大环内酯类药物预防慢性阻塞性肺疾病急性发作的Meta分析
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摘要
目的慢性阻塞性肺疾病急性发作(AECOPD)可以导致高住院率和高死亡率。慢性阻塞性肺疾病急性发作(AECOPD)与气道炎症加重和细菌感染有关,大环内酯类抗生素是一类同时具有抗菌作用和抗炎作用以及免疫调节作用的药物。本研究采用发表的随机对照试验进行Meta分析,探讨大环内酯类药物预防慢性阻塞性肺病的急性发作期有效性和安全性。方法通过检索PUBMed、Embase、Cochrane Library、CNKI、EBM数据库,检索出随机对照试验相关文献,并使用RevMan5.3软件进行Meta分析,评价大环内酯类药物是否能预防AECOPD的发生。主要结局指标是随访期间试验组与对照组患者至少发生一次急性加重的频次,次要结局指标包括住院率、死亡率、SGRQ(圣乔治呼吸问卷)评分、不良反应事件等。结果纳入文献包括10项RCT试验,1702名患者。对纳入的研究进行Meta分析后结果显示,大环内酯类药物能显著减少COPD患者至少发生一次急性加重的频次(RR=0.67, 95%CI:0.55-0.83, P<0.05,Ⅰ2=63%),即使用大环内酯类药能预防COPD急性发作。亚组分析显示只有使用红霉素或阿奇霉素疗程6-12个月才有效,大环内酯类药能显著降低患者住院率(RR=0.76, 95%CI:0.64-0.90, P<0.05,Ⅰ2=0%),不能显著减少SGRQ总评分(Mean difference=-4.42, 95%CI:-8.79 to-0.04, P=0.05,Ⅰ2=95%),总的不良反应发生事件率与死亡率在治疗组与对照组之间无显著性差异。结论使用红霉素或阿奇霉素治疗6-12个月,可有效减少COPD患者至少发生一次急性发作频率,降低因急性加重住院的住院率,不能提高患者日常生活质量(SGRQ评分),而且大环内酯类药物不会显著增加患者不良反应事件的发生。对于死亡率,大环内酯类药物与对照组并无显著差异性,得出大环内酯类药物并不会显著降低患者死亡率。然而纳入文献数量较少,因此我们使用这些结论必须要谨慎,今后需要更多设计科学严谨的前瞻性随机对照双盲的高质量试验来支持。
Objective The acute episode of chronic obstructive pulmonary disease(AECOPD) can lead to high hospitalization rates and high mortality rates. The acute episode of chronic obstructive pulmonary disease(AECOPD) is associated with airway inflammation and bacterial infection.The macrolide antibiotics are a class of drugs that have both antibacterial, anti-inflammatory effects and immune regulation, so the macrolides can effectively prevent AECOPDs attack. In this study, meta analysis of published randomized controlled trials was conducted to investigate the feasibility and safety of macrolides in the prevention of acute exacerbation of chronic obstructive pulmonary disease(COPD).Methods By retrieving the pubmed, embase, cochrane library databases,CNKI, EBM, a meta-analysis of the rct-related literature was conducted to evaluate the occurrence of preventive macrolides in preventing aecopds. The first outcome measure was the frequency of at least one acute exacerbation in the trial group and the control group during follow-up in the literature.The second measure including hospitalization rate,mortality,SGRQ score and adverse events. Results A meta-analysis of the included studies showed that macrolides significantly reduced the frequency of at least one acute exacerbation in copd patients(RR=0.67,95%CI:0.55-0.83, P<0.05,Ⅰ2=63%), using macrolidesto prevent acute onset of COPD. The subgroup analysis showed that the use of erythromycin or azithromycin for 6-12 months was effective, and macrolides could significantly reduce the patient's hospitalization(RR=0.76,95%CI:.64-0.90, P<0.05,Ⅰ2=0%). Macrolides could not significantly reduce the total SGRQ score(Meandiffirence=-4.42,95%CI=-8.79 to-0.04, P=0.05, Ⅰ2=95%). There was no significant difference in the incidence of adverse events and mortality between the treatment group and the control group.Conclusion Our results suggest that 6-12 months of erythromycin or azithromycin treatment can effectively reduce the frequency of acute episodes in patients with copd and reduce hospitalization rates for acute exacerbation. Not improve the quality of daily life of patients with SGRQ scores, although macrolides may increase the incidence of adverse events in patients. However, there is no significant difference between macrolides and the control group, suggesting that macrolides can not significantly reduce the mortality of patients. The quality is low, so we have to becareful in using these conclusions, and more scientifically rigorous, prospective, randomized, double-blind, high-quality trials are needed in the future.
