冬季慢性阻塞性肺部疾病急性加重期住院患者病原学与预后分析
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摘要
目的:慢性阻塞性肺部疾病(chronic obstructive pulmonary diseases,COPD)是指是一种以气流受限为特征的、可以预防和治疗的疾病,气流受限不完全可逆、呈进行性发展,与肺部对香烟、烟雾等有害气体或有害颗粒的异常炎症反应有关。COPD主要累及肺脏,但也可引起全身(或称肺外)的不良效应。流行病调查认为COPD患病率占40岁以上人群的8.2%,其患病率之高十分惊人。慢性阻塞性肺部疾病急性加重(acute exacerbation chronic obstructive pulmonary diseases,AECOPD)是疾病自然病程中的一种事件,其特征是患者的呼吸困难、咳嗽和(或)痰出现了超过日常基础状态的变化,需要对治疗进行调整[1]。
大量研究表明,感染是COPD急性加重的重要诱因。但由于以往条件所限,我国大部分的病原学调查多以血清学或培养为基本技术,应用多聚酶链式反应(Polymerase Chain Reaction,PCR)技术的病原学调查数量有限。本实验旨在应用PCR技术,检测住院AECOPD患者呼吸道病原体,特别是呼吸道相关病毒所占比例,探讨病毒感染对AECOPD患者康复时间及气道炎症因子的影响,为避免临床工作中不必要的抗生素应用,加强病毒的预防与治疗提供理论依据。
方法:收集2008.11月至2009.3月河北省10家三级甲等医院和1家二级甲等医院呼吸内科,收住院3天内的AECOPD患者痰标本,冻存于-70℃冰箱。同时,采集患者基本信息、入院前情况(疫苗接种史、用药史、吸烟史、家庭吸氧等)、此次发病期间症状和体征、住院期间辅助检查(影像学资料、微生物资料及血常规、肝、肾功能、血气分析等)、治疗方案等临床资料。应用病毒基因组DNA/RNA提取试剂盒提取106份合格痰标本中的DNA和RNA,将所得RNA反转录成cDNA,细菌聚合酶链式反应试剂盒和病毒聚合酶链式反应试剂盒扩增特异性病原体基因片段,得出病原学结果。酶联免疫吸附法(ELISA)测定痰液中白介素6(IL-6)和肿瘤坏死因子α(TNF-α)含量。
结果:1病例临床资料收集116例患者痰液,痰涂片镜检剔除不合格样本10例。剩余106例患者中,男性构成比69.3%,年龄(70.67±10.13岁),体重指数(24.08±6.71kg/m2), FEV1(1.29±0.53L),FEV1/FVC(55.18±10.19%),既往3年因AECOPD住院人数83例(78.30%),无吸烟史42例(39.62%),已戒烟63例(59.43%),流感疫苗接种40例(37.73%),家庭氧疗2例(1.88%),长期应用激素5例(4.72%),单纯COPD急性发作的患者29例(27.36%),X线胸片或CT片肺野出现炎性改变51例(48.11%),合并支气管哮喘7例(6.60%)、2型糖尿病20例(18.87%)、冠状动脉粥样硬化性心脏病30例(28.30%)、高血压42例(39.62%)、肺栓塞3例(2.83%)、慢性肺源性心脏病33例(31.13%)、其他疾病17例(16.04%)。
2病原体PCR结果病毒阳性例数为40例(37.70%),甲型流感病毒17例(16.04%)、鼻病毒11例(10.38%),呼吸道合胞病毒B 2例(1.89%)、冠状病毒229E/NL63 2例(1.89%)、偏肺病毒1例(0.94%)、腺病毒1例(0.94%)、副流感病毒3 1例(0.94%)及混合感染5例(4.72%),混合感染包括甲型流感病毒+腺病毒2例(1.89%)、甲型流感病毒+鼻病毒1例(0.94%)、呼吸道合胞病毒B+副流感病毒3+甲型流感病毒1例(0.94%)、呼吸道合胞病毒B+鼻病毒1例(0.94%);细菌阳性例数43例(40.57%),肺炎链球菌28例(26.42%)、流感嗜血杆菌8例(7.55%)、肺炎链球菌+流感嗜血杆菌6例(5.66%)、流感嗜血杆菌+肺炎链球菌+肺炎支原体1例(0.94%)。其中,病毒与细菌混合感染16例(15.09%),甲型流感病毒+肺炎链球菌3例(2.83%)、甲型流感病毒+流感嗜血杆菌3例(2.83%)、鼻病毒+肺炎链球菌5例(4.72%)、鼻病毒+流感嗜血杆菌1例(0.94%)、呼吸道合胞病毒B+肺炎链球菌1例(0.94%)、鼻病毒+呼吸道合胞病毒B+肺炎链球菌1例(0.94%)、冠状病毒229E/NL63+流感嗜血杆菌+肺炎链球菌1例(0.94%)、甲型流感病毒+呼吸道合胞病毒B+副流感病毒3+肺炎链球菌1例(0.94%)。
3病毒对COPD患者的影响病毒阳性组总体的平均康复时间31.59 d(95%CI:15.88～47.31)。病毒阴性组14.82d(95%CI:12.81～16.83)。经log-rank检验显示两组患者的康复率有差别(χ2=5.17,P=0.02)。
4感染对炎症因子的影响病毒阳性组痰中IL-6含量(114.92±44.82ng/L)高于阴性组(70.74±46.59ng/L),P<0.001;两组TNF-α含量无明显差别。细菌阳性组与阴性组痰中IL-6、TNF-α含量均无明显差别。细菌与病毒混合感染者痰中IL-6含量(120.31±46.62ng/L)高于单一感染(83.61±47.83ng/L),P=0.02。
结论:甲型流感病毒、鼻病毒、肺炎链球菌和流感嗜血杆菌感染是COPD患者急性加重的重要诱因;病毒感染影响COPD患者的康复率、康复时间和痰液中气道炎症因子含量;甲型流感病毒值得关注。
