Yupingfeng Powder regulates immunity in patients with stable chronic obstructive pulmonary disease: a meta-analysis

Objective: To use Meta-analysis to evaluate the effectiveness and safety of Yupingfeng Powder (YPFP) in regulating the immune function of patients with chronic obstructive pulmonary disease. Methods: Computers were used to search databases such as China National Knowledge Infrastructure (CNKI), VIP Database, China Biology Medicine disc (CBMdisc), Wanfang Database, PubMed, Cochrane Library, etc. Search all randomized controlled trials (RCTs) of YPFP in the treatment of stable chronic obstructive pulmonary disease, with CD4, CD8, CD4/CD8, IgE, IgA, IgM, and IgG as the outcome indicators. Two reviewers independently conducted literature search, conducted literature quality evaluation with the risk bias assessment tool recommended by Cochrane Handbook, and conducted data extraction, discussed and resolved disputes, and used RevMan 5.3 software for Meta-analysis. Results: A total of 11 randomized controlled trials with 1,058 patients were included. According to the Meta-analysis, the results of the effectiveness analysis showed that after oral administration of YPFP in the stable phase of chronic obstructive pulmonary disease, the test group CD3, CD4, CD8, CD4/CD8, IgA, IgE, IgM, IgG8 were better than the control group ( P < 0.05). Conclusion: Oral administration of YPFP in the stable period of chronic obstructive pulmonary disease can effectively regulate the immunity. However, the number of studies included in this study is small and the heterogeneity is large, and it is still necessary to design high-quality clinical trials for in-depth research.


Introduction
Chronic obstructive pulmonary disease (COPD) is a preventable and curable [1] chronic airway inflammatory disease characterized by airflow limitation.The acute exacerbation phase overlaps with the stable phase, leading to the continuous progression of disease inflammation.At present, COPD ranks the third cause of death in the world [2], and the total number of patients in China is about 100 million [3].Modern medicine has become increasingly standardized in the standardized management of chronic obstructive pulmonary disease in stable period.The combined use of effective β2 receptor agonists (LABA), long-acting anticholinergic drugs (LAMA), and inhaled corticosteroid (ICS) have made a great contribution to controlling airway inflammation and reducing acute exacerbations in patients.In recent years, the correlation between immunity, matrix metalloproteinases, oxidative stress, intestinal microecology and other mechanisms and COPD has been discovered, and humoral immunity and cellular immunity have become research hotspots [4][5].In cellular immunity, T helper cells and T regulatory cells check and balance each other, and CD4/CD8, Th1/Th2, Th17/Treg immune imbalance runs through the occurrence and development of airway inflammation.Plasma cells differentiated from B lymphocytes synthesize and secrete immunoglobulins with the assistance of various T lymphocyte subgroups, and play a defensive role against pathogenic microorganisms.Humoral immunity and cellular immunity play an important role in the whole course of chronic obstructive pulmonary disease.Yupingfeng Powder (YPFP) is composed of Radix Astragali, Rhizoma Atractylodis Macrocephalae, and Radix Saposhnikoviae, with a ratio of 2:2:1.Radix Astragali in the prescription is sweet and warm, nourishes the lungs and spleen, consolidates the surface to stop sweating, and takes care of both inside and outside.Rhizoma Atractylodis Macrocephalae is sweet and warm, invigorating the spleen and replenishing qi to stop sweating.Radix Saposhnikoviae is pungent and warm to dispel wind from the surface.The three medicines work together, complement each other, and focus on replenishment, which has the effect of replenishing qi and solidifying the surface, antiperspirant and preventing wind.Modern basic medical research [6][7] confirmed that it has the effect of regulating the immunity.From 2014 to 2017, a multi-center, randomized, double-blind study led by Academician Zhong Nanshan [8] confirmed that YPFP can significantly reduce the number of acute exacerbations of COPD, but the mechanism of action has not been further clarified.The published randomized controlled study of YPFP in the treatment of chronic obstructive pulmonary disease in stable phase is now retrieved to explore the evidence-based medicine basis for YPFP to improve immunity.

