| BackgroundWith the deterioration of the ecological environment,the change of living habits and the aggravation of aging population,the incidence rate and mortality rate of malignant tumors have increased rapidly worldwide.Malignant tumors have become an important disease burden in China.In China,the group of patients with advanced cancer accounts for a considerable proportion of the total number of cancer patients.The results show that the prevalence of advanced cancer diagnosis in Chinese patients remained above 52.0%from 2016 to 2017.Infection is the main cause of death and morbidity in patients with advanced cancer.Pulmonary bacterial infection is very common in patients with malignant tumors.It is the second cause of infection after urinary tract infection.The incidence rate and mortality rate of patients with advanced cancer are significantly increased.Immune,inflammatory and coagulation systems are the three main physiological and pathological systems for the body to complete life activities.They are independent of each other and have complex interactions.The dysfunction of any system may trigger a series of cascade amplification reactions,resulting in complex pathological changes.Previous studies on traditional Chinese medicine in treating bacterial infectious diseases focused on the direct bacteriostatic and bactericidal mechanisms of drugs,with less attention to the overall regulation of Chinese medicine on the body.This study intends to explore the intervention effect of qiguiyin Recipe on the treatment of advanced cancer patients complicated with pulmonary bacterial infection from the perspective of traditional Chinese medicine regulating the immune function of infected body,mediating the release of inflammatory factors,improving the coagulation function of the body,adjusting the balance between various systems of the body,improving the disease resistance of the body,and changing the internal environment of bacterial infection.Objective(1)Predict the main active components,targets and signal pathways of qiguiyin formula in the treatment of pulmonary bacterial infection based on network pharmacology,and explore its potential biological mechanism.(2)The clinical data of patients with stage IV malignant tumor complicated with pulmonary infection were retrospectively analyzed,risk factors were screened,and a nomogram of the risk prediction model was further established.In order to provide a theoretical basis for the risk prediction of pulmonary infection in patients with advanced cancer,and provide reference and basis for clinical prevention of pulmonary infection in patients with advanced cancer.(3)A prospective randomized controlled clinical trial was conducted to observe the clinical efficacy of Qiguiyin prescription in the treatment of advanced cancer complicated with pulmonary bacterial infection.To evaluate the intervention effect of Qiguiyin prescription on inflammation,immunity and coagulation system of patients with advanced cancer complicated with pulmonary bacterial infection and to explore its related mechanism.Method(1)The Chinese herbal medicine chemical composition of Qiguiyin formula was searched through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,and the potential active compounds were screened with the oral bioavailability(OB)>30%and drug-likeness(DL)≥0.18 as the threshold.The target of the active compound was queried through the SwissTargetPrediction database and the disease target was predicted using the GeneCards database.The intersection of the active ingredient target and the disease target were found by Excel software and the interaction network of the target proteins of the active components was constructed by using the software of Cytoscape 3.7.2.The intersection target protein-protein interaction(PPI)network was constructed by using the String online database.Finally,go function and KEGG pathway enrichment of target genes were analyzed by metascape database.(2)Risk factor prediction and model establishment:the clinical data of inpatients with stage IV malignant tumor complicated with pulmonary infection and inpatients with stage IV malignant tumor without pulmonary infection admitted to the Affiliated Tumor Hospital of Xinjiang Medical University from January 2016 to December 2020 were reviewed.Mann-whitney U test was used for continuous variables and Fisher’s exact χ2 test was used for bivariate analysis for categorical variables.The result was concurrent pulmonary infection.Variables with P<0.2 in bivariate analysis were included in the multiple regression model.Using a forward stepwise algorithm,odds ratios(ORs)and 95%confidence intervals(CIs)were calculated.The significance level of the P value was set at 0.05.The variables included in the final logistic regression model were carefully selected using forward stepwise methods,Akaike’s Information Criterion(AIC)was used as the stopping rule,and the AIC value of the final model was minimized with the least number of variables.Use the Nomolog feature in STATA to derive a rote plot from the results of multivariate logic analysis.Subsequently,the prediction model was validated by checking the lipopograph discrimination and calibration using the validation data sets.