM for 3 d1, 5, 3, 7, 2NAChangru Wang2015China60/60TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 5, 3, 7, 6NAChenjia Qian2018China50/50TC + MSDIV AZM 10 mg/kg/d for 5 days, then stop for 4 days, changed to daily oral intake of AZM 10 mg/kg/d for 5 days5, 3, 7, 4NAChenwen Zhang2018China60/60TC + MSDIV AZM 10 mg/kg/d for 7 d1, 8Vomiting, diarrhea, abdominal discomfort, and nauseaCuiliu Liu2015China68/68TC + MSDIV AZM 10 mg/kg/d for 5 d, and changed to oral intake of AZM for 7 d1, 6NAGanlin Xu2020China40/40TC + MSDIV AZM 10 mg/kg/d for 7 d1, 5, 3, 7, 8Abdominal discomfort, nausea, and local rednessGuangchao Zhang2019China145/145TC + MSDIV AZM 10 mg/kg/d for 5 d1, 5, 3, 7NAGuiling Li2020China50/50TC + MSDIV AZM 10 mg/kg/d for 3 days, then stop for 4 days, changed to daily oral intake of AZM 10 mg/kg/d for 3 days1, 8Abdominal discomfort, vomiting, indigestion, and rashHai Zhang2016China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, and changed to oral intake of AZM for 3 d, stop for 4 d. Repeat for 3 times5, 7, 2NAHaizhu Zhan2020China48/48TC + MSDIV AZM 10 mg/kg/d for 3–5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3–5 d1, 5, 3, 7, 4, 2NAHongbo Wang2009China53/53TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 8Vomiting, diarrhea, and nauseaHua Jiang2014China100/100TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, and changed to oral intake of AZM for 3 d, stop for 4 d. Repeat for 3 times1NAHuihuan Guo2014China240/240TC + MSDIV AZM 10 mg/kg/d for 3 days, then stop for 3 days, changed to daily oral intake of AZM 10 mg/kg/d for 3 days and then stop for 2 days, continue oral AZM for 3 d1, 4, 6, 8UnspecifiedJiahong Wang2020China30/30TC + MSDOral intake of AZM 10 mg/kg/d for 1 d, changed to oral intake of AZM 5 mg/kg/d for 5 d and stopped for 2 days, repeat 1 time1, 5, 3NAJin Li2007China48/28TC + MSDIV AZM 10 mg/kg/d for 10 d1, 5, 3, 7, 2NAJin Yang2018China27/27TC + MSDIV AZM 10 mg/kg/d for 5 d1, 5, 3, 7, 4, 8UnspecifiedJinping Song2018China60/60TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d and changed to oral intake of AZM for 5 d, stop for 4 d5, 3, 7, 4, 8Gastrointestinal reaction and skin hypersensitivityJunwen Zeng2007China100/80TC + MSDIV AZM 5–10 mg/kg/d for 5–7 d, and changed to oral intake for 5–7 d1NAKeyan Sheng2013China60/60TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d and continue IV AZM for 5 d, then changed to oral intake of AZM 10 mg/kg/d for 3 d, stop for 4 d and continue oral intake for 3 d1, 8Nausea, vomiting, gastrointestinal reactions, and local vascular painLiangai Yao2014China40/40TC + MSDIV AZM 10 mg/kg/d for 3–5 d, changed to oral AZM intake of AZM for 4 d and stop for 3 d1, 5, 3, 6, 8Nausea, vomiting, rash, elevated transaminase, and enlarged lymph nodesLijun Fei2017China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d and stop for 4 d. Then repeated for 3 times1, 5, 7, 2NALijun Fei2017China42/42TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d, then repeated for 1 times1, 5, 3, 7, 2NALizhen Zhu2020China30/30TC + MSDOral intake of AZM 10 mg/kg/d for 3 days and stop for 4 d, then continue oral intake for 3 days1, 8Gastrointestinal reactionsLizhou Zhang2010China30/30TC + MSDIV AZM 10 mg/kg/d for 3 d and stopped for 4 d, repeat 3 times1NAMinfei Yang2019China30/30TC + MSDIV