Synergistic effect of Mahaenggamseok-tang in the treatment of pediatric patients with lower respiratory tract infections
Globally, lower respiratory tract infections (LRTIs) are a major cause of infant hospitalization.  In 2016, LRTIs caused 13.1% of deaths in children younger than 5 years.  LRTIs in childhood can cause pulmonary dysfunction and lung abnormality during growth.  In particular, the Coronavirus Disease 2019 (COVID-19) pandemic and fine dust pollution represent major threats to the respiratory health of children.  Antibiotics are commonly prescribed to treat LRTIs in children. However, widespread overuse or misuse of antibiotics is prevalent in such patients and has caused the emergence of antibiotic-resistant bacteria.  In 2019, the Centers for Disease Control and Prevention reported that more than 2.8 million antibiotic-resistant infections occurred in the United States, leading to >35,000 deaths.  In addition, approximately 20% of patients who receive antibiotic treatment experienced adverse events, such as allergic reactions and end-organic toxic effects  ; in the United States, 70,000 infants visit the emergency department because of antibiotic-related adverse events each year.  For these reasons, the use of antibiotics worldwide must be reduced. Complementary and alternative medicine (CAM) therapy has been considered as an alternative to antibiotics to treat pediatric infectious diseases.  In particular, herbal medicine is more effective and safe than antibiotics.  Many recent studies have reported that, compared to Western medicine (WM) alone, combined treatment using both herbal and WM showed more prominent effects on respiratory diseases including COVID-19.  According to Sanghanron  (a traditional Chinese medicine book on infectious diseases), Mahaenggamseok-tang (MHGT) consists of Mahuang ( Ephedra sinica ), Gamcho ( Glycyrrhiza uralensis Fisch.), Haengin ( Prunus armeniaca ), and Seokgo ( Gypsum fibrosum ). In CAM, LRTI is characterized by wet cough, sputum, and fever, and is diagnosed based on wind-heat Zheng .  MHGT removes wind-heat invading the body; therefore, it is one of the main herbal medicines prescribed to treat various respiratory complaints in Asian countries.  In addition, the most common pathogenesis of LRTI is airway inflammation caused by viruses.  According to preliminary results, MHGT inhibits immune cell proliferation and decreases inflammatory mediators such as IL (interleukin)-1b and IL-13.  It follows that MHGT may have an effect on LRTIs. Previously, a systematic review was carried out in Korea, but it had several limitations. First, it did not conduct a full search of Asian countries’ databases, even though MHGT is widely prescribed in Asian countries. Secondly, it included trials that used various modified MHGTs, which prevented the exact effect of MHGT from being identified. Thirdly, it only considered randomized controlled trials (RCTs) involving mycoplasma pneumonia. Therefore, the effect of MHGT on LRTIs remains poorly understood. Thus, the purpose of the present study was to perform a systematic review of original MHGT (not modified) to treat all types of LRTIs in children. 