Objective:COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. COPD mostly implicates lung, and adversely effects on all over the body(or extrapulmonary)sometimes. Epidemiologic survey has showed that the morbidity rate of COPD was surprisingly high, 8.2% in the population Aged 40 and Older. An exacerbation of COPD is an event in the natural course of the disease characterized by a change in the patient's baseline dyspnoea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management. Many studies have indicated that infection was an important trigger for AECOPD. Because of limited condition, only serology and culture technology have been used for the most of etiological investigations in our country. Few of investigations utilized PCR detection technology. Our present study would detect several pathogens in respiratory tract of hospitalized patients suffered AECOPD, especially the distribution of respiratory-tract-related virus, and explore the influence of virus infection on patients’recovery time and inflammatory factors of hospital patients with AECOPD, in order to avoid unnecessary antibiotic application on clinic and provide theoretical proof for augmenting prevention and treatment of virus.
Methods: Collecting sputum samples, which was frozen in -70℃refrigerator, of 106 hospitalized patients with AECOPD within 3 days admission from respiratory departments of ten Grade 3A hospitals and one Grade 2A hospital from Nov,2008 to Mar,2009. Meanwhile, recording patients’clinical data, such as basic information, history prior to admission (vaccine inoculation, medication, smoking, home oxygen therapy and so on),signs and symptoms during this exacerbation, auxiliary examination in hospital (imaging data, pathogen data, blood routine test, hepatic function, renal function, blood gas analysis) and treatment plan. The DNA and RNA in 106 qualified sputum samples was extracted by TIANamp Virus DNA/RNA Kits, followed by cDNA synthesis using reverse transcription technology .And then,the specific gene fragment of microorganisms in DNA and cDNA would be amplified by Bacteria polymerase chain reaction (PCR) kits and virus PCR kits. The concentration of interleukin-6(IL-6) and tumor necrosis factor alpha(TNF-α) in sputum samples was measured by Enzyme-linked Immunosorbent Assay(ELISA)kits.