(3)The clinical study is a prospective randomized controlled trial involving inpatients admitted to the Cancer Hospital Affiliated to Xinjiang Medical University between Jan uary 1,2021 and November 30,2021.The diagnosis was consistent with stage IV mali gnant tumor(with distant metastases)combined with bacterial pulmonary infection.The diagnostic criteria for pulmonary infection were formulated according to Internal Medi cine(8th Edition).The above patients were randomly divided into Qiguiyin treatment g roup and control group,30 cases in each group.The two groups were treated with sen sitive antibiotics according to bacterial culture and drug sensitivity results,conventional anti-tumor therapy,maintenance of water,electrolyte and acid-base balance.On this ba sis,the treatment group was given "Qiguiyin Prescription":Astragalus 60g,Angelica 15g,Honeysuckle 15g,Artemisia annua 10 g,Polygonum cuspidatum 10g,granules,200 ml/time,200 ml/time,twice a day,observation course of 14 days.The sputum bac terial culture conversion rate of the two groups on the 8th day and the 15th day after treatment was compared.The levels of cytokines(interleukin-2,interleukin-6,interleuki n-1β,interleukin-10,interleukin-4,interleukin-17,interleukin-12P70,tumor necrosis factor-a,interferon-γ),immune Function(CD3+,CD3+CD8+,CD3+CD4+,proportion of NK cel 1s,CD4+/CD8+ratio),coagulation function indexes(D-polymeric,prothrombin time,act ivated partial thrombin time,thrombin time,plasma fibrinogen),blood routine(WBC co unt,neutrophil percentage,lymphocyte percentage,platelet count)and procalcitonin lev el were compared between the two groups after treatment.Result(1)Network pharmacology:Qiguiyin recipe has the characteristics of multi-target,multi-channel and multi-channel in the treatment of pulmonary bacterial infection.The main biological mechanism of qiguiyin recipe in the treatment of pulmonary bacterial infection may be related to PI3K Akt signal pathway,RAS signal pathway,HIF-1 signal pathway and MAPK signal pathway.(2)Risk factor screening suggests that male,advanced age,ethnic group(Han,Uyghur),primary cancer is lung cancer,pulmonary metastases,no history of chemotherapy,no history of radiotherapy,and central venous catheterization are independent risk factors for pulmonary infection in patients with advanced cancer.The established risk prediction model is sufficiently discriminative(0.77,95%confidence interval,0.75 to 0.81)to be tested on the validation dataset.The nomogram is well calibrated and the model had a significant clinical net benefit at a threshold probability of 20%-95%.(3)Compared with the control group,Qiguiyin prescription did not improve the negative rate of sputum bacterial culture in patients with advanced cancer complicated by pulmonary bacterial infection on the 8th day of treatment(20%VS 13.3%)and after treatment(93.3%VS 86.7%).The difference was not statistically significant.Compared with the control group,the proportion of CD3+CD4+cells(41.5 ± 10.2 VS 34.6±9.2)and the ratio of CD4+/CD8+(2.7 ± 4.5 VS 1.3±0.6)in the Qiguiyin prescription treatment group increased after treatment.The comparison was statistically significant(P<0.05).There was no statistical difference in the changes of coagulation function indexes between the treatment group and the control group.The levels of interferon-γ(INF-γ)in Qiguiyin treatment group was higher than that in control group after treatment,and the difference between the groups was marginally significant(P=0.065).The serum procalcitonin(PCT)level in Qiguiyin treatment group was lower than that in control group after treatment,and the difference between the two groups was marginally significant(P=0.067).After stratified analysis of patients with lung cancer as the primary cancer,it was found that after 14 days of treatment,the level of IL-12P70 in the blood of patients with lung cancer in the Qiguiyin treatment group showed a trend of increase compared with the control group,and the difference between the groups was marginal significant(P=0.084).There were no statistical differences in the remain monitoring indicators between the two groups.Conclusion(1)Qiguiyin decoction may affect the inflammatory response and immune function of infected body through PI3K Akt signal pathway,RAS signal pathway,HIF-1 signal pathway and MAPK signal pathway,so as to play a role in the treatment of pulmonary bacterial infection.(2)Accurately predicting the risk of lung infections in patients with advanced cancer could help improve patient’s treatment effect.In this study,by retrospectively analyzing the data of clinical patients,constructing a risk prediction model for pulmonary infection in advanced cancer patients has certain clinical benefits.(3)Qiguiyin prescription can improve the proportion of CD3+CD4+cells in patients with advanced cancer complicated with pulmonary bacterial infection,improve the patient’s T cell immune function,increase the CD4+/CD8+ratio,and effectively restore the body’s immune balance disorder caused by infection.It has a tendency to increase the level of INF-γ in patients with advanced cancer complicated with pulmonary bacterial infection.It has a tendency to increase the level of IL-12P70 in patients with advanced lung cancer complicated with pulmonary bacterial infection.It has a downward trend in the patient’s blood PCT level.However,it has no effect on the negative rate of sputum bacterial culture and coagulation function of patients. |
PDF Full Text Request