2.1. Study protocol and registration The protocol of this review was published in the Medicine Journal in 2020 and registered with PROSPERO (registration number: CRD42020165698). 2.2. Data sources Twelve electronic databases were searched by 2 independent reviewers, with no language restrictions. We limited the publication period from January 2000 to February 2020. One Chinese database (Chinese National Knowledge Infrastructure), 5 English databases (Allied and Complementary Medicine Database, Excerpta Medica dataBASE, Cumulative Index to Nursing and Allied Health Literature, MEDLINE, and The Cochrane Database of Systematic Reviews), 5 Korean databases (DBPIA, Oriental Medicine Advanced Searching Integrated System, National Digital Science Library, Korean Studies Information Service System, and Research Information Service System), and 1 Japanese database (J-Stage) were searched. We searched for studies with database-mapped terms, such as Medical Subheading terms. For instance, Mahaenggamseoktang , Maxing Ganshi , MXSGT decoction, Maxingshigan , Ma- Xing-Gan-Shi Tang , and Ma Xing Shi Gan can all be mapped to MHGT. The full search strategies are presented in Appendix A (used in the English databases) and Appendix B (used in the Chinese databases), http://links.lww.com/MD/E765 . We translated the terms properly to the other databases. 2.3. Criteria for study selection 2.3.1. Types of studies. All RCTs assessing the efficacy of MHGT in patients with LRTIs were selected. All the selected studies included the term “randomization” methodologically. There were no restrictions on language, reporting type, or blinding. 2.3.2. Types of patients. This review involved acute LRTIs in pediatric patients. We included studies on acute LRTIs, such as pneumonia bronchiolitis and bronchitis, regardless of the cause, but we excluded chronic infection persisting for >3 weeks, LRTIs, or chronic respiratory diseases such as bronchiectasis, tuberculosis, and asthma. We also excluded studies on aspiration pneumonia. The patients were aged 0 to 16years, according to the US Food and Drug Administration classification of pediatric patients.  2.3.3. Types of interventions. We selected studies that used MHGT combined with conventional WMs as an experimental intervention and conventional WMs as a control intervention. Only oral administration of MHGT was allowed, regardless of the formulation; dose adjustment according to age was not allowed, nor was modified MHGT. The PRISMA flow chart provides detailed selection criteria (Fig. ). 2.4. Outcome measures The following outcome measures were used for data synthesis: Total effective rate: This is the proportion of patients who showed an effect after treatment. An effect was defined as any kind of improvement except for ineffectiveness (invalid). Since this outcome measure is commonly used to represent effectiveness in Chinese RCTs, we adopted these outcome measures. Symptom disappearance time: The following symptoms of LRTIs were reported in the selected studies: cough, fever, abnormal lung sound, and dyspnea. We used the disappearance time of cough, fever, and abnormal lung sounds for data synthesis. Inflammatory markers: C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor (TNF)-α, IL-6, immunoglobulin E (IgE), erythrocyte sedimentation rate (ESR), and antibody positivity rate were reported in the selected studies. We used CRP, PCT, TNF-α, IL-6, and IgE levels for data synthesis. Adverse events: This outcome measure was expressed as the proportion of all participants who experienced side effects. 2.5. Data extraction and quality assessment 2.5.1. Data extraction. All extraction was performed independently by 2 reviewers and proceeded as planned. We extracted the following data from the final set of studies: first author name, publication year, diagnosis, sample size (age and sex), interventions in experimental and control groups, outcome measures, and results. We converted the studies’ raw results into unified statistics for quantitative synthesis using Review Manager Version 5.4 Software. We used risk ratio (RR) to analyze dichotomous data and standardized mean differences (SMDs) for continuous data, both with 95% confidence intervals (CIs). 2.5.2. Quality assessment. Quality assessment was independently performed by two reviewers. We evaluated the following categories using the Cochrane risk of bias (ROB) assessment tool: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Our assessments were reported as low risk, unclear risk, or high risk. In case of any disagreement, a consensus was reached through discussion with other reviewers. The ROB is shown in Figure A and the risk of bias summary (Fig. B) details each risk of bias category. 2.5.3. Dealing with missing data. In cases of insufficient data, we attempted to contact the authors. If data were not obtained, the study was excluded. 2.6. Data analysis Data were synthesized and analyzed using Review Manager version 5.4 Software. 2.6.1. Issues with units of analysis. All the studies in this review were parallel design studies and not crossover design studies; therefore, there were no issues with the units of analysis. 2.6.2. Assessment heterogeneity. To evaluate heterogeneity of the studies, the I 2 statistic was used. If the I 2 value exceeded 50%, there was significant heterogeneity. In such cases, we discussed the reasons for the heterogeneity. However, no subgroup analysis was performed because each comparison only included a small number of studies. 2.6.3. Assessment of reporting bias. We evaluated reporting bias by drawing funnel plots when sufficient studies (>10) were synthesized. If the funnel plot was symmetrical, there was no reporting bias. 2.6.4. Sensitivity analysis. For the sensitivity analysis, iterative meta-analysis was performed while excluding each study one by one. 2.7. Quality of evidence We used the GRADEpro Guideline Development Tool ( https://gradepro.org/ ) to evaluate the level of evidence. We assessed the following categories: study design, risk of bias, inconsistency, indirectness, imprecision, and other considerations. After reviewing the authors’ assessment, the GRADE system classified the certainty of evidence as high, moderate, low, or very low (Table ). 2.8. Ethical approval As this review was based on published research, no ethical approval was required. 