Results:
1 Patients clinical data 10 unqualified sputum samples, tested by sputum smear, were removed from 116 patients’sputum samples. In the rest of 106 patients, with the characters as followings: 69.3% male, age (70.67±10.13),body mass index (24.08±6.71kg/m2),FEV1(1.29±0.53L),FEV1/FVC(55.18±10.19%),hospitalized for AECOPD in the past three years 83 patients (78.30%),nonsmoking history 42 patients(39.62%), quitting smoking 63 patients(59.43%),influenza vaccine inoculation 40 patients (37.73%),home oxygen therapy 2 patients(1.88%),long term hormone application 5 patients (4.72%),only suffered by AECOPD 29 patients(27.36%),inflammatory exudation in X-ray film or CT film 51 patients(48.11%),complicating with asthma 7 patients(6.60%),Type 2 Diabetes 20 patients(18.87%),Coronary Atherosclerotic Heart Disease 30 patients(28.30%),hypertension 42 patients(39.62%), pulmonary embolism 3 patients (2.83%),chronic pulmonary heart disease 33 patients(31.13%),other diseases 17 patients(16.04%).
2 Pathogen PCR results 40 samples (37.70%) were positive for at least one viral pathogen, including influenza A virus 17 samples (16.04%), rhinoviruses 11 samples (10.38%),respiratory syncytial virus B 2 samples (1.89%),coronavirus229E/NL63 2 samples (1.89%), metapneumovirus 1 sample(0.94%),adenovirus 1 sample (0.94%),parainfluenza3 virus 1 sample (0.94%),mixed infection 5 samples (4.72%).Mixed infection included influenza A virus and adenovirus 2 samples (1.89%),influenza A virus and rhinoviruses 1 sample(0.94%),respiratory syncytial virus B,parainfluenza3 virus and influenza A virus 1 sample (0.94%),respiratory syncytial virus B and rhinoviruses 1 sample (0.94%);43 samples (40.57%) were positive for at least one bacteria pathogen,streptococcus pneumoniae 28 samples (26.42%), haemophilus influenzae 8 samples (7.55%), streptococcus pneumoniae and haemophilus influenzae 6 samples (5.66%),haemophilus influenzae, streptococcus pneumoniae and mycoplasma pneumoniae 1 sample (0.94%).Of the total, virus-and-bacteria mixed infection 16 samples (15.09%),influenza A virus and streptococcus pneumoniae 3 samples (2.83%), influenza A virus and haemophilus influenzae 3 samples (2.83%), rhinoviruses and streptococcus pneumoniae 5 samples (4.72%),rhinoviruses and haemophilus influenzae 1 samples (0.94%),respiratory syncytial virus B and streptococcus pneumoniae 1 sample (0.94%),rhinoviruses, respiratory syncytial virus B and streptococcus pneumoniae 1 sample (0.94%), coronavirus 229E/NL63,haemophilus influenzae and streptococcus pneumoniae 1 sample (0.94%),influenza A virus, respiratory syncytial virus B,parainfluenza3 and streptococcus pneumoniae 1 sample (0.94%).
3 The influence of virus on COPD patients The average recovery time in virus- positive group was 31.59d (95%CI: 15.88~47.31), and in virus- negtive group was 14.82d (95%CI:12.81~16.83). Log-rank test showed that the recovery rate of two groups was significantly different (χ2=5.17,P=0.02).
4 The influence of infection on inflammatory cytokines The concentration of IL-6(114.92±44.82ng/L) in sputum samples of virus- positive group was higher than in virus-negtive group(70.74±46.59ng/L),but TNF-αwas not significantly different between both groups.The concentration of IL-6 and TNF-αin sputum was not significantly different between bacteria-positive and bacteria-negtive group. The concentration of IL-6 in sputum of bacteria-virus mixed infection group(120.31±46.62ng/L)was higher than bacteria or virus single infection group (83.61±47.83ng/ L),P=0.02.
Conclusions: influenza virus A, rhinoviruses, Streptococcus pneumoniae and haemophilus influenzae infection are important factors for AECOPD patients. Virus infection would lower recovery rate, prolong recovery time and increase the concentration of inflammatory cytokines of airway. A-type influenza virus is worth paying attention to.
