Efficacy of Lianhua Qingwen Compared with Conventional Drugs in the Treatment of Common Pneumonia and COVID-19 Pneumonia: A Meta-Analysis

Methods Seven English and Chinese databases were used to search for qualified experimental studies as of July 27, 2020. All data were extracted directly from the included studies, and no special conversion formula was used. The weighted mean difference (WMD), 95% confidence interval (CI), and odds ratio (OR) were used for evaluation. Results Forty-two studies involving 3793 subjects met the qualification criteria. For common pneumonia, a short duration of flu-like symptoms (WMD = −1.81, 95% CI = −2.12 to −1.50, P < 0.001), sputum (WMD = −1.10, 95% CI = −1.50 to −0.70, P < 0.001), pulmonary rale (WMD = −2.03, 95% CI = −2.74 to −1.31, P < 0.001), pulmonary imaging improvement (WMD = −1.88, 95% CI = −2.28 to −1.47, P < 0.001), curative effect (OR = 3.65, 95% CI = 2.81 to 4.76, P < 0.001), and healing period (WMD = −1.68, 95% CI = −2.62 to −0.74, P < 0.001) were associated with the Lianhua Qingwen group; subgroup analysis based on flu-like symptoms showed statistically significant improvements in fever and cough. For COVID-19 pneumonia, improvements in flu-like symptoms (OR = 3.18, 95% CI = 2.36 to 4.29, P < 0.001), shortness of breath (OR = 10.62, 95% CI = 3.71 to 30.40, P < 0.001), curative effect (OR = 2.49, 95% CI = 1.76 to 3.53, P < 0.001), healing period (WMD = −2.06, 95% CI = −3.36 to −0.75, P = 0.002), and conversion of severe cases (OR = 0.46, 95% CI = 0.27 to 0.77, P = 0.003) were associated with the Lianhua Qingwen group; subgroup analysis indicated statistically significant improvements of fever, cough, fatigue, and muscle pain in the Lianhua Qingwen group compared to the conventional drug group. Regarding adverse reactions, no significant difference was detected for common pneumonia (OR = 0.75, 95% CI = 0.54 to 1.05, P = 0.097). Conclusions Lianhua Qingwen combined with conventional drugs may be a promising therapy for treating common pneumonia and COVID-19 pneumonia.


Study Inclusion and Exclusion Criteria.
Studies were selected based on the following criteria: (1) experimental studies; (2) pneumonia was diagnosed according to clinical symptoms, laboratory tests, chest X-ray results, or relevant diagnostic criteria; (3) the Lianhua Qingwen group was treated with Lianhua Qingwen or Lianhua Qingwen combined with conventional drugs (the conventional drug group was given conventional antibiotics, antiviral drugs, or symptomatic treatment); and (4) relevant data of the efficacy index (i.e., flu-like symptoms (fever, cough, sore throat, nausea, diarrhoea, loss of appetite, fatigue, muscle pain, and headache); sputum; pulmonary rales; shortness of breath; breathlessness; chest tightness; pulmonary imaging improvement; curative effect; healing period; conversion of severe cases; and adverse reactions) were provided. e following types of studies were excluded: letters, case reports, those with duplicate or incomplete data (including those in which the efficacy index did not meet the inclusion criteria), reviews or commentaries, animal-based studies, irrelevant studies, and those with a non-Western medicine control.

Data Extraction and Quality Evaluation.
e following information was collected: the first author's name, year of publication, age, sex, sample size, efficacy index, and adverse reactions. All data were extracted directly from the included studies, and no special conversion formula was used. Continuous variables included the total number of patients with symptoms (reported as the mean and standard deviation), and categorical variables included the number of patients with symptoms and the number of patients without symptoms. Disagreements were resolved by a panel discussion with other reviewers. e quality of the eligible studies was evaluated by the CONSORT statement [13] and the Jadad scale [14], which considered sample size determination, randomization, blinding, and loss to follow-up/ withdrawal; scores of 0-2, 3-4, and 5-7 were rated as low, moderate, and high quality, respectively. e Cochrane Collaboration risk of bias tool [15], which consists of seven items, was used to classify each item as low risk of bias, high risk of bias, and unclear risk of bias.

Statistical Analysis.
Statistical analysis was performed using Stata 14 (Stata Corporation, College Station, TX, USA). Continuous variables are expressed as the weighted mean difference (WMD) and 95% confidence interval (CI), and categorical variables are expressed as the odds ratio (OR) and 95% CI. Heterogeneity was evaluated with the I 2 statistic: when I 2 > 50%, indicating obvious heterogeneity, a random-effects model was used; otherwise, a fixed-effects model was used [16,17]. Subgroup, sensitivity, and regression analyses were used to explore possible sources of heterogeneity. Subgroup analysis was performed based on the pneumonia type or flu-like symptoms. Sensitivity analysis was performed to assess the influence of each study on a pooled estimate by excluding studies individually and rerunning the meta-analysis. Publication bias was assessed by Begg's test and Egger's test, and visual estimation (via a funnel plot) was also considered; if bias existed, the "trim and fill" method was used to assess publication bias [18]. A P value <0.05 was considered statistically significant.