The protocol of this review was published in the Medicine Journal in 2020 and registered with PROSPERO (registration number: CRD42020165698). 

Twelve electronic databases were searched by 2 independent reviewers, with no language restrictions. We limited the publication period from January 2000 to February 2020. One Chinese database (Chinese National Knowledge Infrastructure), 5 English databases (Allied and Complementary Medicine Database, Excerpta Medica dataBASE, Cumulative Index to Nursing and Allied Health Literature, MEDLINE, and The Cochrane Database of Systematic Reviews), 5 Korean databases (DBPIA, Oriental Medicine Advanced Searching Integrated System, National Digital Science Library, Korean Studies Information Service System, and Research Information Service System), and 1 Japanese database (J-Stage) were searched. We searched for studies with database-mapped terms, such as Medical Subheading terms. For instance, Mahaenggamseoktang , Maxing Ganshi , MXSGT decoction, Maxingshigan , Ma- Xing-Gan-Shi Tang , and Ma Xing Shi Gan can all be mapped to MHGT. The full search strategies are presented in Appendix A (used in the English databases) and Appendix B (used in the Chinese databases), http://links.lww.com/MD/E765 . We translated the terms properly to the other databases. 

2.3.1. Types of studies. All RCTs assessing the efficacy of MHGT in patients with LRTIs were selected. All the selected studies included the term “randomization” methodologically. There were no restrictions on language, reporting type, or blinding. 2.3.2. Types of patients. This review involved acute LRTIs in pediatric patients. We included studies on acute LRTIs, such as pneumonia bronchiolitis and bronchitis, regardless of the cause, but we excluded chronic infection persisting for >3 weeks, LRTIs, or chronic respiratory diseases such as bronchiectasis, tuberculosis, and asthma. We also excluded studies on aspiration pneumonia. The patients were aged 0 to 16years, according to the US Food and Drug Administration classification of pediatric patients.  2.3.3. Types of interventions. We selected studies that used MHGT combined with conventional WMs as an experimental intervention and conventional WMs as a control intervention. Only oral administration of MHGT was allowed, regardless of the formulation; dose adjustment according to age was not allowed, nor was modified MHGT. The PRISMA flow chart provides detailed selection criteria (Fig. ). 

The following outcome measures were used for data synthesis: Total effective rate: This is the proportion of patients who showed an effect after treatment. An effect was defined as any kind of improvement except for ineffectiveness (invalid). Since this outcome measure is commonly used to represent effectiveness in Chinese RCTs, we adopted these outcome measures. Symptom disappearance time: The following symptoms of LRTIs were reported in the selected studies: cough, fever, abnormal lung sound, and dyspnea. We used the disappearance time of cough, fever, and abnormal lung sounds for data synthesis. Inflammatory markers: C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor (TNF)-α, IL-6, immunoglobulin E (IgE), erythrocyte sedimentation rate (ESR), and antibody positivity rate were reported in the selected studies. We used CRP, PCT, TNF-α, IL-6, and IgE levels for data synthesis. Adverse events: This outcome measure was expressed as the proportion of all participants who experienced side effects. 