大量研究表明,感染是COPD急性加重的重要诱因。但由于以往条件所限,我国大部分的病原学调查多以血清学或培养为基本技术,应用多聚酶链式反应(Polymerase Chain Reaction,PCR)技术的病原学调查数量有限。本实验旨在应用PCR技术,检测住院AECOPD患者呼吸道病原体,特别是呼吸道相关病毒所占比例,探讨病毒感染对AECOPD患者康复时间及气道炎症因子的影响,为避免临床工作中不必要的抗生素应用,加强病毒的预防与治疗提供理论依据。
方法:收集2008.11月至2009.3月河北省10家三级甲等医院和1家二级甲等医院呼吸内科,收住院3天内的AECOPD患者痰标本,冻存于-70℃冰箱。同时,采集患者基本信息、入院前情况(疫苗接种史、用药史、吸烟史、家庭吸氧等)、此次发病期间症状和体征、住院期间辅助检查(影像学资料、微生物资料及血常规、肝、肾功能、血气分析等)、治疗方案等临床资料。应用病毒基因组DNA/RNA提取试剂盒提取106份合格痰标本中的DNA和RNA,将所得RNA反转录成cDNA,细菌聚合酶链式反应试剂盒和病毒聚合酶链式反应试剂盒扩增特异性病原体基因片段,得出病原学结果。酶联免疫吸附法(ELISA)测定痰液中白介素6(IL-6)和肿瘤坏死因子α(TNF-α)含量。
结果:1病例临床资料收集116例患者痰液,痰涂片镜检剔除不合格样本10例。剩余106例患者中,男性构成比69.3%,年龄(70.67±10.13岁),体重指数(24.08±6.71kg/m2), FEV1(1.29±0.53L),FEV1/FVC(55.18±10.19%),既往3年因AECOPD住院人数83例(78.30%),无吸烟史42例(39.62%),已戒烟63例(59.43%),流感疫苗接种40例(37.73%),家庭氧疗2例(1.88%),长期应用激素5例(4.72%),单纯COPD急性发作的患者29例(27.36%),X线胸片或CT片肺野出现炎性改变51例(48.11%),合并支气管哮喘7例(6.60%)、2型糖尿病20例(18.87%)、冠状动脉粥样硬化性心脏病30例(28.30%)、高血压42例(39.62%)、肺栓塞3例(2.83%)、慢性肺源性心脏病33例(31.13%)、其他疾病17例(16.04%)。
2病原体PCR结果病毒阳性例数为40例(37.70%),甲型流感病毒17例(16.04%)、鼻病毒11例(10.38%),呼吸道合胞病毒B 2例(1.89%)、冠状病毒229E/NL63 2例(1.89%)、偏肺病毒1例(0.94%)、腺病毒1例(0.94%)、副流感病毒3 1例(0.94%)及混合感染5例(4.72%),混合感染包括甲型流感病毒+腺病毒2例(1.89%)、甲型流感病毒+鼻病毒1例(0.94%)、呼吸道合胞病毒B+副流感病毒3+甲型流感病毒1例(0.94%)、呼吸道合胞病毒B+鼻病毒1例(0.94%);细菌阳性例数43例(40.57%),肺炎链球菌28例(26.42%)、流感嗜血杆菌8例(7.55%)、肺炎链球菌+流感嗜血杆菌6例(5.66%)、流感嗜血杆菌+肺炎链球菌+肺炎支原体1例(0.94%)。其中,病毒与细菌混合感染16例(15.09%),甲型流感病毒+肺炎链球菌3例(2.83%)、甲型流感病毒+流感嗜血杆菌3例(2.83%)、鼻病毒+肺炎链球菌5例(4.72%)、鼻病毒+流感嗜血杆菌1例(0.94%)、呼吸道合胞病毒B+肺炎链球菌1例(0.94%)、鼻病毒+呼吸道合胞病毒B+肺炎链球菌1例(0.94%)、冠状病毒229E/NL63+流感嗜血杆菌+肺炎链球菌1例(0.94%)、甲型流感病毒+呼吸道合胞病毒B+副流感病毒3+肺炎链球菌1例(0.94%)。
3病毒对COPD患者的影响病毒阳性组总体的平均康复时间31.59 d(95%CI:15.88～47.31)。病毒阴性组14.82d(95%CI:12.81～16.83)。经log-rank检验显示两组患者的康复率有差别(χ2=5.17,P=0.02)。
4感染对炎症因子的影响病毒阳性组痰中IL-6含量(114.92±44.82ng/L)高于阴性组(70.74±46.59ng/L),P<0.001;两组TNF-α含量无明显差别。细菌阳性组与阴性组痰中IL-6、TNF-α含量均无明显差别。细菌与病毒混合感染者痰中IL-6含量(120.31±46.62ng/L)高于单一感染(83.61±47.83ng/L),P=0.02。
结论:甲型流感病毒、鼻病毒、肺炎链球菌和流感嗜血杆菌感染是COPD患者急性加重的重要诱因;病毒感染影响COPD患者的康复率、康复时间和痰液中气道炎症因子含量;甲型流感病毒值得关注。
Objective:COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. COPD mostly implicates lung, and adversely effects on all over the body(or extrapulmonary)sometimes. Epidemiologic survey has showed that the morbidity rate of COPD was surprisingly high, 8.2% in the population Aged 40 and Older. An exacerbation of COPD is an event in the natural course of the disease characterized by a change in the patient's baseline dyspnoea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management. Many studies have indicated that infection was an important trigger for AECOPD. Because of limited condition, only serology and culture technology have been used for the most of