AZM 10 mg/kg/d for 5 d and stop for 3 d, changed to oral intake of AZM for 13 d1, 5, 3, 7NAMinhong Deng2015China20/20TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 5 d, stop for 4 d and then continued oral AZM for 3 d5NAPeicheng Wu2011China78/78TC + MSDIV AZM 10 mg/kg/d for 5–7 d, changed to oral intake of AZM1, 5, 3, 7, 2NAQifeng Chen2019China40/40TC + MSDIV AZM 10 mg/kg/d for 5–7 d (max dose 0.5 g/d), changed to daily oral intake of AZM 10 mg/kg/d on the first day, and changed to 5 mg/kg/d for 2–5 days1, 5, 3, 7, 4, 8Sore throat and mild nauseaQingsong Sun2017China42/42TC + MSDIV AZM 10 mg/kg/d for 5 d, changed to oral intake of AZM for 7 d1, 5, 3, 7, 6, 2, 8Nausea, vomiting, diarrhea, and elevated transaminaseRui Kong2017China115/115TC + MSDIV AZM 10 mg/kg/d for 5 d and stopped for 4 d, repeat 3 times1, 5, 3, 7, 6NAShuyuan Dong2019China45/45TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 4, 8Nausea, vomiting, and diarrheaShuzhi Yang2017China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d and stop for 4 d, then changed to oral intake of AZM for 3 d and stop for 4 d. Repeat for 3 times1, 5, 7, 2, 8UnspecifiedWeihong Yu2018China40/40TC + MSDIV AZM 10 mg/kg/d for 5 d, and changed to oral intake of AZM for 7 d1, 5, 3, 7, 2NAWen Hu2017China66/64TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1, 4NAXiaoyan Kong2018China45/45TC + MSDIV AZM or oral intake of AZM 10 mg/kg/d for 3–5 d, stop for 4 d. Repeat 2 times1NAXiaoyan Wang2017China55/55TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, then repeated for 3 times1, 5, 3, 7, 6NAXintan Bie2016China61/61TC + MSDIV AZM 10 mg/kg/d FOR 3–5 d, and changed to oral intake of AZM 10 mg/kg/d for 1 day and changed to oral intake of AZM 5 mg/kg/d1, 5, 3, 7, 2, 8Gastrointestinal reactionsXu Sun2019China40/40TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, repeat 2 times1, 5, 3, 7NAXuewen Wang2019China78/80TC + MSDIV AZM 10 mg/kg/d for 3 d and stop for 4 d, and changed to oral intake of AZM for 3 d1, 4NAYan Huang2016China70/130TC + MSDIV AZM 10 mg/kg/d for 5 days then changed to daily oral intake of AZM 5 mg/kg/d for 3 days, then changed to IV AZM 10 mg/kg/d for 3 d1, 5, 3, 7, 2, 8Liver function impairment, diarrhea, abdominal discomfort, nausea, and vomitingYanqiu Meng2018China14/14TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d, repeat for 2 times1, 5, 3, 7, 2NAYaxiong Wan2020China210/210TC + MSDIV AZM 10 mg/kg/d6NAYinwei Liao2011China50/50TC + MSDIV AZM 10 mg/kg/d for 3 d, stop for 4 d and changed to oral intake of AZM for 3 d, stop for 4 d and continue oral intake for 3 d1, 5, 3, 7, 2NAYuhong Liu2019China35/35TC + MSDIV AZM 10 mg/kg/d1, 8Nausea and vomitingZhaofan Qin2019China42/42TC + MSDIV AZM 10 mg/kg/d for 5 d, stop for 4 d, changed to oral intake of AZM 10 mg/kg/d for 3 d1NAZhihua Wang2018China31/30TC + MSDIV AZM 10 mg/kg/d for 5 d1NATC, treatment of the control group; MSD, MAXING SHIGAN decoction; IV, intravenous; AZM, azithromycin. Notes: 1∼8 in outcomes column represents the clinical effective rate, chest X-ray recovery time, cough disappearance time, CRP, fever disappearance time, average hospitalization days, moist rale disappearance time, and adverse effects, respectively.Figure 2
The assessment of study quality using the Cochrane 5.1.0 assessment tool.


