Theophylline Combined With ICS In The Treatment Of Chronic Obstructive Pulmonary Disease: A Systematic Review And Clinical Study

Objective:Chronic obstructive pulmonary disease(COPD)is a chronic inflammatory disease with high incidence rate and can be controlled and delayed by prevention and treatment.Pathophysiology is manifested by irreversible airway changes and expiratory limitation.Exposure to harmful particles and gases may lead to limited breathing,such as cooking fumes,tobacco,air dust,etc.smoking has been clearly and closely related to the occurrence and progress of COPD.Studies also show that cooking fumes may also be related to the occurrence of COPD.Chronic obstructive pulmonary disease(COPD)is one of the three leading causes of death in the world.Theophylline has been gradually withdrawn from the main treatment programs in developed countries,mainly because of its long-term or high-dose side effects.However,it is still widely used in economically backward countries,especially in low-income to middle-income countries(LMICs),Recently,some randomized controlled trials and observational studies have explored the efficacy of low-dose theophylline combined with ICs in the treatment of COPD,such as the frequency of AECOPD,improvement of lung function,changes of biomarkers and inflammatory markers.However,the results of these studies are different.Therefore,this study explored the efficacy and safety of theophylline combined with ICs in the treatment of COPD through meta-analysis.At the same time,a retrospective study was conducted to determine whether the use of low-dose theophylline in the first hospital of Lanzhou university can improve the incidence of AECOPD and the length of stay,so as to provide reference for clinical treatment.Methods:We explore this topic through the research methods of evidence-based medicine and clinical retrospective research.In the part of evidence-based medicine,we reviewed and sorted out the related articles about theophylline combined with hormone,long-term and short-term bronchodilators,long-term and short-term anticholinergic antagonists in COPD through literature search.Objective to systematically understand the research status in this field,find out the controversial points in the current research,and explore the relevant strategies and prognosis for the treatment of COPD;to explore the clinical application effect of low-dose theophylline combined with inhaled hormone on COPD through systematic review and meta analysis;in the clinical research part,we included the statistics of patients with COPD who were admitted to the hospital from January 2018 to October 2019,according to the treatment plan The frequency of acute exacerbation,length of stay,cost of hospitalization and all-cause mortality were observed.Results:In the part of systematic review and meta-analysis,theophylline as an additional treatment of ICS was not associated with the decrease of COPD exacerbation(HR 1.08,95%CI 0.97 to 1.19,I~2=95.2%).In subgroup analysis based on study design,randomized controlled trials and cohort studies showed that theophylline supplementation in ICS did not reduce the exacerbation of COPD.There was no significant difference in hospitalization and mortality between theophylline group and non theophylline group(HR 1.12,95%CI 1.10 to 1.15,I~2=20.4%,and HR1.19,95%CI 1.14 to 1.25,I~2=0%).Compared with non theophylline group,the activity of HDAC in theophylline group was significantly increased,and the concentrations of TNF-αand IL-8 in sputum were further decreased.Clinical part:multiple logistic regression model showed that there was no significant difference in all-cause mortality between theophylline group and control group.COPD patients with liver disease has an impact on all-cause mortality.The risk of all-cause death in COPD patients with liver disease was 3.14 times higher than that in patients without liver disease(95%CI,(1.03,9.57);P=0.044).After controlling for other possible confounding factors,the number of readmission in theophylline group was lower than that in control group(β=-0.19;95%CI,(-0.30,-0.08);P=0.001).The age of COPD patients,type 2 diabetes mellitus,cardiovascular disease and liver disease have influence on readmission in one year.Elderly(β=0.01;95%CI,(0.00,0.01);P=0.007),with type 2 diabetes mellitus(β=0.17;95%CI,(0.04,0.31);P=0.011),cardiovascular disease(β=0.20;95%CI,(0.08,0.32);P=0.002)increased the number of readmission in one year,but with liver disease(β=-0.15;95%CI,(-0.27,-0.03);P=0.017)decreased the number of readmission in one year.The length of hospital stay in theophylline group was slightly longer than that in control group(β=0.65;95%CI,(0.26,1.05);P=0.001).The age of COPD patients,COPD control therapy and COPD remission therapy have an impact on the length of hospital stay.Among them,elderly patients increased the length of hospital stay(β=0.02;95%CI,(0.00,0.05);P=0.019);the use of ICS+LABA+LAMA(β=-0.96;95%CI,(-1.76,-0.16);P=0.019)or LAMA(β=-1,41;95%CI,(-2.25,-0.57);P=0.001)could shorten the length of hospital stay of COPD patients compared with the use of ICS alone.After controlling for other possible confounding factors,the cost of hospitalization in theophylline group was higher than that in control group(β=1045.70;95%CI,(326.481764.91);P=0.004).The age of COPD patients,type II respiratory failure,cardiovascular disease and different COPD control treatment have an impact on the total cost of hospitalization.The elderly(β=57.07;95%CI,(19.30,94.84);P=0.003),with type II respiratory failure(β=1679.36;95%CI,(623.392735.33);P=0.002),cardiovascular disease(β=936.39;95%CI,(131.081741.70);P=0.023)increased the total cost of hospitalization;the total cost of LAMA treatment was lower than that of ICS treatment(β=-2283.29;95%CI,(-3798.65,-767.92);003),while there was no significant difference in the total cost of hospitalization between ICS and other control treatments.Conclusion:the use of low-dose theophylline does not reduce all-cause mortality,and evidence-based evidence does not reduce readmission and acute exacerbation of AECOPD.Theophylline may reduce inflammatory factors and HDAC2,slow down the progress of COPD,and control the clinical symptoms of COPD.However,theophylline is still widely used at present,so there is an urgent need for higher treatment,which will provide very strong evidence for the current clinical treatment,and may change the current treatment plan.