etiological investigations in our country. Few of investigations utilized PCR detection technology. Our present study would detect several pathogens in respiratory tract of hospitalized patients suffered AECOPD, especially the distribution of respiratory-tract-related virus, and explore the influence of virus infection on patients’recovery time and inflammatory factors of hospital patients with AECOPD, in order to avoid unnecessary antibiotic application on clinic and provide theoretical proof for augmenting prevention and treatment of virus.
Methods: Collecting sputum samples, which was frozen in -70℃refrigerator, of 106 hospitalized patients with AECOPD within 3 days admission from respiratory departments of ten Grade 3A hospitals and one Grade 2A hospital from Nov,2008 to Mar,2009. Meanwhile, recording patients’clinical data, such as basic information, history prior to admission (vaccine inoculation, medication, smoking, home oxygen therapy and so on),signs and symptoms during this exacerbation, auxiliary examination in hospital (imaging data, pathogen data, blood routine test, hepatic function, renal function, blood gas analysis) and treatment plan. The DNA and RNA in 106 qualified sputum samples was extracted by TIANamp Virus DNA/RNA Kits, followed by cDNA synthesis using reverse transcription technology .And then,the specific gene fragment of microorganisms in DNA and cDNA would be amplified by Bacteria polymerase chain reaction (PCR) kits and virus PCR kits. The concentration of interleukin-6(IL-6) and tumor necrosis factor alpha(TNF-α) in sputum samples was measured by Enzyme-linked Immunosorbent Assay(ELISA)kits.
Results:
1 Patients clinical data 10 unqualified sputum samples, tested by sputum smear, were removed from 116 patients’sputum samples. In the rest of 106 patients, with the characters as followings: 69.3% male, age (70.67±10.13),body mass index (24.08±6.71kg/m2),FEV1(1.29±0.53L),FEV1/FVC(55.18±10.19%),hospitalized for AECOPD in the past three years 83 patients (78.30%),nonsmoking history 42 patients(39.62%), quitting smoking 63 patients(59.43%),influenza vaccine inoculation 40 patients (37.73%),home oxygen therapy 2 patients(1.88%),long term hormone application 5 patients (4.72%),only suffered by AECOPD 29 patients(27.36%),inflammatory exudation in X-ray film or CT film 51 patients(48.11%),complicating with asthma 7 patients(6.60%),Type 2 Diabetes 20 patients(18.87%),Coronary Atherosclerotic Heart Disease 30 patients(28.30%),hypertension 42 patients(39.62%), pulmonary embolism 3 patients (2.83%),chronic pulmonary heart disease 33 patients(31.13%),other diseases 17 patients(16.04%).