2.5.1. Data extraction. All extraction was performed independently by 2 reviewers and proceeded as planned. We extracted the following data from the final set of studies: first author name, publication year, diagnosis, sample size (age and sex), interventions in experimental and control groups, outcome measures, and results. We converted the studies’ raw results into unified statistics for quantitative synthesis using Review Manager Version 5.4 Software. We used risk ratio (RR) to analyze dichotomous data and standardized mean differences (SMDs) for continuous data, both with 95% confidence intervals (CIs). 2.5.2. Quality assessment. Quality assessment was independently performed by two reviewers. We evaluated the following categories using the Cochrane risk of bias (ROB) assessment tool: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Our assessments were reported as low risk, unclear risk, or high risk. In case of any disagreement, a consensus was reached through discussion with other reviewers. The ROB is shown in Figure A and the risk of bias summary (Fig. B) details each risk of bias category. 2.5.3. Dealing with missing data. In cases of insufficient data, we attempted to contact the authors. If data were not obtained, the study was excluded. 

Data were synthesized and analyzed using Review Manager version 5.4 Software. 2.6.1. Issues with units of analysis. All the studies in this review were parallel design studies and not crossover design studies; therefore, there were no issues with the units of analysis. 2.6.2. Assessment heterogeneity. To evaluate heterogeneity of the studies, the I 2 statistic was used. If the I 2 value exceeded 50%, there was significant heterogeneity. In such cases, we discussed the reasons for the heterogeneity. However, no subgroup analysis was performed because each comparison only included a small number of studies. 2.6.3. Assessment of reporting bias. We evaluated reporting bias by drawing funnel plots when sufficient studies (>10) were synthesized. If the funnel plot was symmetrical, there was no reporting bias. 2.6.4. Sensitivity analysis. For the sensitivity analysis, iterative meta-analysis was performed while excluding each study one by one. 

We used the GRADEpro Guideline Development Tool ( https://gradepro.org/ ) to evaluate the level of evidence. We assessed the following categories: study design, risk of bias, inconsistency, indirectness, imprecision, and other considerations. After reviewing the authors’ assessment, the GRADE system classified the certainty of evidence as high, moderate, low, or very low (Table ). 

As this review was based on published research, no ethical approval was required. 