Inclusion criteria
Research type Clinical randomized controlled trials (RCT), describing "random" groups are included.There is no restriction on whether to use the "blind method".

Research object
The original research object meets the diagnostic criteria for chronic obstructive pulmonary disease, is in the stable phase of COPD, and the acute exacerbation is ruled out.The diagnostic criteria refer to the 2007 and 2013 "Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease" [9][10], and the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD Guidelines) [11][12] does not limit the course of the disease and the severity of COPD.Demographic data such as race, age, gender, etc. are not limited.

Intervention measures
The treatment group was treated with YPFP combined with conventional Western medicine.The control group was treated with conventional Western medicine, including hormones, bronchodilators, etc.The course of treatment is not limited.

Exclusion criteria
Exclude the study subjects who have serious primary and secondary diseases such as breathing, circulation, blood, and nervous system, which affect the test results; Excluding studies that include other characteristic therapies of traditional Chinese medicine does not confirm that Yupingfeng Powder is the main intervention; Exclude repeated publications; After excluding incomplete data and contacting the corresponding author, complete data cannot be obtained or research indicators have nothing to do with the outcome indicators of this meta-analysis.

Literature search
Computer search of Chinese and English databases.Chinese databases include China National Knowledge Infrastructure (CNKI), Wanfang database, China Biology Medicine disc (CBMdisc), VIP database, and English databases include the PubMed, Cochrane Library.The search period is from the establishment of the database to September 2021.Use the combination of subject words and free words to formulate search strategies.Chinese search terms include "Yupingfeng Powder", "Yupingfeng Capsule", "Yupingfeng Granules", "chronic obstructive pulmonary disease", "chronic obstructive pulmonary disease", "obstructive pulmonary disease", "obstructive pulmonary disease", "random ", English search terms include, "Yupingfeng powder", "Yupingfeng capsule", "chronic obstructive pulmonary disease", "slow obstructive pulmonary disease", "obstructive pulmonary disease", "obstructive pulmonary disease", "random", etc.

Literature selection
Import the retrieved bibliography into the document management software NoteExpress to establish a bibliographic database.Categorize and sort the first-checked documents, and use the duplicate check function to remove duplicate documents.Documents that failed to be imported are manually removed.Two researchers independently screened the literature.By reading the titles and abstracts of each study, we excluded documents that clearly did not meet the inclusion criteria.Read the full text and determine whether to include in the study based on the inclusion and exclusion criteria.All excluded documents must record the reason for the exclusion.A total of 11 documents [13][14][15][16][17][18][19][20][21][22][23] were obtained, all of which were in Chinese.

Data extraction
Use Microsoft Excel spreadsheets to create data extraction tables.Extract research number, first author, publication time, sample size, research objects, intervention measures, outcome indicators, quality evaluation and other information.The two researchers conducted independently, contacted the author with incomplete information, repeated publications were removed, the same research was merged, and there were divergent discussions, and it was impossible to reach an agreement to consult a third party to finally determine the information.

Literature quality evaluation
According to the "risk of bias assessment" tools recommended by the Cochrane Collaboration, the tools include selection bias (generated by random sequence), selection bias (allocation concealment), implementation bias (blind method for subjects and experimenters), and measurement bias (for outcomes), the assessor implements blinding), follow-up bias (results are Submit a manuscript: https://www.tmrjournals.com/agingincomplete), reporting bias (selective reporting of results), and other biases to evaluate the quality of the evidence in the included studies.According to the judgment criteria in the Cochrane handbook, "high risk", "low risk", and "unclear" are used to represent the evaluation results.When evaluating the quality of evidence, the two investigators performed independently and reviewed the evaluation results with each other.If there is a disagreement, negotiate with a third party to resolve it.Revman 5.3 software was used to draw the risk bias map.