## 3.2. Clinical Effective Rate

There were 43 trials that examined the clinical effectiveness of using azithromycin and MSD to treat MPP in children [10–12, 16–25, 27, 28, 31–44, 46, 48–58, 60, 61], and there was no heterogeneity across these studies (p=0.84, I2 = 0%). The results of the meta-analysis revealed that the clinical efficacy of MSD combined with azithromycin was significantly better than azithromycin alone for the treatment of pediatric MPP (OR = 5.31, 95% CI: (4.35, 6.49), and p<0.001) (Figure 3).Figure 3
Comparison of clinical effective rate between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


## 3.3. Chest X-Ray Recovery Time

Statistical analysis of 14 RCTs [11, 16, 21, 23, 27, 31, 32, 35, 39, 40, 43, 53, 56, 59] showed a high heterogeneity across studies when comparing the differences in chest X-ray recovery time between groups (p<0.001, I2 = 89%). The meta-analysis results showed that the chest X-rays recovery time of MSD combined with azithromycin was significantly better than azithromycin alone for the treatment of MPP in children (MD = −2.25, 95% CI: (−2.86, −1.65), and p<0.001) (Figure 4).Figure 4
Comparison of chest X-rays recovery time between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


## 3.4. Cough Disappearance Time

Statistical analysis of 27 RCTs [10, 11, 16, 18, 20, 21, 23, 25, 27, 29, 31, 35, 37, 39–41, 43–45, 47, 49–51, 53–55, 57] revealed a high between-study heterogeneity across studies when comparing the differences in cough disappearance time between groups (p<0.001, I2 = 96%). The meta-analysis results showed that the cough duration of MSD combined with azithromycin was significantly lower than azithromycin alone for the treatment of MPP in children (MD = −2.48, 95% CI: (−2.87, −2.08), and p<0.001) (Figure 5).Figure 5
Comparison of the cough disappearance time between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


## 3.5. CRP

Severe heterogeneity was observed across 10 RCTs [11, 20, 22, 24, 33, 34, 41, 45, 47] when comparing differences in CRP between groups (p<0.001, I2 = 100%). The results of the meta-analysis showed that the CRP level in the MSD combined with azithromycin was significantly lower than azithromycin alone for the treatment of MPP in children (MD = −7.84, 95% CI: (−9.51, −6.17), and p<0.001) (Figure 6).Figure 6
Comparison of CRP between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


## 3.6. Fever Disappearance Time

We observed a high heterogeneity across 31 RCTs [10–12, 16, 18, 20, 21, 23, 25, 27, 29–32, 35, 37, 39–41, 43–45, 47, 49, 51, 53–57, 59] when comparing the differences in fever disappearance time between groups (p<0.001, I2 = 95%). The pooled results demonstrated that the fever disappearance time of MSD combined with azithromycin was significantly lower than azithromycin alone for the treatment of MPP in children (MD = −1.53, 95% CI: (−1.78, −1.28), and p<0.001) (Figure 7).Figure 7
Comparison of fever disappearance time between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


## 3.7. Average Hospitalization Days

Ten trials mentioned this outcome, and the random-effect model was used owing to the heterogeneity across 10 studies (p<0.001, I2 = 92%) [17, 21, 26, 33, 37, 41, 44, 49, 51, 57]. The pooled results showed that the hospitalization days of MSD combined with azithromycin were significantly lower than azithromycin alone for the treatment of MPP in children (MD = −2.70, 95% CI: (−3.35, −2.06), and p<0.001) (Figure 8).Figure 8
Comparison of average hospitalization days between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


## 3.8. Moist Rale Disappearance Time

Twenty-seven studies reported the efficacy of shortening moist rale time between two groups [10, 11, 16, 18, 20, 21, 23, 25, 27, 31, 32, 35, 37, 39–41, 43–45, 47, 49, 51, 53–56, 59], and the random-effect model was applied due to the heterogeneity among the trials (p<0.001, I2 = 90%). The results of the meta-analysis demonstrated that the moist rale disappearance time of the integrated group was significantly lower than that of azithromycin alone for the treatment of MPP in children (MD = −2.00, 95% CI: (−2.33, −1.68), and p<0.001) (Figure 9).Figure 9
Comparison of moist rale disappearance time between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