Search Results.
e detailed flowchart of article selection is presented in Figure 1. A total of 314 citations were identified, and of these, 148 duplicate citations were removed; 59 citations were excluded for irrelevant or animal studies by screening the title and abstract. After full-text screening of the remaining 107 citations, an additional 65 citations were excluded due to the reasons given in Figure 1. Ultimately, 42 experimental Chinese studies involving 3793 subjects were subjected to the meta-analysis. e publication year ranged from 2012 to 2020 . Of these studies, 35 researched common pneumonia (including viral pneumonia, mycoplasma pneumonia, community-acquired pneumonia, bronchial pneumonia, bacterial pneumonia, or pneumonia), and the remaining 7 studies researched COVID-19 pneumonia (diagnosed according to the National Health Commission of the People's Republic of China published guidelines for the diagnosis and treatment of COVID-19 pneumonia: Trial version from the Fourth/Fifth Edition). e control groups were given conventional antibiotics, antiviral drugs, or symptomatic treatment. e main characteristics and quality scores of the eligible studies on common pneumonia and COVID-19 pneumonia are shown in Table 1. Regarding the risk of bias assessment, 33 studies reported randomization (of which 12 studies clearly described the randomized methods), and the remaining 9 studies were grouped according to interventions or the hospitalization order. Only one study reported allocation concealment and blinding method, since the symptom indicators needed to be measured by instruments or humans. erefore, most studies with blinded participants and personnel and a blinded outcome assessment were classified as "unclear risk of bias." Concerning incomplete outcome data and selective reporting, since most studies reported complete data on all symptom indicators, there was a low risk of attrition bias and reporting bias. e percentage of risk of bias is shown in Figure 2.

Flu-Like Symptoms.
irty-one studies compared the duration of flu-like symptoms between the Lianhua Qingwen and conventional drug groups. Among these studies, 29 reported the symptom remission time for fever, and 26 reported the symptom remission time for cough. A short duration of flu-like symptoms was observed in the Lianhua Qingwen group (WMD � −1.81, 95% CI � −2.12 to −1.50, P < 0.001). Subgroup analysis showed significant differences in the durations of fever (WMD � −1.58, 95% CI � −1.99 to −1.17, P < 0.001) and cough (WMD � −2.07, 95% CI � −2.57 to −1.57, P < 0.001) between the Lianhua Qingwen and conventional drug groups. Figure 3 shows a forest plot of flulike symptoms for common pneumonia.

Other Symptoms
Sputum. Four studies reported the effects of Lianhua Qingwen and those of conventional drugs on the duration of sputum. e duration of sputum was shorter in the Lianhua Qingwen group than in the conventional drug group (WMD � −1.10, 95% CI � −1.50 to −0.70, P < 0.001). Pulmonary Rale. Eighteen studies reported an effect on the duration of pulmonary rale. e duration of fever was shorter in the Lianhua Qingwen group than in the conventional drug group (WMD � −2.03, 95% CI � −2.74 to −1.31, P < 0.001). Pulmonary Imaging Improvement. Seven studies reported the duration of pulmonary imaging improvement.
e difference between the Lianhua Qingwen group and the conventional drug group was statistically significant (WMD � −1.88, 95% CI � −2.28 to −1.47, irty studies reported the curative effect of Lianhua Qingwen and that of conventional drugs. e difference between the Lianhua Qingwen group and the conventional drug group was statistically significant (OR � 3.65, 95% CI � 2.81 to 4.76, P < 0.001). Healing Period. Twelve studies reported the healing period of the Lianhua Qingwen and conventional drug groups. e Lianhua Qingwen group had a shorter healing period than the conventional drug group (WMD � −1.68, 95% CI � −2.62 to −0.74, P < 0.001).
Results from the quantitative analysis of common pneumonia are shown in Table 2. Forest plots of other symptoms related to common pneumonia are shown in Figure S1.

Flu-Like Symptoms.
Four studies compared improving flu-like symptoms (fever, cough, sore throat, nausea, diarrhoea, loss of appetite, fatigue, muscle pain, and headache) between the Lianhua Qingwen and conventional drug groups. e difference in improving flu-like symptoms between the Lianhua Qingwen and conventional drug groups was statistically significant (OR � 3. 18 Figure 3 shows a forest plot of flu-like symptoms for COVID-19 pneumonia.