Objective The acute episode of chronic obstructive pulmonary disease(AECOPD) can lead to high hospitalization rates and high mortality rates. The acute episode of chronic obstructive pulmonary disease(AECOPD) is associated with airway inflammation and bacterial infection.The macrolide antibiotics are a class of drugs that have both antibacterial, anti-inflammatory effects and immune regulation, so the macrolides can effectively prevent AECOPDs attack. In this study, meta analysis of published randomized controlled trials was conducted to investigate the feasibility and safety of macrolides in the prevention of acute exacerbation of chronic obstructive pulmonary disease(COPD).Methods By retrieving the pubmed, embase, cochrane library databases,CNKI, EBM, a meta-analysis of the rct-related literature was conducted to evaluate the occurrence of preventive macrolides in preventing aecopds. The first outcome measure was the frequency of at least one acute exacerbation in the trial group and the control group during follow-up in the literature.The second measure including hospitalization rate,mortality,SGRQ score and adverse events. Results A meta-analysis of the included studies showed that macrolides significantly reduced the frequency of at least one acute exacerbation in copd patients(RR=0.67,95%CI:0.55-0.83, P<0.05,Ⅰ2=63%), using macrolidesto prevent acute onset of COPD. The subgroup analysis showed that the use of erythromycin or azithromycin for 6-12 months was effective, and macrolides could significantly reduce the patient's hospitalization(RR=0.76,95%CI:.64-0.90, P<0.05,Ⅰ2=0%). Macrolides could not significantly reduce the total SGRQ score(Meandiffirence=-4.42,95%CI=-8.79 to-0.04, P=0.05, Ⅰ2=95%). There was no significant difference in the incidence of adverse events and mortality between the treatment group and the control group.Conclusion Our results suggest that 6-12 months of erythromycin or azithromycin treatment can effectively reduce the frequency of acute episodes in patients with copd and reduce hospitalization rates for acute exacerbation. Not improve the quality of daily life of patients with SGRQ scores, although macrolides may increase the incidence of adverse events in patients. However, there is no significant difference between macrolides and the control group, suggesting that macrolides can not significantly reduce the mortality of patients. The quality is low, so we have to becareful in using these conclusions, and more scientifically rigorous, prospective, randomized, double-blind, high-quality trials are needed in the future.
引文
[1]Mannino DM,Buist AS.Global burden of COPD:risk factors,prevalence,and future trends[J].Lancet,2007,370:765-733.
[2]World Health Organization.Chronic obstructive pulmonary disease[EB/OL].http://www.who.int/respiratory/copd/en/.
[3]Stephanie PT,Associate P,Eric S,et al.Azithromycin for the prevention of COPD exacerbations:The good,bad,and ugly[J].Respirolog,2015,07:032.
[4]Victoria B,Priya VJ,Aran S,et al.Lung microbiology and exacerbations in COPD[J].Inter national JCOPD,2012,7:555-569.
[5]Wouters EF.The burden of COPD in The Netherlands:results from the Confronting COPD survey[J].Respir Med,2003:S51-9.
[6]Milewska A,Rysiak E,Zareba I,et al.Cost of treatment of chronic obstructive pulmonary disease[J].Advances in Experimental Medicine and Biology,2016,885:67-75.
[7]Fanny WK,Kapang C,David SH,et al.Acute exacerbation of COPD[J].Respirolog,2016,21:1152-1165.
[8]Sevim U,Remco SD,Kluytmans JAJW,et al.Influence of macrolidemaintenance the rapy and bacterial colonisation on exacerbation frequency and progression of COPD(COLUMBUS):Study protocol for a randomised controlled trial[J].trialsjournal,2012,13:82.
[9]Sanjay S,Timothy F.Infection in the pathogenesis and course of chronic obstructive pulmonary disease[J].N Engl J Med,2008,359:2355-65.
[10]Elie D,Abubakr C,Leonel FH,et al.A meta-analysis on the prophylactic use of macrolide antibiotics for the prevention of disease exacerbations in patients with chronic obstructive pulmonary disease[J].Respiratory Medicine,2013,107:1385-1392.
[11]Guo YY,Yan LM,Mo QZ,et al.Macrolide therapy decreaseschronic obstructivepulmonarydisease exacerbation[J].Respiration,2013,86:254-260.
[12]Maeva Z,Francois C,Bruno H,et al.Pharmacological treatment optimisation for stable COPD:an endless story?[J].Eur Respir J,2017,50:1701-250.
[13]Tomoko S,Masaru Y,Mutsuo Y,et al.Erythromycin and common cold in COPD[J].Chest,2001,120:730-733.