3.1. Study selection Initially, 533 studies were identified. After removing eight duplicate studies, 525 studies were included. A total of 258 studies were excluded during abstract and title screening. At fulltext screening, 26 studies were excluded for “not RCT,” 57 for “age >16years,” 101 for “using modified MHGT,” 23 for “dose adjustment according to age,” and 41 for other reasons. Ultimately, 19 studies remained. After excluding the group using MHGT only as the treatment group, 17 studies were finally extracted for our meta-analysis (Fig. ). 3.2. Participants The 17 selected studies involved 1993 participants, all of whom were aged between 0 and 16years. They were radiologically and clinically diagnosed with acute LRTIs (Table ). 3.3. Intervention 3.3.1. Experimental intervention. Oral decoction of MHGT plus WM was used in 17 studies.  Two studies  using only oral decoction of MHGT were excluded from the metaanalysis owing to differences in trial design (MHGT vs WM). The longest treatment period was 28 days, whereas the shortest was 3 days. The mean treatment period was approximately 9 days. The treatment frequency was once daily to ≥3 times per day. The period and frequency of the treatment were diverse (Table ). 3.3.2. Control intervention. WMs were used in all studies.  Mycoplasma or bacterial infection was treated with antibiotics. Viral infections were treated with antiviral drugs. Drugs were administered via intravenous injection, infusion, or orally. Various medical interventions were used in the study (Table ). 3.4. Outcomes As outcome measures in the final 17 studies, 14 studies  used total effective rate, 8  used cough disappearance time, 7  used fever disappearance time, and 7  used abnormal lung sound disappearance time. Eight studies  used CRP, 3  used PCT, 2  used TNF-α, 2  used IL-6, and 2  used IgE. Eight studies  used adverse events (Table ). 3.5. Risk of bias All 17 studies performed randomized clinical trials and mentioned random sequence generation. However, 7 studies  mentioned that their trials were randomized. Seven studies used random numbers. None of the 17 studies mentioned allocation concealment, blinding of participants and personnel, blinding of outcome assessment, or selective reporting. Because decoctions, rather than a placebo, were used, blinding was not feasible. None of the studies had incomplete outcome data (Fig. ). 3.6. Effect of interventions All 17 studies that performed meta-analysis were compared using the MHGT plus WM group using the WM only group (Table ). 3.6.1. Total effective rate. Sixteen studies  reported the total effective rate and 14 of these  were included in the meta-analysis. These 14 studies involved 1743 participants. Twelve studies  had significant outcomes ( P < .05), and 2  did not have significant outcomes ( P > 0 .05). The meta-analysis of total effective rate showed that MHGT plus WM had a greater effect than WM alone (RR: 1.20, 95% CI: 1.10-1.31, P < .001; Fig. ). 3.6.2. Symptom disappearance time. Eight studies  involving 602 participants reported cough disappearance time. Fever disappearance time was reported in 7 studies  involving 510 participants. Seven studies  used abnormal lung sound disappearance time as an outcome measure, with 522 participants. All of these studies showed significant outcomes ( P < .05), and the results of cough disappearance time (SMD: -1.62, 95% CI: -2.30 to -0.95, P < .001), fever disappearance time (SMD: -2.04, 95% CI: -2.87 to -1.21, P < .001), and abnormal lung sound disappearance time (SMD: -1.68, 95% CI: -2.43 to -0.93, P < .001) indicated that the MHGT plus WM group had a shorter symptom duration than the WM only group (Fig. ). 3.6.3. Inflammatory markers. Eight studies  presented CRP as an outcome measure, with 1090 participants. Three studies  involving 298 participants reported PCT levels. TNF-α was detected in 2 studies  , with 283 participants. Two studies  reported that IL-6 was involved in 283 participants. Finally, 2 studies  used IgE as an outcome measure and involved 610 participants. All studies with any these five outcomes showed significant results ( P < .05). However, meta-analysis of IL-6 (SMD: -1.59, 95% CI: -3.48 to 0.30, P > .05) showed no significant effect of MHGT plus WM on IL-6. The meta-analyses of CRP (SMD: -3.18, 95% CI: -4.36- to -1.99, P < .001), PCT (SMD: -5.04, 95% CI: -9.20 to -0.88, P < .05), TNF-α (SMD: -0.84, 95% CI: -1.46 to -0.23, P < .01), and IgE (SMD: -2.69, 95% CI: -2.91 to -2.47, P < .001) showed that MHGT plus WM had a greater antiinflammatory effect than WM alone (Fig. ). 3.6.4. Adverse events. Nine studies  used adverse events as outcome measures, and one study  was excluded because only MHGT was used. A total of 1165participants were included in the 8 studies.  Only 3 studies  had significant outcomes ( P < .05). However, the meta-analysis of adverse events (RR: 0.44, 95% CI: 0.29-0.68; P < .001) showed that MHGT plus WM had better safety than WM alone (Fig. ). 3.7. Sensitivity analysis As a result of the sensitivity analysis on total effective rate, among the 14 studies, the pooled estimate of the study that published by Guo et al was 1.16 (95% CI: 1.10 to -1.23), which occupied a large proportion, but had no effect on the overall pooled estimate (Table ). 3.8. GRADE quality of evidence The Grading of Recommendations, Assessment, Development, and Evaluation approach was performed using the GRADEpro Guideline Development Tool ( https://gradepro.org/ ). The quality of evidence was low to very low. A funnel plot of the total effective rate showed that studies reporting the total effective rate might have reporting bias. The quality of evidence was moderate for IgE and adverse events (Table , Fig. ). 