Other Symptoms
Sputum. ree studies reported the improvement in sputum. e difference in sputum improvement was statistically significant between the Lianhua Qingwen and conventional drug groups (OR � 4.30, 95% CI � 1.01 to 18.22, P � 0.048). Shortness of Breath. ree studies compared the effect of Lianhua Qingwen with that of conventional drugs on the shortness of breath, and Lianhua Qingwen was associated with a better effect than conventional drugs (OR � 10.62, 95% CI � 3.71 to 30.40, P < 0.001). Breathlessness. ree studies reported improvement in breathlessness in the Lianhua Qingwen and conventional drug groups. However, it failed to identify a statistically significant difference between the two groups (OR � 4.81, 95% CI � 0.97 to 23.86, P � 0.055).

Chest Tightness.
ree studies reported the curative effect of chest tightness. A statistically significant difference was identified between the Lianhua Qingwen group and the conventional drug group (OR � 3.02, 95% CI � 1.23 to 7.42, P � 0.016).
Pulmonary Imaging Improvement. Five studies reported improvement in pulmonary imaging. A statistically significant difference was identified between the Lianhua Qingwen group and the conventional drug group (OR � 1.77, 95% CI � 1.29 to 2.42, P < 0.001).
Curative Effect. Five studies compared the curative effect of Lianhua Qingwen with that of conventional drugs. A statistically significant difference was identified between the two groups (OR � 2.49, 95% CI � 1.76 to 3.53, P < 0.001).
Healing Period. Two studies reported the healing period of the Lianhua Qingwen and conventional drug groups.

Conversion of Severe Cases.
Four studies reported the conversion of severe cases in both groups. A statistically significant difference was detected between the two groups (OR � 0.46, 95% CI � 0.27 to 0.77, P � 0.003).

Publication Bias.
e index involving the largest number of qualified studies was used to assess publication bias. For common pneumonia, 30 studies that reported curative effects were used to assess publication bias, and neither Begg's test nor Egger's test found any visible evidence for publication bias (P Begg � 0.153, P Egger � 0.577). Since

