| Objective To investigate the effectiveness of doxophylline as an adjuvant on the severe exacerbations numbers and prognosis of different clinical subtypes and frequent acute aggravation phenotype of COPD.Method The clinical trial was a prospective dynamic cohort study that enrolled patients with acute exacerbation of COPD in the Department of Respiratory and critical Diseases,affiliated Central Hospital of Shenyang Medical College between September 13,2019,and July 31,2020.Final follow-up ended on January 31,2021.This study included 155 participants.These patients were divided into doxofylline exposure group(n=68)and non-exposed group(n=87)according to whether doxophylline was used in the treatment plan.After discharge,doxophylline group continued to take doxophylline sustained-release tablets(0.2g/12 tablets,0.2 g bid,oral for 6 months)+ inhaled drugs,while non-doxophylline group only used inhaled drugs.The primary outcome was the number of participant-reported severe exacerbations and clinical symptoms over the 6 months treatment period.Results1.Enrollment and Follow-up.The participants were patients with acute exacerbation of COPD in the Respiratory critical Care Department of the affiliated Central Hospital of Shenyang Medical College from September 13,2018 to October 31,2019.The final follow-up ended on April 31,2020.A total of 306 participants were recruited: 147 in the doxophylline exposure group and 159 in the non-exposure group.134 patients were excluded because they did not meet the inclusion criteria(n = 45),met the exclusion criteria(n = 32)and refused to participate(n = 37).Finally,172 cases were included,including 82 cases in doxophylline exposure group and 90 cases in non-exposure group.During the period of drug adaptation(1 week)and follow-up,17 cases were excluded because of adverse reactions(n = 5),withdrawal(n = 4),poor compliance(n= 3)and loss of follow-up(n = 5).In the end,155 participants completed the study.2.Baseline data of doxophylline exposure group and non-exposure group.Of the 155 participants analyzed(68 in the doxophylline exposure group and 87 in the non-exposure group),the average age was 71.2 ± 10.1 years old,81 males(52.3%)and 74 females(44.7%).BMI22.6kg/m2,smokers accounted for 56.1%.The average age of smoking was 27.0 years old,and the smoking index was 600.The median duration of the disease was 8.0 years,and the most common complications were hypertension / coronary heart disease(69.7%),diabetes(16.8%),digestive system diseases(11.6%),cerebrovascular diseases(9.7%)and cor pulmonale(7.1%).FEV1 suggested that most of the subjects were severe COPD,29.7%,the subjects were extremely severe COPD,67.8%,the subjects were moderate to severe COPD,2.6%,and the subjects were mild COPD.The average CAT score was 22.6±2.7,which seriously affected the life of the patients.81.6% of the subjects used long-acting muscarinic receptor antagonist + ICS,long-acting β 2-agonist + IC or long-acting muscarinic receptor antagonist + long-acting β 2 receptor agonist + ICS.The median number of leukocytes is 8.5±3.5 × 10 ^ 9 / L,the percentage of neutrophils is 68.5%,the percentage of lymphocytes is 20.2%,and the percentage of eosinophils is 1.5%.According to the proportion of inflammatory cells,the subjects were divided into neutrophil subtype(49.0%),eosinophil subtype(17.4%)and mixed granulocyte subtype(33.5%).According to the number of acute exacerbations in the past year,frequent acute exacerbations accounted for 15.5%.Non-frequent acute exacerbation accounted for 84.5%.3.The main results of doxophylline exposure group and non-exposure group.(1)100% of the participants(68 in the doxophylline exposure group and 87 in the non-exposure group)obtained the main results(severe deterioration)data,and a total of 155 participants completed a 6-month follow-up.A total of 81 cases had severe acute exacerbation,including 28 cases in doxophylline exposure group and 53 cases in non-exposure group.One month after discharge,acute exacerbation occurred in doxophylline exposure group was 5(3.2%)and 6(3.9%)in non-exposure group.The IRR=1.0[95% CI 0.3-3.4].There was no significant difference between the two groups(P>0.05).Three months after discharge,there were 17 cases(11.0%)in doxophylline exposure group and 24 cases(15.5%)in non-exposure group.There was no significant difference between the two groups(P>0.05).Six months after discharge,severe acute exacerbation occurred in 6 cases(3.9%)in the doxophylline exposure group,while in 23 cases(14.8%)in the non-exposure group,IRR= 0.3(95%CI,0.1-0.7),and the difference was statistically significant(P=0.005).