Initially, 533 studies were identified. After removing eight duplicate studies, 525 studies were included. A total of 258 studies were excluded during abstract and title screening. At fulltext screening, 26 studies were excluded for “not RCT,” 57 for “age >16years,” 101 for “using modified MHGT,” 23 for “dose adjustment according to age,” and 41 for other reasons. Ultimately, 19 studies remained. After excluding the group using MHGT only as the treatment group, 17 studies were finally extracted for our meta-analysis (Fig. ). 

The 17 selected studies involved 1993 participants, all of whom were aged between 0 and 16years. They were radiologically and clinically diagnosed with acute LRTIs (Table ). 

3.3.1. Experimental intervention. Oral decoction of MHGT plus WM was used in 17 studies.  Two studies  using only oral decoction of MHGT were excluded from the metaanalysis owing to differences in trial design (MHGT vs WM). The longest treatment period was 28 days, whereas the shortest was 3 days. The mean treatment period was approximately 9 days. The treatment frequency was once daily to ≥3 times per day. The period and frequency of the treatment were diverse (Table ). 3.3.2. Control intervention. WMs were used in all studies.  Mycoplasma or bacterial infection was treated with antibiotics. Viral infections were treated with antiviral drugs. Drugs were administered via intravenous injection, infusion, or orally. Various medical interventions were used in the study (Table ). 

As outcome measures in the final 17 studies, 14 studies  used total effective rate, 8  used cough disappearance time, 7  used fever disappearance time, and 7  used abnormal lung sound disappearance time. Eight studies  used CRP, 3  used PCT, 2  used TNF-α, 2  used IL-6, and 2  used IgE. Eight studies  used adverse events (Table ). 

All 17 studies performed randomized clinical trials and mentioned random sequence generation. However, 7 studies  mentioned that their trials were randomized. Seven studies used random numbers. None of the 17 studies mentioned allocation concealment, blinding of participants and personnel, blinding of outcome assessment, or selective reporting. Because decoctions, rather than a placebo, were used, blinding was not feasible. None of the studies had incomplete outcome data (Fig. ). 

All 17 studies that performed meta-analysis were compared using the MHGT plus WM group using the WM only group (Table ). 3.6.1. Total effective rate. Sixteen studies  reported the total effective rate and 14 of these  were included in the meta-analysis. These 14 studies involved 1743 participants. Twelve studies  had significant outcomes ( P < .05), and 2  did not have significant outcomes ( P > 0 .05). The meta-analysis of total effective rate showed that MHGT plus WM had a greater effect than WM alone (RR: 1.20, 95% CI: 1.10-1.31, P < .001; Fig. ). 3.6.2. Symptom disappearance time. Eight studies  involving 602 participants reported cough disappearance time. Fever disappearance time was reported in 7 studies  involving 510 participants. Seven studies  used abnormal lung sound disappearance time as an outcome measure, with 522 participants. All of these studies showed significant outcomes ( P < .05), and the results of cough disappearance time (SMD: -1.62, 95% CI: -2.30 to -0.95, P < .001), fever disappearance time (SMD: -2.04, 95% CI: -2.87 to -1.21, P < .001), and abnormal lung sound disappearance time (SMD: -1.68, 95% CI: -2.43 to -0.93, P < .001) indicated that the MHGT plus WM group had a shorter symptom duration than the WM only group (Fig. ). 3.6.3. Inflammatory markers. Eight studies  presented CRP as an outcome measure, with 1090 participants. Three studies  involving 298 participants reported PCT levels. TNF-α was detected in 2 studies  , with 283 participants. Two studies  reported that IL-6 was involved in 283 participants. Finally, 2 studies  used IgE as an outcome measure and involved 610 participants. All studies with any these five outcomes showed significant results ( P < .05). However, meta-analysis of IL-6 (SMD: -1.59, 95% CI: -3.48 to 0.30, P > .05) showed no significant effect of MHGT plus WM on IL-6. The meta-analyses of CRP (SMD: -3.18, 95% CI: -4.36- to -1.99, P < .001), PCT (SMD: -5.04, 95% CI: -9.20 to -0.88, P < .05), TNF-α (SMD: -0.84, 95% CI: -1.46 to -0.23, P < .01), and IgE (SMD: -2.69, 95% CI: -2.91 to -2.47, P < .001) showed that MHGT plus WM had a greater antiinflammatory effect than WM alone (Fig. ). 3.6.4. Adverse events. Nine studies  used adverse events as outcome measures, and one study  was excluded because only MHGT was used. A total of 1165participants were included in the 8 studies.  Only 3 studies  had significant outcomes ( P < .05). However, the meta-analysis of adverse events (RR: 0.44, 95% CI: 0.29-0.68; P < .001) showed that MHGT plus WM had better safety than WM alone (Fig. ). 