Statistical analysis
Use Review Manager 5.3 software to conduct Meta-analysis on the data.Firstly, the chi-square test is used to confirm whether there is heterogeneity in each clinical trial.If P > 0.1 and I 2 < 50%, it can be considered that multiple similar studies are homogeneous, and a fixed-effects model is used for Meta-analysis.If P < 0.1, I 2 > 50%, indicating that the heterogeneity between the studies is large, the random effects model is selected for Meta-analysis.And use sensitivity analysis, subgroup analysis to explore the source of heterogeneity or abandon the combined effect size for only descriptive analysis.The measurement data uses the standardized mean difference (MD) as the effect size, and the count data uses the relative risk (RR), and each effect size is in the 95% confidence interval (CI).

Search results
A total of 311 clinical studies on the treatment of stable chronic obstructive pulmonary disease with YPFP were retrieved, 11 qualified literatures were screened, and 1,058 patients were enrolled.The flow chart of literature screening is shown in Figure 1.The basic information of the included studies is shown in Table 1.

Literature quality evaluation
Random method: 11 studies mentioned "random", 2 studies described specific random methods, rated as Low risk, and the rest as Unclear risk.Allocation concealment: 11 studies did not mention allocation concealment, and they were all rated as Unclear risk.Subject blinding method: One study mentioned the use of blinding method, which was rated as Low risk, and the rest of the trial design was considered as High risk.Results Evaluator's blinding method: Two studies described specific random methods and rated them as Low risk.The rest did not mention allocation concealment, and both were rated as Unclear risk.Outcome indicator bias: 7 research outcome indicators are complete and rated as Low risk, 4 indicators have fallen out, and the reason for the fallout is not mentioned, and rated as High risk.Selective reporting bias: 11 studies were unable to judge the results of selective reporting and were rated as Unclear risk.Other biases: The characteristics of the 11 studies are not clear, the criteria for including patients are not uniform, and other sources of bias cannot be judged, and they are all rated as Unclear risk.The specific results are shown in Figure 2.

CD3
Three studies [13,14,19] evaluated CD3 levels and included a total of 282 patients.The differences between the studies were too significant (P < 0.001, I 2 = 97%), and random effects model was used.Meta-analysis results show that YPFP combined with conventional Western medicine treatment is significantly better than the control group in improving the level of CD3 (MD = 5.18, 95% CI (0.62-9.73),P < 0.001).A subgroup analysis based on the course of treatment found that when the course of treatment was less than 3 months, the CD3 after treatment in the treatment group was significantly higher than that of the control group (P = 0.03).When the course of treatment was ≥ 3 months, the CD3 after treatment in the treatment group was significantly better than that of the control group (P < 0.001) (Figure 3).

CD4
Six studies [13][14][15][17][18][19]] evaluated CD4 levels and included a total of 748 patients.The differences between the studies were significant (P < 0.001, I 2 = 96%), and random effects models were used.Meta-analysis results showed that YPFP combined with conventional Western medicine treatment was significantly better than the control group in improving the level of CD4 (MD = 6.27, 95% CI (2.94-9.60),P < 0.001).The subgroup analysis was carried out by the course of treatment.When the course of treatment was less than 3 months, the CD4 of the treatment group was equivalent to that of the control group (P = 0.12).When the course of treatment was ≥ 3 months, the CD3 of the treatment group after treatment was significantly better than that of the control group (P < 0.001) (Figure 4).

CD8
Six studies [13][14][15][17][18][19] evaluated the level of CD8.A total of 748 patients were included.The differences between the studies were significant (P < 0.001, I 2 = 87%), and random effects models were used.Meta-analysis results showed that YPFP combined with conventional Western medicine treatment was significantly better than the control group in improving the level of CD8 (MD = -1.36,95% CI (-2.78, 0.06), P < 0.001).The subgroup analysis was performed by the course of treatment.When the course of treatment was less than 3 months, the CD4 of the treatment group was equivalent to the control group after treatment (P = 0.45).
When the course of treatment was ≥ 3 months, the CD3 of the treatment group after treatment was significantly better than that of the control group (P = 0.03) (Figure 5).