Discussion
Antibiotics are a traditional choice used to treat treating pneumonia; however, the inappropriate use of antibiotics leads to increasing problems such as antimicrobial resistance and is related to multiple adverse effects [61,62]. According to recent research, the death toll will reach 10 million by 2050, due to infections caused by resistant bacteria [63]. A simple infection may be fatal in the future, and it is of crucial importance to identify and find an effective and safe alternative for treating pneumonia. Traditional Chinese medicine has been extensively used, as it offers unique advantages in regulating homeostasis and improving immunity, prevention, and control. Lianhua Qingwen is a traditional Chinese medicine that can relieve fever, act as an antitussive expectorant, dispel a cold, eliminate inflammation, provide endogenous heat, act as an antiviral agent, and improve immunity [64][65][66]. Some studies have reported that Lianhua Qingwen is effective against viral or bacterial infections in pneumonia [40,46,48,67]; however, its principle of treatment remains inconclusive. Animal experiments have shown that Lianhua Qingwen plays a protective role in lung tissue damage by inhibiting inflammatory cell infiltration and improving protein expression in alveolar epithelial and pulmonary vascular endothelial cells [68]. Pharmacological experiments have indicated that a high dosage of Lianhua Qingwen alters the effectiveness of cyclooxygenase-2 in the arachidonic acid metabolic pathway and decreases decrease virus replication, producing significant improvements in lung inflammation [69]. It was recently reported that Lianhua Qingwen plays a significant role in the treatment of pneumonia by significantly reducing pathological changes, which might be correlated with the levels of enzymes regulated by Lianhua Qingwen, such as glutathione peroxidase, lactate dehydrogenase, superoxide dismutase, and malonaldehyde [65]. Previous studies reviewed historical records and prevention measures against SARS, H1N1 influenza, and Middle East respiratory syndrome (MERS) and reported that traditional Chinese medicine might be an alternative for the prevention and treatment of COVID-19 pneumonia [70][71][72][73]. Lu et al. [74] reported that Lianhua Qingwen plays an active role in controlling COVID-19 pneumonia, especially mild symptoms. Our meta-analysis was performed to compare the effect of Lianhua Qingwen and conventional drugs on pneumonia symptoms. For common pneumonia, this study observed that the Lianhua Qingwen group was associated with shorter durations of flu-like symptoms, sputum, pulmonary rale, pulmonary imaging improvement, and healing period than  conventional drugs; a statistically significant curative effect was also identified. e subgroup analysis based on flu-like symptoms showed statistically significant differences in fever and cough; sensitivity analysis showed that the pooled results related to common pneumonia were stable. A metaanalysis by Zhou et al. [75] revealed that Lianhua Qingwen combined with another treatment for patients with community-acquired pneumonia could improve the effective rate and pulmonary imaging and shorten durations of fever and cough, consistent with our meta-analysis. However, our meta-analysis was more comprehensive, as more new studies were included, and other important indicators of pneumonia, such as pulmonary rale, sputum, and healing period, were also taken into account. For COVID-19 pneumonia, we found that Lianhua Qingwen was more useful for improving flu-like symptoms, sputum, shortness of breath, chest tightness, pulmonary imaging improvement, curative effect, healing period, and conversion of severe cases than conventional drugs. Subgroup analysis indicated statistically significant improvements in fever, cough, fatigue, and muscle pain; however, sensitivity analysis revealed unstable results related to sputum, chest tightness, and pulmonary imaging improvement. is inconsistency might be due to the limited number of eligible studies. Only three qualified studies that reported curative effects of typical clinical symptoms were identified, and a further stratified analysis was unavailable for the meta-analysis. Several recent studies support our conclusion that Lianhua Qingwen has a positive effect on the recovery of common pneumonia and COVID-19 pneumonia. Runfeng  However, no other analysis was performed to detect possible sources of heterogeneity and assess the stability of the results. Even though the efficacy and outcome indicators were not as complete as ours, the results support our results to a certain extent. Our study found a statistically significant difference in adverse reactions between the Lianhua Qingwen group and the conventional drug group. Although sensitivity analysis revealed changes in adverse reactions, subgroup analysis showed no significant difference concerning common pneumonia. Yiling Pharmaceutical, which is responsible for research on the production of Lianhua Qingwen, has reported no genotoxicity or nephrotoxicity of Lianhua Qingwen according to systemic toxicology studies [77]. A meta-analysis focused solely on the safety of Lianhua Qingwen that involved 40 RCTs reported that the incidence of adverse reactions in the Lianhua Qingwen group was significantly lower than that in the control group (RR � 0.562, 95% CI � 0.412-0.767, P value not reported). Subgroup analysis showed that the incidence of digestive system adverse reactions in the Lianhua Qingwen group was also lower than that in the control group (RR � 0.70, 95% CI � 0.50 to 0.97, P value not reported), suggesting the safety of Lianhua Qingwen [78]. Previous studies have also shown that Lianhua Qingwen has therapeutic effects on influenza.
ree meta-analyses explored the efficacy/safety of Lianhua Qingwen and conventional drugs for treating influenza. Among them, Wang et al. [79] showed that Lianhua Qingwen has a superior curative effect on the treatment of viral influenza, but the incidence of adverse reactions was higher than that of conventional drugs; therefore, clinicians should pay should pay close attention to the safety of Lianhua Qingwen. Niu et al. [80] reported that Lianhua Qingwen was highly safe and had a better curative effect on Evidence-Based Complementary and Alternative Medicine the treatment of influenza than oseltamivir, ribavirin, ammonia yellow capsules, and even Huaqing Pesti capsules. Zhao et al. [81] concluded that Lianhua Qingwen was better than oseltamivir in improving the symptoms of influenza A virus infection, and no significant drug-related adverse reactions were observed in any of the included studies. us, these findings suggest that Lianhua Qingwen exerts better therapeutic effects by improving disease symptoms than conventional drugs, but the safety of Lianhua Qingwen cannot be ignored. Additional studies with a focus on the safety and association of Lianhua Qingwen with diseases should be performed.
Several limitations to our meta-analysis should be noted. First, the quality of the included studies was generally moderate, and only seven studies on COVID-19 pneumonia were included; thus, more high-quality research is needed. Second, the results of some indicators of COVID-19 pneumonia and adverse reactions were unstable. Since the number of studies on COVID-19 pneumonia were limited, publication bias and meta-regression analysis have not been performed. Finally, although English and Chinese articles were retrieved, only Chinese studies were qualified; therefore, language bias might not be excluded.
Some advantages should be mentioned. First, to our knowledge, this is the most comprehensive meta-analysis of the efficacy of Lianhua Qingwen for the treatment of common pneumonia and COVID-19 pneumonia. Second, to our knowledge, this is the first meta-analysis of the use of Lianhua Qingwen for the treatment of pneumonia based on several indicators (i.e., sputum, curative effect, and healing period for common pneumonia; flu-like symptoms, shortness of breath, breathlessness, chest tightness, pulmonary imaging improvement, healing period, and conversion of severe cases for COVID-19 pneumonia). Finally, we determined that Lianhua Qingwen combined with conventional drugs can better promote the recovery of certain clinical symptoms related to common pneumonia and COVID-19 pneumonia than conventional drugs.

Conclusion
Lianhua Qingwen combined with conventional drugs may be a promising therapy for treating pneumonia, including common pneumonia and COVID-19 pneumonia, but more high-quality studies are needed to explore the efficacy and mechanism of Lianhua Qingwen in treating pneumonia.

Data Availability
e data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
e authors declare that they have no conflicts of interest.