## 3.9. Adverse Effects

Eighteen trials reported the adverse effects and provided sufficient data to compare the differences between the experiment and control groups (Figure10). The most common side effects include nausea, vomiting, and diarrhea. Moreover, rash, elevated transaminase, enlarged lymph nodes, and indigestion were also reported. No heterogeneity was observed across studies, and thus, the fixed-effect model was applied (p=0.834, I2 = 0.0%). The pooled results demonstrated that the adverse effects of the integrated group were significantly lower than that of the group treated with azithromycin alone (OR = 0.55, 95% CI: (0.41, 0.75), and p<0.001).Figure 10
Comparison of adverse effects between Maxing Shigan decoction combined with azithromycin and azithromycin alone.


## 3.10. Publication Bias

As shown in Figure11, the funnel plots for fever disappearance time, cough disappearance time, moist rale disappearance time, CRP, average hospitalization days, and Chest X-rays recovery time were basically asymmetric, whereas the funnel plots for average hospitalization days, adverse effects, and clinical effective rate were basically symmetrical. In addition, the results of Begg and Egger’s tests are shown in Table 2, which demonstrated the potential publication bias across studies when evaluating the following outcomes: fever disappearance time, cough disappearance time, moist rale disappearance time, CRP, and chest X-rays recovery time. Taken together, our data suggested that this study might have a relatively high degree of publication bias.Figure 11
Funnel plots of fever disappearance time (a), cough disappearance time (b), moist rale disappearance time (c), CRP (d), average hospitalization days (e), chest X-rays recovery time (f), adverse effects (g), and clinical efficacy (h).
(a)(b)(c)(d)(e)(f)(g)(h)Table 2
The results of the publication bias detected by Begg’s and Egger’s test.
OutcomesBeggEggerZptpClinical effective rate1.8900.0580.6900.493Fever disappearance time−1.5600.118−3.7600.001Cough disappearance time−1.4800.139−4.810≤0.001Moist rale disappearance time0.0001.000−2.7500.011CRP−2.4100.016−5.750≤0.001Average hospitalization days−1.3400.180−1.2800.238Chest X-rays recovery time1.3100.1892.5600.025Adverse effects−0.7200.472−0.6400.532CRP, C-reactive protein. The bold values were statistical significant and we sought to highlight these values in the table.


## 3.11. Meta-Regression Analysis

Due to the observation of severe heterogeneity when comparing several outcomes, meta-regression analysis was conducted to reveal possible factors influencing heterogeneity. We assessed the influence of age, course of disease, male/female ratio, and duration of medication. The results are shown in Table3 and demonstrated that CRP, fever disappearance time, and cough disappearance time were significantly associated with several included variables. Specifically, the course of disease was revealed to be associated with CRP (t = −3.1, p=0.027), fever disappearance time (t = 2.39, p=0.026), and cough disappearance time (t = −2.17, p=0.043). Meanwhile, fever disappearance time was also associated with the duration of medication (t = 2.47, p=0.02).Table 3
Meta-regression analysis of the outcomes according to characteristics of the cohort.
OutcomesCovariatesNumber of obstpCoeff.Average hospitalization daysAge8−1.430.202−0.307Cod5−1.870.1580.027Mfr90.170.867−0.136Duration90.120.9060.027Chest X-rays recovery timeAge8−0.830.438−0.212Cod110.510.622−0.557Mfr11−0.610.5580.316Duration130.610.5570.012CRPAge80.760.4750.655Cod7−3.100.027−0.693Mfr90.630.5516.286Duration10−1.440.188−0.390Fever disappearance timeAge24−1.110.277−0.090Cod232.390.0260.052Mfr28−1.390.175−0.164Duration302.470.020.046Cough disappearance timeAge21−0.210.837−0.040Cod20−2.170.043−0.112Mfr24−0.110.915−0.024Duration26−0.990.333−0.048Moist rale disappearance timeAge21−1.330.200−0.124Cod220.890.3840.026Mfr24−1.360.189−0.183Duration260.310.7560.007Side effectsAge13−1.000.341−0.146Cod101.450.1850.071Mfr161.050.3110.741Duration16−0.620.547−0.015Clinical effective rateAge32−0.950.349−0.063Cod251.580.1270.043Mfr39−0.280.778−0.031Duration410.950.3490.017Cod, course of disease; Mfr, male/female ratio; Coeff., coefficient; CRP, C-reactive protein. The bold values were statistical significant and we sought to highlight these values in the table.