CD4/CD8
Six studies [13][14][15][17][18][19] evaluated the level of CD4/CD8 and included a total of 748 patients.The differences between the studies were significant (P = 0.009, I 2 = 65%), and random effects models were used.Meta-analysis results showed that YPFP combined with conventional Western medicine treatment was significantly better than the control group in improving CD4/CD8 levels (MD = 0.30, 95% CI (0.21, 0.39), P < 0.001).The subgroup analysis was carried out by the course of treatment.When the course of treatment was less than 3 months, the CD4 of the treatment group was equivalent to that of the control group (P = 0.84).When the course of treatment was ≥ 3 months, the CD3 of the treatment group after treatment was significantly better than that of the control group (P < 0.001) (Figure 6).

IgA
Seven studies [16,[18][19][20][21][22][23] evaluated IgA levels and included a total of 565 patients.The differences between the studies were significant (P < 0.001, I 2 = 79%), and random effects models were used.Meta-analysis results showed that YPFP combined with conventional Western medicine treatment had no significant difference with the control group in terms of improving IgA levels (MD = 0.25, 95% CI (-0.02, 0.52), P = 0.07).The subgroup analysis was carried out by the course of treatment.When the course of treatment was 3 months, IgA in the treatment group was significantly better than that in the control group (P = 0.01) (Figure 7).

IgE
Four studies [16,[20][21][22] evaluated the level of IgE and included a total of 290 patients.The differences between the studies were significant (P = 0.0008, I 2 = 82%), and random effects models were used.Meta-analysis results showed that YPFP combined with conventional Western medicine treatment had no significant difference with the control group in terms of improving IgE levels (MD = -6.56,95% CI (-63.99,50.87),P = 0.82).The subgroup analysis was carried out by the course of treatment.When the course of treatment was 6 months, IgE in the treatment group was significantly better than that in the control group (P = 0.05) (Figure 8).

IgM
Seven studies [16,[18][19][20][21][22][23] evaluated IgM levels and included a total of 565 patients.The differences between the studies were significant (P < 0.001, I 2 = 95%), and random effects models were used.Meta-analysis results showed that YPFP combined with conventional Western medicine treatment had no significant difference with the control group in terms of improving IgM levels (MD = 0.32, 95% CI (-0.03, 0.67), P = 0.07).According to the subgroup analysis by the course of treatment, when the course of treatment = 6 months, IgM in the treatment group was significantly better than the control group after treatment (P < 0.001) (Figure 9).

IgG
Six studies [16,18,[20][21][22][23] evaluated the IgG level and included a total of 490 patients.The differences between the studies were significant (P < 0.001, I 2 = 78%), and random effects models were used.Meta-analysis results showed that YPFP combined with conventional Western medicine treatment was significantly better than the control group in improving IgG levels (MD = 2.33, 95% CI (1.47, 3.20), P < 0.001).The subgroup analysis was carried out by treatment course, and there was no significant difference between treatment courses (P = 0.45) (Figure 10).

Security analysis
Only 2 studies [14,17] mentioned adverse reactions in 11 literatures.One article reported that there were 6 cases of dry mouth and 1 case of hoarseness in the treatment group; 5 cases of dry mouth and 1 case of urinary retention in the control group.Another article reported 2 cases of diarrhea and 4 cases of nausea in the treatment group, and 2 cases of diarrhea and nausea in the control group.Both studies reported no significant difference

Assessment of publication bias
Funnel chart analysis with CD4/CD8 test showed that the funnel chart was not completely symmetrical, suggesting that there may be a certain publication bias (Figure 11).