As a result of the sensitivity analysis on total effective rate, among the 14 studies, the pooled estimate of the study that published by Guo et al was 1.16 (95% CI: 1.10 to -1.23), which occupied a large proportion, but had no effect on the overall pooled estimate (Table ). 

The Grading of Recommendations, Assessment, Development, and Evaluation approach was performed using the GRADEpro Guideline Development Tool ( https://gradepro.org/ ). The quality of evidence was low to very low. A funnel plot of the total effective rate showed that studies reporting the total effective rate might have reporting bias. The quality of evidence was moderate for IgE and adverse events (Table , Fig. ). 

In this review, all but 1  of the 17 trials compared combined MHGT plus WM therapy with WM alone and were analyzed in the meta-analysis. In comparison to WM alone, MHGT plus WM significantly improved the total effective rate and symptom disappearance time (cough, fever, and abnormal lung sound), decreased inflammatory parameters (CRP, PCT, TNF-α, IL-6, and IgE), and reduced adverse events. Previous experimental studies suggest that these findings might be due to an anti-inflammatory effect caused by the inhibition of pro-inflammatory NF-κB expression in lung inflammation.  And also, in traditional medicine, when respiratory patients have kinds of inflammatory symptoms like fever and cough, they are commonly diagnosed as heat syndrome.  According to traditional medicine, one of MHGT, gypsum fibrosum , have been known to have cooling effects on fever accumulated in the body.  Thus, in this study, the alleviation of LRTI symptoms and inflammatory parameters may have been mediated through the above-mentioned cooling mechanism. Especially, inflammatory parameters in the lung disease are known to be meaningful in determining the prognosis of respiratory disease.  Several studies reported that the respiratory inflammatory response increased the expression of solid tumors and chronic severe lung disease.  Considering the above, reducing the inflammatory parameters of respiratory diseases is critical not only for decreasing the prevalence of LRTI, but also for preventing the exacerbation of more severe chronic respiratory diseases such as cancer and COPD. Our results may also suggest that MHGT could have a potential effect to treat COVID-19, whose symptoms are similar to those of LRTIs. According to pharmacological network analysis, MHGT and SARS-CoV-2 have 42 common targets, a few of which are deeply related to inflammation and immune responses.  In fact, MHGT also inhibits the synthesis of viral proteins and RNA and abolishes viral entry regulated by the PI3K/AKT signaling pathway.  In addition, previous experimental study reported that several compounds of MHGT ( Ephedra sinica and Glycyrrhiza uralensis Fisch.) have antiviral effects by relieving airway inflammation.  As a result, MHGT seems to have a similar effect on COVID-19 infection as LRTI. Especially, in regard to above antiviral effect, MHGT can lead to various positive effects to not only health issue but also social issue. Recently, the rapid spread of viral infections such as COVID-19 is causing serious problems such as burnout and worsening quality of life among healthcare professionals as well as COVID-19 patients. Since respiratory disease pandemic, according to the measures taken by the Canada administration, the prevalence of severe burnout among health care professionals due to the acute viral infection outbreak was 30% to 40% in 2020, and even 60% in 2021.  Now such burnout has become a major emerging issue as a result of the sudden increase of the number of patients with respiratory viral infections. Their burnout is harmful for the health care system and affects less-safe patient care  and immense cost on the society.  In accordance with these issues, it is believed that reducing the prevalence of respiratory diseases through the antiviral effect of MHGT will benefit both medical and social aspects. Furthermore, one previous study reported that in patients with severe respiratory diseases such as COPD, microbial infection can cause airway stenosis, which can lead to serious complications.  