[14]Banerjee D,Khair OA,Honeybourne D.The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD[J].Respiratory Medicine,2005,99:208-215.
[15]Terence ARS,Tom MAW,John RH,et al.Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations[J].Am J Respir Crit Care Med,2008,178,:1139-1147.
[16]Francesco B,Daniela B,Stefano A,et al.Long-term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy[J].Pulmonary Pharmacology Therapeutics,2010:200-207.
[17]He ZY,Ou LM,Zhang JQ,et al.Effect of 6 months of erythromycin treatment on inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease[J].Respiration,2010,80:445-452.
[18]Richard KA,John C,William CB,et al.Azithromycin for prevention of exacerbations of COPD[J].N Engl J Med,2011,365:689-98.
[19]Farida FB,Nynke EDH,Steven MU,et al.Azithromycin and cough-specific health status in patients with chronic obstructive pulmonary disease and chronic cough:a randomised controlled trial[J].Respiratory Research,2013,14:125.
[20]Jodie LS,Heather P,Katherine A,et al.The Effect of azithromycin in adults with stable neutrophilic COPD:A double blind randomised placebo controlled trial[J].PLoS ONE,9(8):e105609.
[21]Sevim U,Remco SD,Jan AJWK,et al.Azithromycin ma in tenance treatmentinpatients with frequentexace rbations of chronic obstructive pulmonary disease(COLUMBUS):a randomised,double-blind,placebocontrolled trial[J].Lancet Respir Med,2014,2:361-68.
[22]Caimei T,Huijuan H,Jianquan Z,et al.Effect of low-dose and long-term treatment with erythromycin on interleukin-17and interleukin-23 in peripheral blood and induced sputum in patients with stable chronic obstructive pulmonary Ddisease[J].Hindawi Publishing Corporation,2016.
[23]Global initiative for obstructive lung Disease GOLD,global strategy for the diagnosis,management and prevention of chronic obstructive pulmonary disease[EB/OL].http://www.goldcopd.com.Accessed July 11,2012.
[24]中华医学会呼吸病学分会慢性阻塞性肺疾病学组,慢性阻塞性肺疾病诊治指南[J].中华结核和呼吸杂志,2013,36(4):259.
[25]Martinez FJ,Han MK,Flaherty K,et al.Role of infection and antimicrobial therapy in acute exacerbations of chronic obstructive pulmonary disease[J].Expert Rev Anti Infect Ther,2006,4:101-24.
[26]Remco SD,Sevim U,Jan AJWK,et al.Macrolides for reducing acute exacerbations of chronic obstructive pulmonary disease:new evidence[J].Clin Pulm Med,2016,23:16-22.
[27]邹文,周文.对大环内酯类药物的新认识[J].中华内科杂志,2007,26(8):484-486.
[28]林江涛,张永明,王长征,等.大环内酯类药物的抗菌外作用与临床应用专家共识[J].中华内科杂志,2017,56(7):546-557.
[29]Mammen MJ,Sethi S.Macrolide therapy for the prevention of acute exacerbations in chronic obstructive pulmonary disease[J].Polskle Archlwum Medycyny WewnetrzneJ,2012,122:1-2(54-59).
[30]Fernando JM,Jeffrey LC,Richard A.Role of macrolide therapy in chronic obstructive pulmonary disease[J].Inter JCOPD,2008,3(3):331-350.
[31]Thomas R,Gerd M,Peter l.A Comparison of the assessment of Life with CAT,CCQ,and SGRQ in COPD patients participating in pulmonary rehabilitation[J].Joural of Chronic Obstructive Pulmonarydisea,2012,9:12-15.
[32]Clement A,Tamalet A,Leroux E,et al.Long term effects of azithromycin in patients with cystic firosis:a double blind,placebo controlled trial[J].Thorax,2006,61:895-902.
[33]Gómez J,Ba?os V,Simarro E,et al.Prospective comparative study(1994-1998)of the influence of short-term prophylactic treatment with azithromycin on patients with advanced COPD[J].Rev Esp Quimioter,2000,13:379-383.
[34]Rabe KF,Fabbri LM,Vogelmeier C,et al.Seasonal distribution of COPD exacerbations in the prevention of exacerbations with tiotropium in COPD trial[J].Chest,2013,143:711-719.
[35]Cameron EJ,McSharry C,Chaudhuri R,et al.Thomson NC.Long-term macrolide treatment of chronic inflammatory airway diseases:risks,benefits and future developments[J].Clin Exp Allergy,2012,42:1302-1312.