Sensitivity analysis
After eliminating each test one by one, the results are consistent with the original results, indicating that the research results are robust.Infiltration of large airways inflammatory cells, increased mucus secretion, small airway remodeling, terminal airway loss, alveolar septum, and vascular destructive changes constitute the pathological basis of chronic obstructive pulmonary disease.COPD belongs to the categories of "Asthma Syndrome" and "Lung Distention" in traditional Chinese medicine [24].The stable phase is caused by the deficiency of the lung, spleen and kidney.In the acute exacerbation period, the disease is usually caused by the lack of solid health, the six evils invading the human body, the loss of the lung health, and the invincibility of the evil.Due to the perennial wheezing, the lung, spleen and kidney are all deficient, and the patient is prone to exogenous diseases during the change of seasons.Active intervention in the stable period of chronic obstructive pulmonary disease to prevent acute exacerbations and delay the progressive decline of lung function is the purpose of the current study of stable chronic obstructive pulmonary disease, and it is also an important part of pulmonary rehabilitation.[25].AMWP-Ag NP can inhibit Gram-negative bacteria [26].Atractylenolide I-III have anti-inflammatory effects [27].Polysaccharide of Radix Saposhnikoviae has the effect of stimulating the release of cytokines from macrophages [28].From the perspective of compatibility analysis, Radix Astragali combined with Rhizoma Atractylodis Macrocephalae can increase the concentration of effective components of Astragalus [29], and Rhizoma Atractylodis Macrocephalae combined with Radix Saposhnikoviae can improve the cell barrier function [30].This meta-analysis involves 8 indicators of CD3, CD4, CD8, CD4/CD8, IgA, IgE, IgM, and IgG in terms of efficacy.The results of the study show that the heterogeneity is large, which may be related to the difference in intervention time, dosing frequency and sample size.In this study, the treatment course was different, and the subgroup analysis was carried out.After treatment, the levels of various indicators in the treatment group were significantly better than those in the control group.The curative effect is better when the treatment course is 3 months and 6 months, suggesting that the treatment course is longer than 3 months, which is more conducive to the improvement of the curative effect.Only 2 of the 11 studies discussed safety, and only a small amount of description was made, and there were no statistics on specific indicators, which made it impossible to discuss safety.The stable period of chronic obstructive pulmonary disease patients is mostly concentrated in the early spring and autumn for about 6 months.Because the research has less discussion on safety, it is difficult to determine the treatment course of 3 or 6 months.Taking 3 months as the intervention time and conducting a 3-month follow-up study after stopping the drug as a protocol design experiment may effectively avoid side effects and fully understand the after effects.The results show that YPFP can effectively improve the humoral and cellular immunity of patients with chronic obstructive pulmonary disease in stable stage.

Discussion
Most of the studies included in this Meta-analysis only mentioned "random" and did not mention random methods.Therefore, the accuracy of random methods is questionable, and there is no allocation concealment.The use of placebo has not been fully implemented, and double-blind and triple-blind cannot be achieved.There is no clear calculation method for sample size estimation.After randomization, the number of cases in the two groups is uneven, and the dropout and elimination after the test cannot be accurately explained.The lack of the above test methodology will cause bias.In summary, the results of this meta-analysis suggest that oral administration of YPFP in the stable period of chronic obstructive pulmonary disease can effectively improve the immune function of patients.However, the original research has certain shortcomings, and further verification is required for a large sample size, multi-center, and safety-designed trial.

Figure 2 Figure 3
Figure 2 Literature quality evaluation

Figure 4 Figure 5 Figure 6
Figure 4 Comparison of CD4 after treatment in both groups

Figure 7 Figure 8
Figure 7 Comparison of IgA after treatment in both groups

Figure 9 Figure 10 Figure 11
Figure 9 Comparison of IgM after treatment in both groups
Dueto multiple factors such as repeated infections, poor exercise endurance, and loss of appetite, patients with chronic obstructive pulmonary disease have poor physical fitness and belong to the category of "virtual people" in Chinese medicine.Acute exacerbations are mostly caused by respiratory tract infections, which are due to lack of righteousness, loose physique, and pathogenic qi or virus enters from the fur or nose and mouth, and invades the lungs.Lung loss is the main onset process, which is similar to the etiology and pathogenesis of colds in traditional Chinese medicine.YPFP comes from "Zhu Yuan Fang" and is composed of Radix Astragali, Rhizoma Atractylodis Macrocephalae, and Radix Saposhnikoviae.The compatibility of the three drugs prevents evil from invading, and is a classic prescription for the treatment of COPD.The humoral and cellular immunity of COPD patients are affected to varying degrees.Secreted IgA exists on the mucosal surface of the respiratory tract, IgG is the highest content of immunoglobulin in serum, and IgM is the earliest antibody produced by infection.In cellular immunity, the surface markers are roughly divided into two major subgroups, CD4 and CD8.