Therefore, the prevention effect of MHGT for LRTI might helpful for not only alleviating the burden of medical care but also reducing severity of respiratory symptoms. Based on these results, MHGT may represent a therapeutic and preventive approach to treat LRTI. And it also has meaningful result to reduce antibiotic overuse. However, these results are not sufficient to make recommendations. The limitations of this study must be considered. First, the ROB summary and quality of evidence showed that the quality of the included studies was low. None of the included studies involved blinding, and many had unclear points regarding ROB. The quality of evidence regarding IgE and adverse events was evaluated as “moderate,” but few studies evaluated IgE and adverse events, and almost all of those that did were poorly randomized RCTs. Second, the included RCTs were all Chinese-based studies, and therefore there was a lack of diversity. Third, many results of the meta-analysis showed high heterogeneity. Limited differences in patient status, patient age, intervention, etc., in the included studies may result in high heterogeneity. For example, studies  reporting IL-6 as an outcome measure did not indicate a significant outcome in metaanalysis because of heterogeneity resulting from differences in patient status and the methods of intervention. In particular, different patient statuses resulted in high heterogeneity. None of the included studies used the same intervention method. Because of these limitations, the results of this review should be interpreted carefully. Third, in our systematic review, all included RCTs used the MHGT and WM as their intervention not MHGT alone. Although most of control group are WM, it means that the effect of MHGT might be controversial in terms of replacement of antibiotics. Therefore, further high-quality RCT studies are needed using MHGT alone. The strengths of this study are summarized as follows: we fully searched all Asian databases, including the Japanese database, without language restrictions, compared to other systematic reviews. And, to our knowledge, this is the first systematic review investigating the synergistic effect of the MHGT in children with LRTI. This showed that the synergistic effect which is combined therapy using MHGT and WM had better effects on LRTIs, with improved safety. In future research, more highly controlled RCTs with similar interventions are needed to allow confident recommendations to be made. 

In this study, we found the synergistic effect of MHGT for LRTI in pediatric patients. Combined therapy using MHGT and WM had better effects on childhood LRTIs than WM only in terms of total effective rate, symptom disappearance time, inflammatory factors, and adverse events. However, the results of this review must be interpreted cautiously because the studies included had low quality. Therefore, high-quality RCTs with rigorous study design and large numbers of patients are needed before clinicians can prescribe MHGT to treat patients with LRTIs. And because this study investigated only the synergistic effect of MHGT with WM, additional RCT studies are needed to prove the efficacy and safety of MHGT alone in the treatment of LRTIs and its potential as an alternative to antibiotics. 

MSH and ARJ designed the study. HBB, HJL searched, selected, and excluded studies and analyzed the data. HBB, HJL, and ARJ wrote the manuscript and SBY interpreted the results. All of them reviewed the study and contributed to revising the manuscript for the final version. Conceptualization: Aram Jeong, Man-suk Hwang. Data curation: Han-Bum Bae, Hyun-Jung Lee. Funding acquisition: Aram Jeong, Man-suk Hwang. Methodology: Han-Bum Bae. Project administration: Man-suk Hwang. Software: Han-Bum Bae. Supervision: Aram Jeong, Man-suk Hwang. Writing - original draft: Han-Bum Bae, Hyun-Jung Lee, Man-suk Hwang. Writing - review & editing: Seung-Bo Yang, Aram Jeong. 