[36]Marjanovi?N,Bosnar M,Michielin F,et al.Macrolide antibiotics broadly and distinctively inhibit cytokine and chemokine production by COPD sputum cells in vitro[J].Pharmacol Res,2011,63:389-397.
[37]Han MK,Tayob N,Murray S,et al.Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy[J].Am J Respir Crit Care Med,2014,189:1503-1508.
[38]Miravitlles M,Soler-Catalu?a JJ,Calle M,et al.Spanish COPD guidelines(GesEPOC).Pharmacological treatment of stable COPD[J].Arch Bronconeumol,2012,48:247e57.
[39]Yamaya M,Azuma A,Takizawa H,et al.Macrolide effects on the prevention of COPD exacerbations[J].Eur Respir J.2012,40:485-494.
[40]Schembri S,Williamson PA,Short PM,et al.Cardiovascular events after clarithromycin use in lower respiratory tract infections:analysis of two prospective cohort studies[J].BMJ,2013,346:f1235.
[41]Ray WA,Murray KT,Meredith S,et al.Oral erythromycin and the risk of sudden death from cardiac causes[J].N Engl J Med,2004,351:1089-1096.
[42]Wayne RA,Murray KT,Hall K,et al.Azithromycin and the risk of cardiovascular death[J].N Engl J Med,2012,366:1881-1890.
[2]World Health Organization.Chronic obstructive pulmonary disease[EB/OL].http://www.who.int/respiratory/copd/en/.
[3]Stephanie PT,Associate P,Eric S,et al.Azithromycin for the prevention of COPD exacerbations:The good,bad,and ugly[J].Respirolog,2015,07:032.
[4]Victoria B,Priya VJ,Aran S,et al.Lung microbiology and exacerbations in COPD[J].Inter national JCOPD,2012,7:555-569.
[5]Wouters EF.The burden of COPD in The Netherlands:results from the Confronting COPD survey[J].Respir Med,2003:S51-9.
[6]Milewska A,Rysiak E,Zareba I,et al.Cost of treatment of chronic obstructive pulmonary disease[J].Advances in Experimental Medicine and Biology,2016,885:67-75.
[7]Fanny WK,Kapang C,David SH,et al.Acute exacerbation of COPD[J].Respirolog,2016,21:1152-1165.
[8]Sevim U,Remco SD,Kluytmans JAJW,et al.Influence of macrolidemaintenance the rapy and bacterial colonisation on exacerbation frequency and progression of COPD(COLUMBUS):Study protocol for a randomised controlled trial[J].trialsjournal,2012,13:82.
[9]Sanjay S,Timothy F.Infection in the pathogenesis and course of chronic obstructive pulmonary disease[J].N Engl J Med,2008,359:2355-65.
[10]Elie D,Abubakr C,Leonel FH,et al.A meta-analysis on the prophylactic use of macrolide antibiotics for the prevention of disease exacerbations in patients with chronic obstructive pulmonary disease[J].Respiratory Medicine,2013,107:1385-1392.
[11]Guo YY,Yan LM,Mo QZ,et al.Macrolide therapy decreaseschronic obstructivepulmonarydisease exacerbation[J].Respiration,2013,86:254-260.
[12]Maeva Z,Francois C,Bruno H,et al.Pharmacological treatment optimisation for stable COPD:an endless story?[J].Eur Respir J,2017,50:1701-250.
[13]Tomoko S,Masaru Y,Mutsuo Y,et al.Erythromycin and common cold in COPD[J].Chest,2001,120:730-733.
[14]Banerjee D,Khair OA,Honeybourne D.The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD[J].Respiratory Medicine,2005,99:208-215.
[15]Terence ARS,Tom MAW,John RH,et al.Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations[J].Am J Respir Crit Care Med,2008,178,:1139-1147.
[16]Francesco B,Daniela B,Stefano A,et al.Long-term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy[J].Pulmonary Pharmacology Therapeutics,2010:200-207.
[17]He ZY,Ou LM,Zhang JQ,et al.Effect of 6 months of erythromycin treatment on inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease[J].Respiration,2010,80:445-452.
[18]Richard KA,John C,William CB,et al.Azithromycin for prevention of exacerbations of COPD[J].N Engl J Med,2011,365:689-98.
[19]Farida FB,Nynke EDH,Steven MU,et al.Azithromycin and cough-specific health status in patients with chronic obstructive pulmonary disease and chronic cough:a randomised controlled trial[J].Respiratory Research,2013,14:125.
[20]Jodie LS,Heather P,Katherine A,et al.The Effect of azithromycin in adults with stable neutrophilic COPD:A double blind randomised placebo controlled trial[J].PLoS ONE,9(8):e105609.