2 Pathogen PCR results 40 samples (37.70%) were positive for at least one viral pathogen, including influenza A virus 17 samples (16.04%), rhinoviruses 11 samples (10.38%),respiratory syncytial virus B 2 samples (1.89%),coronavirus229E/NL63 2 samples (1.89%), metapneumovirus 1 sample(0.94%),adenovirus 1 sample (0.94%),parainfluenza3 virus 1 sample (0.94%),mixed infection 5 samples (4.72%).Mixed infection included influenza A virus and adenovirus 2 samples (1.89%),influenza A virus and rhinoviruses 1 sample(0.94%),respiratory syncytial virus B,parainfluenza3 virus and influenza A virus 1 sample (0.94%),respiratory syncytial virus B and rhinoviruses 1 sample (0.94%);43 samples (40.57%) were positive for at least one bacteria pathogen,streptococcus pneumoniae 28 samples (26.42%), haemophilus influenzae 8 samples (7.55%), streptococcus pneumoniae and haemophilus influenzae 6 samples (5.66%),haemophilus influenzae, streptococcus pneumoniae and mycoplasma pneumoniae 1 sample (0.94%).Of the total, virus-and-bacteria mixed infection 16 samples (15.09%),influenza A virus and streptococcus pneumoniae 3 samples (2.83%), influenza A virus and haemophilus influenzae 3 samples (2.83%), rhinoviruses and streptococcus pneumoniae 5 samples (4.72%),rhinoviruses and haemophilus influenzae 1 samples (0.94%),respiratory syncytial virus B and streptococcus pneumoniae 1 sample (0.94%),rhinoviruses, respiratory syncytial virus B and streptococcus pneumoniae 1 sample (0.94%), coronavirus 229E/NL63,haemophilus influenzae and streptococcus pneumoniae 1 sample (0.94%),influenza A virus, respiratory syncytial virus B,parainfluenza3 and streptococcus pneumoniae 1 sample (0.94%).
3 The influence of virus on COPD patients The average recovery time in virus- positive group was 31.59d (95%CI: 15.88~47.31), and in virus- negtive group was 14.82d (95%CI:12.81~16.83). Log-rank test showed that the recovery rate of two groups was significantly different (χ2=5.17,P=0.02).
4 The influence of infection on inflammatory cytokines The concentration of IL-6(114.92±44.82ng/L) in sputum samples of virus- positive group was higher than in virus-negtive group(70.74±46.59ng/L),but TNF-αwas not significantly different between both groups.The concentration of IL-6 and TNF-αin sputum was not significantly different between bacteria-positive and bacteria-negtive group. The concentration of IL-6 in sputum of bacteria-virus mixed infection group(120.31±46.62ng/L)was higher than bacteria or virus single infection group (83.61±47.83ng/ L),P=0.02.
Conclusions: influenza virus A, rhinoviruses, Streptococcus pneumoniae and haemophilus influenzae infection are important factors for AECOPD patients. Virus infection would lower recovery rate, prolong recovery time and increase the concentration of inflammatory cytokines of airway. A-type influenza virus is worth paying attention to.