## 4. Discussion

The effectiveness of MSD with azithromycin against MPP in children is being assessed in this first meta-analysis. A total of 49 RCTs involving 5704 people were included. The pooled effects of seven outcomes were analyzed, including clinical effective rate, chest X-rays recovery time, cough disappearance time, CRP level, fever disappearance time, average hospitalization days, and moist rale disappearance time. Our findings showed that the combination of MSD and azithromycin presented a better impact on clinical efficacy and alleviating clinical symptoms and adverse effects than azithromycin alone. As a result, continued clinical promotion of MSD with azithromycin for the treatment of MPP in children seems merited.Azithromycin has been used extensively to lessen respiratory and other bacterial infections since it has a prolonged half-life and broad-spectrum antibacterial activity. It exerts antibacterial activity via inhibiting protein synthesis, quorum sensing, and reducing biofilm formation [62]. In the United States, azithromycin is applied as the first-line choice on patients with bacterial pneumonia [63, 64]. Meanwhile, azithromycin is also frequently used in China to treat kids with MPP. Nonetheless, long-term administration of azithromycin may raise the danger of bacterial resistance and cause aberrant liver function, ultimately attenuating its clinical usefulness [65]. TCM, or integrated Chinese-Western therapies, has garnered a lot of attention in recent years and has proven to be more successful in treating MPP in young patients. Azithromycin is one of the most commonly used western medicines in the strategy of integrative medicine, and it is crucial to evaluate the clinical effectiveness of TCM combined with azithromycin in the treatment of children with MPP.A number of TCMs, including Shashen Maidong decoction [66], Qingfei Huatan Huoxue decoction [67], Jiedu Pingsou decoction [68], and MSD, have been therapeutically utilized to treat MPP in children. Importantly, the combination of TCMs with azithromycin was demonstrated to be more effective in the treatment of pediatric MPP. Although some studies lack sufficient evidence for higher safety, most meta-analytic studies suggested that TCMs combined with azithromycin have better clinical efficacy and fewer side effects in the treatment of MPP among children [69–73]. In China, MSD was commonly used in the clinical treatment of upper respiratory tract infections, pneumonia, and bronchial asthma, and accumulating studies revealed that MSD or MSD with western medicine also showed positive therapeutic benefits on MPP in children [15, 74]. Traditional Chinese medicine is able to coordinately mobilize the synergistic functions of numerous tissues and organs in the human body to alleviate symptoms and treat diseases because of its intricate and reasonable formulation. For MPP in children, TCMs are generally effective in relieving cough, fever, and pulmonary rales. This is reflected in many oral liquids [72], Chinese herb injections [71], or decoctions. A number of active compounds have been identified in MSD by contemporary pharmacological investigations, including liquiritin, glycyrrhizin, glycyrrhetinic acid, amygdalin, sagoside, ephedrine, pseudoephedrine, and methylephedrine [75]. Interestingly, a recent study found that MSD mitigates MPP-induced pyroptosis via the NLRP3 inflammasome [15]. This discovery gave the follow-up study on the mechanism of MSD against MPP a strong base and fresh perspectives.The best part of this review is how it covers the most recent research from RCTs using MSD and azithromycin to treat MPP in children. This study has certain restrictions as well. First, many of the included RCTs did not specify the random method in detail, which could bias the selection process. Second, all the RCTs were from China and the patients were Chinese. Third, the sample size of included RCTs was small, which could lead to publication bias. Therefore, to verify our findings, more RCTs with high quantities and large samples are required.


## 5. Conclusion

In conclusion, MSD combined with azithromycin results in increased clinical efficacy with higher safety. The dissemination of the evidence should be cautioned due to the limitations. Finally, more high-quality, double-blind, and multicenter RCTs with a focus on patient-important outcomes are required in the future to support more evidence-based therapies.



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*Source: 2596562-2023-02-04.xml*