[21]Sevim U,Remco SD,Jan AJWK,et al.Azithromycin ma in tenance treatmentinpatients with frequentexace rbations of chronic obstructive pulmonary disease(COLUMBUS):a randomised,double-blind,placebocontrolled trial[J].Lancet Respir Med,2014,2:361-68.
[22]Caimei T,Huijuan H,Jianquan Z,et al.Effect of low-dose and long-term treatment with erythromycin on interleukin-17and interleukin-23 in peripheral blood and induced sputum in patients with stable chronic obstructive pulmonary Ddisease[J].Hindawi Publishing Corporation,2016.
[23]Global initiative for obstructive lung Disease GOLD,global strategy for the diagnosis,management and prevention of chronic obstructive pulmonary disease[EB/OL].http://www.goldcopd.com.Accessed July 11,2012.
[24]中华医学会呼吸病学分会慢性阻塞性肺疾病学组,慢性阻塞性肺疾病诊治指南[J].中华结核和呼吸杂志,2013,36(4):259.
[25]Martinez FJ,Han MK,Flaherty K,et al.Role of infection and antimicrobial therapy in acute exacerbations of chronic obstructive pulmonary disease[J].Expert Rev Anti Infect Ther,2006,4:101-24.
[26]Remco SD,Sevim U,Jan AJWK,et al.Macrolides for reducing acute exacerbations of chronic obstructive pulmonary disease:new evidence[J].Clin Pulm Med,2016,23:16-22.
[27]邹文,周文.对大环内酯类药物的新认识[J].中华内科杂志,2007,26(8):484-486.
[28]林江涛,张永明,王长征,等.大环内酯类药物的抗菌外作用与临床应用专家共识[J].中华内科杂志,2017,56(7):546-557.
[29]Mammen MJ,Sethi S.Macrolide therapy for the prevention of acute exacerbations in chronic obstructive pulmonary disease[J].Polskle Archlwum Medycyny WewnetrzneJ,2012,122:1-2(54-59).
[30]Fernando JM,Jeffrey LC,Richard A.Role of macrolide therapy in chronic obstructive pulmonary disease[J].Inter JCOPD,2008,3(3):331-350.
[31]Thomas R,Gerd M,Peter l.A Comparison of the assessment of Life with CAT,CCQ,and SGRQ in COPD patients participating in pulmonary rehabilitation[J].Joural of Chronic Obstructive Pulmonarydisea,2012,9:12-15.
[32]Clement A,Tamalet A,Leroux E,et al.Long term effects of azithromycin in patients with cystic firosis:a double blind,placebo controlled trial[J].Thorax,2006,61:895-902.
[33]Gómez J,Ba?os V,Simarro E,et al.Prospective comparative study(1994-1998)of the influence of short-term prophylactic treatment with azithromycin on patients with advanced COPD[J].Rev Esp Quimioter,2000,13:379-383.
[34]Rabe KF,Fabbri LM,Vogelmeier C,et al.Seasonal distribution of COPD exacerbations in the prevention of exacerbations with tiotropium in COPD trial[J].Chest,2013,143:711-719.
[35]Cameron EJ,McSharry C,Chaudhuri R,et al.Thomson NC.Long-term macrolide treatment of chronic inflammatory airway diseases:risks,benefits and future developments[J].Clin Exp Allergy,2012,42:1302-1312.
[36]Marjanovi?N,Bosnar M,Michielin F,et al.Macrolide antibiotics broadly and distinctively inhibit cytokine and chemokine production by COPD sputum cells in vitro[J].Pharmacol Res,2011,63:389-397.
[37]Han MK,Tayob N,Murray S,et al.Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy[J].Am J Respir Crit Care Med,2014,189:1503-1508.
[38]Miravitlles M,Soler-Catalu?a JJ,Calle M,et al.Spanish COPD guidelines(GesEPOC).Pharmacological treatment of stable COPD[J].Arch Bronconeumol,2012,48:247e57.
[39]Yamaya M,Azuma A,Takizawa H,et al.Macrolide effects on the prevention of COPD exacerbations[J].Eur Respir J.2012,40:485-494.
[40]Schembri S,Williamson PA,Short PM,et al.Cardiovascular events after clarithromycin use in lower respiratory tract infections:analysis of two prospective cohort studies[J].BMJ,2013,346:f1235.
[41]Ray WA,Murray KT,Meredith S,et al.Oral erythromycin and the risk of sudden death from cardiac causes[J].N Engl J Med,2004,351:1089-1096.
[42]Wayne RA,Murray KT,Hall K,et al.Azithromycin and the risk of cardiovascular death[J].N Engl J Med,2012,366:1881-1890.