引文
1 Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper[J]. Eur Respir J, 2004,23:932-946
2 Soler N, Ewig S, Torres A, et al. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease[J]. Eur Respir J, 1999,14:1015-1022
3 Sethi S. Bacterial infection and the pathogenesis of COPD[J]. Chest, 2000,117:286S-91S
4 Bellau-Pujol S, Vabret A, Legrand L, et al. Development of three multiplex RT-PCR assays for the detection of 12 respiratory RNA viruses[J]. J Virol Methods, 2005,126:53-63
5 Chun JY, Kim KJ, Hwang IT, et al. Dual priming oligonucleotide system for the multiplex detection of respiratory viruses and SNP genotyping of CYP2C19 gene[J]. Nucleic Acids Res, 2007,35:e40
6中华医学会呼吸病分会慢性阻塞性肺疾病学组.慢性阻塞性肺疾病诊治指南(2007年修订版)[J].中华结核和呼吸杂志, 2007,30:8-17
7 Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system[J]. Crit Care Med, 1985,13:818-829
8 Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2001,164:1618-1623
9 Wilkinson TM, Donaldson GC, Johnston SL, et al. Respiratory syncytial virus, airway inflammation, and FEV1 decline in patients with chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2006,173:871-876
10 Pichler M, Herrmann G, Schmidt H, et al. Persistent adenoviral infection and chronic obstructive bronchitis in children: is there a link[J]. Pediatr Pulmonol, 2001,32:367-371
11 Matsuse T, Matsui H, Shu CY, et al. Adenovirus pulmonary infections identified by PCR and in situ hybridisation in bone marrow transplant recipients[J]. J Clin Pathol, 1994,47:973-977
12 den Hoogen BG v, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease[J]. Nat Med, 2001,7:719-724
13 Rohde G, Borg I, Arinir U, et al. Relevance of human metapneumovirus in exacerbations of COPD[J]. Respir Res, 2005,6:150
14 Martinello RA, Esper F, Weibel C, et al. Human metapneumovirus and exacerbations of chronic obstructive pulmonary disease[J]. J Infect, 2006,53:248-254
15 Sivaprakasam V, Collins TC, Aitken C, et al. Life-threatening human metapneumovirus infections in West of Scotland[J]. J Clin Virol, 2007,39:234-237
16 Zhao Q, Li S, Xue F, et al. Structure of the main protease from a global infectious human coronavirus, HCoV-HKU1[J]. J Virol, 2008, 82: 8647-8655
17陈杭薇.成人呼吸道病毒、肺炎衣原体、支原体感染研究[J].中华医院感染学杂志, 2003:12-14
18周一平,陆学东,陈小可,等.呼吸道病毒与成人下呼吸道感染相关性探讨[J].中华实用诊断与治疗杂志, 2010:121-124
19 Beckham JD, Cadena A, Lin J, et al. Respiratory viral infections in patients with chronic, obstructive pulmonary disease[J]. J Infect, 2005,50:322-330
20 Krug RM, Aramini JM. Emerging antiviral targets for influenza A virus[J]. Trends Pharmacol Sci, 2009,30:269-277
21区映研,秦笙,杨子峰,等.广州市不同时段成人上呼吸道感染病毒鉴定与临床分析[J].中国实用内科杂志, 2009:707-709+713
22 Wongsurakiat P, Maranetra KN, Wasi C, et al. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study[J]. Chest, 2004,125:2011-2020
23 Wang CS, Wang ST, Lai CT, et al. Impact of influenza vaccination on major cause-specific mortality[J]. Vaccine, 2007,25:1196-1203
24 Laitinen LA, Elkin RB, Empey DW, et al. Bronchial hyperresponsiveness in normal subjects during attenuated influenza virus infection[J]. Am Rev Respir Dis, 1991,143:358-361
25 Roger T, Bresser P, Snoek M, et al. Exaggerated IL-8 and IL-6 responses to TNF-alpha by parainfluenza virus type 4-infected NCI-H292 cells[J]. Am J Physiol Lung Cell Mol Physiol, 2004,287:L1048-1055
26 Hacievliyagil SS, Gunen H, Mutlu LC, et al. Association between cytokines in induced sputum and severity of chronic obstructive pulmonary disease[J]. Respir Med, 2006,100:846-854
27 Wilkinson TM, Hurst JR, Perera WR, et al. Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD[J]. Chest, 2006,129:317-324
28王永兴,郭梅,刘德江.慢性阻塞性肺病急性加重期呼吸道病原菌分布及耐药性分析[J].第四军医大学学报, 2004:1874-1876
29周志祥,周洋,陈宗宁,等.慢性阻塞性肺疾病急性加重期痰致病菌检测及其临床意义[J].临床医药实践杂志, 2008:955-956
30 Murphy TF, Brauer AL, Schiffmacher AT, et al. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2004,170:266-272