(2)There was no significant difference in FEV1%,CAT score,m MRC dyspnea score or adverse events(COPD related events and overall events)between doxophylline exposed group and non-exposed group.Serum was collected 6 months after discharge,and the changes of leukocytes,neutrophils,lymphocytes and eosinophils were compared and analyzed.The results showed that the percentage of neutrophils in the doxophylline exposure group was lower than that in the non-exposure group and the difference was statistically significant [62.2% Vs65.8;P=0.002].The eosinophil percentage in the exposure group was lower than that in the non-exposure group,but there was no significant difference(1.5% Vs2.3%;P > 0.05).4.Main results of different clinical subtypes.(1)The number of severe acute exacerbation in doxophylline exposure group:neutrophil was 11,eosinophil was 5 and mixed granulocyte was 12 while the non-exposure group of neutrophil was 33,eosinophil was 5 and mixed granulocyte was 15.One month after discharge,there was no significant difference in the number of acute exacerbations among neutrophil,eosinophil and mixed granulocyte subtype.Three months after discharge,acute exacerbation occurred in neutrophil type: 5 cases(6.6%)in doxophylline exposure group,17 cases in non-exposure group(22.4%),IRR=0.4 [95% CI,0.2-0.9] and significant difference(P= 0.024),while eosinophilic IRR=4.0 [95% CI,0.5-29.8] and mixed granulocyte IRR=1.9 [95%CI,0.7-4.8],The difference was not statistically significant.Six months after discharge,acute exacerbation occurred 3 cases(3.9%)of neutrophil in doxophylline exposure group Vs 13 cases(17.1%)of non-exposure group,and the difference was statistically significant(IRR=0.3[95%CI,0.1-0.9];P=0045).The number of cases for acute exacerbation of eosinophil subtype: 0 cases in exposure group(0.0%),4 cases in non-exposure group(14.8%),and the difference was statistically significant(P=0.028).There was significant difference in the number of acute exacerbation between neutrophil and eosinophil subtype after discharge in6 months,but there was no significant difference in mixed granulocyte type.(2)Among the three clinical subtypes,there was no significant difference in FEV1%,CAT score,m MRC dyspnea score or adverse events(COPD related events and overall events)between the doxophylline exposure group and the non-exposure group.In eosinophil subtype,FEV1% and MMF% in doxophylline exposed group were significantly higher than those in non-exposed group [55.0% Vs 46.5%;45.0%Vs 34.0%;P>0.05],but the difference was not statistically significant.Serum was collected 6 months after discharge,and the changes of leukocytes,neutrophils,lymphocytes and eosinophils were compared and analyzed.The results showed that the percentage of neutrophils in neutrophils [62.9% Vs 66.8%;P=0.023] and the percentage of eosinophils in neutrophils were significantly different [1.0% Vs 1.8%;P=0.009],and the percentages of neutrophils in eosinophils were significantly different.5.Main results of frequent acute exacerbation phenotype.(1)A total of 81 patients with frequent acute exacerbation and non-frequent acute exacerbation occurred severe acute exacerbation,including 28 patients in doxophylline group(25 patients with non-frequent acute exacerbation,3 patients with frequent acute exacerbation)and 53 patients in non-doxophylline group(39 patients with non-frequent acute exacerbation and 14 patients with frequent acute exacerbation).In non-frequent acute exacerbations,there was a significant difference in the number of acute exacerbations 6 months after discharge(P<0.007).The number of acute exacerbations was 4 cases(3.1%)in doxophylline group and 18 cases(24.7%)in non-doxophylline group.IRR=0.3[95% CI,0.1-0.8].In frequent acute exacerbations,there was a significant difference in the incidence of severe acute exacerbation at 3months after discharge [0(0.02%)Vs 7(29.2%),P=0.008],but there was no significant difference at 6 months after discharge(P> 0.05).(2)There was no significant difference in FEV1%,CAT score,m MRC dyspnea score or adverse events(COPD related events and overall events)among the groups.In frequent acute exacerbation,the MMF% of doxophylline group(38%)was significantly higher than that of non-doxophylline group(18%),and the difference was statistically significant(P < 0.022).The results of inflammatory cells showed that there was a significant difference in the percentage of neutrophils in frequent acute exacerbation between the two groups [62.3% Vs 66.5%,P= 0.003].6.The use of inhaled drugs containing corticosteroids.(1)Among the participants,125 patients were treated with inhaled drugs containing corticosteroids,including 54 patients in the doxophylline group and 71 patients in the non-doxophylline group,and there was no significant difference in drug use between the two groups(P>0.05).During the 6-months follow-up,54 patients in the doxophylline group reduced the frequency of inhaled corticosteroids because the disease is well controlled or stability,and 28 patients increased the frequency of inhaled corticosteroids due to the aggravation of the disease.53 patients in the non-doxophylline group reduced the frequency of inhaled corticosteroids and52 increased the frequency of inhaled corticosteroids.However,there was no significant difference in the dose adjustment rate of inhaled drugs containing corticosteroids between the two groups at the 1st and 3rd month(P>0.05).At the 6th month,33 patients in the doxophylline group reduced the frequency of inhaled glucocorticoid,and 6 patients increased the frequency of inhaled glucocorticoid.In the non-doxophylline group,28 people reduced and 22 people increased the frequency of inhaled glucocorticoid,and the difference between the two groups was statistically significant(P= 0.015).(2)In the neutrophil type,25 patients in the doxophylline group were treated with inhaled drugs containing glucocorticoids,and 35 patients in the non-doxophylline group.The drug dose adjustment rate of inhaled drugs containing corticosteroids in the first month after discharge showed that there was no significant difference between the two groups(P>0.05).In the third month,11 patients in the doxophylline group reduced the frequency of glucocorticoid inhalation drugs,4 patients increased,while in the non-doxophylline group,11 patients reduced the frequency of glucocorticoid inhalation drugs,18 patients increased,and there was significant difference between the two groups(P <0.05).At the 6th month,16 patients in the doxophylline group reduced the frequency of glucocorticoid inhalation drugs,3patients increased;11 patients in the non-doxophylline group reduced the frequency of glucocorticoid inhalation drugs,and 12 patients increased in the non-doxophylline group,and there was significant difference between the two groups(P=0.047).In the eosinophil type,11 patients in the doxophylline group were treated with inhaled drugs containing glucocorticoids,and 10 patients in the non-doxophylline group.There was no significant difference in the dose adjustment rate of glucocorticoid inhaled drugs between the two groups during 1 and 3 months after discharge(P > 0.05).In the doxophylline group,11 patients reduced the frequency of inhaled glucocorticoid inhaled drugs and 4 patients increased.In the non-doxophylline group,4 patients reduced the frequency of glucocorticoid inhaled drugs,and 0 people increased(P=0.027).In the mixed granulocytic type,18 patients in the doxophylline group were treated with inhaled drugs containing glucocorticoids,and 22 patients in the non-doxophylline group.There was no significant difference in the dose adjustment rate of inhaled drugs containing glucocorticoids between the two groups at the 1st,3rd and 6th month of follow-up(P >0.05). (3)In the frequent acute exacerbation,10 patients in the doxophylline group were treated with inhaled drugs containing glucocorticoids,and 14 patients in the non-doxophylline group.There was no significant difference in the dose adjustment rate of inhaled drugs containing corticosteroids between the two groups 1 and 6months after discharge(P>0.05).In the 3 months,the frequency of glucocorticoid inhaled drugs was reduced in 6 patients and increased in 0 patients in the doxophylline group;while in the non-doxophylline group,3 patients reduced the frequency of glucocorticoid inhaled drugs and increased in 7 patients,and there was significant difference between the two groups(P<0.05).In the non-frequent acute exacerbation,44 patients in the doxophylline group were treated with inhaled drugs containing glucocorticoids,and 57 patients in the non-doxophylline group.There was no significant difference in the dose adjustment rate of inhaled drugs containing corticosteroids between the two groups in 1 and 3 months after discharge(P>0.05).At the 6th month,29 patients was reduced and increased in 4 patients in the doxophylline group;while in the non-doxophylline group was reduced in 27 patients and increased in 17 patients,and there was significant difference between the two groups(P<0.05).Conclusions1.Doxophylline can reduce the overall incidence of severe acute exacerbation in patients with COPD.2.Doxophylline can be used as an adjuvant in the treatment of COPD patients to reduce the use of glucocorticoids.3.When doxophylline was used as an adjuvant,the long-term clinical effect of doxophylline was higher than that of short-term clinical effect(the time of administration was at least ≥ 3 months).4.Doxophylline can reduce the overall incidence of neutrophil,eosinophil subtypes and phenotype of frequently severe acute exacerbation,and significantly reduce the inflammatory reaction.5.Slowing down the decline of FEV1% and MMF% can benefit from doxophylline combined with glucocorticoids,especially the clinical subtypes of eosinophils.6.The adverse reactions of taking doxophylline are less,and the clinical use of doxophylline is safe. |
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