31 Banerjee D, Khair OA, Honeybourne D. Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD[J]. Eur Respir J, 2004,23:685-691
32 Sethi S, Maloney J, Grove L, et al. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2006,173:991-998
33倪安平,王辉,董平,等.肺炎、支气管炎和急性上呼吸道感染患者肺炎衣原体感染的研究[J].中华内科杂志, 1995:388-391
34 Hewlett EL, Edwards KM. Clinical practice. Pertussis--not just for kids[J]. N Engl J Med, 2005,352:1215-1222
35徐少华,柏玉红,邵红艳.病毒感染对慢性阻塞性肺疾病患者气道炎症的作用[J].中华医院感染学杂志, 2004:13-15
1 Hewlett EL, Edwards KM. Clinical practice. Pertussis--not just for kids[J]. N Engl J Med, 2005,352(12):1215-1222
2 Ko FW, Ng TK, Li TS, et al. Sputum bacteriology in patients with acute exacerbations of COPD in Hong Kong[J]. Respir Med, 2005,99(4):454-460
3 Ko FW, Ip M, Chan PK, et al. A one-year prospective study of infectious etiology in patients hospitalized with acute exacerbations of COPD and concomitant pneumonia[J]. Respir Med, 2008,102(8):1109-1116
4 Lieberman D, Lieberman D, Gelfer Y, et al. Pneumonic vs nonpneumonic acute exacerbations of COPD[J]. Chest, 2002,122(4):1264-1270
5 Miravitlles M, Espinosa C, Fernandez-Laso E, et al. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD[J]. Chest, 1999,116(1):40-46
6 Borg I, Rohde G, Loseke S, et al. Evaluation of a quantitative real-time PCR for the detection of respiratory syncytial virus in pulmonary diseases[J]. Eur Respir J, 2003,21(6):944-951
7 Rohde G, Wiethege A, Borg I, et al. Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study[J]. Thorax, 2003,58(1):37-42
8 Beckham JD, Cadena A, Lin J, et al. Respiratory viral infections in patients with chronic, obstructive pulmonary disease[J]. J Infect, 2005,50(4):322-330
9 den Hoogen BG v, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease[J]. Nat Med, 2001,7(6):719-724
10 Rohde G, Borg I, Arinir U, et al. Relevance of human metapneumovirus in exacerbations of COPD[J]. Respir Res, 2005,6:150
11 Martinello RA, Esper F, Weibel C, et al. Human metapneumovirus and exacerbations of chronic obstructive pulmonary disease[J]. J Infect, 2006,53(4):248-254
12 Sivaprakasam V, Collins TC, Aitken C, et al. Life-threatening human metapneumovirus infections in West of Scotland[J]. J Clin Virol, 2007,39(3):234-237
13 Ko FW, Ip M, Chan PK, et al. Viral etiology of acute exacerbations of COPD in Hong Kong[J]. Chest, 2007,132(3):900-908
14 Hutchinson AF, Ghimire AK, Thompson MA, et al. A community-based, time-matched, case-control study of respiratory viruses and exacerbations of COPD[J]. Respir Med, 2007,101(12):2472-2481
15 McManus TE, Marley AM, Baxter N, et al. Respiratory viral infection in exacerbations of COPD[J]. Respir Med, 2008,102(11):1575-1580
16 Wilkinson TM, Hurst JR, Perera WR, et al. Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD[J]. Chest, 2006,129(2):317-324
17 Avadhanula V, Rodriguez CA, Devincenzo JP, et al. Respiratory virusesaugment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner[J]. J Virol, 2006, 80 (4): 1629-1636
18 Sajjan US, Jia Y, Newcomb DC, et al. H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression[J]. FASEB J, 2006,20(12):2121-2123
19 Barnes PJ. Chronic obstructive pulmonary disease[J]. N Engl J Med, 2000,343(4):269-280
20 Morris A, Sciurba FC, Lebedeva IP, et al. Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization[J]. Am J Respir Crit Care Med, 2004,170(4):408-413
21 Blasi F, Damato S, Cosentini R, et al. Chlamydia pneumoniae and chronic bronchitis: association with severity and bacterial clearance following treatment[J]. Thorax, 2002,57(8):672-676
22 Murphy TF, Brauer AL, Schiffmacher AT, et al. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2004,170(3):266-272
23 Banerjee D, Khair OA, Honeybourne D. Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD[J]. Eur Respir J, 2004,23(5):685-691
24 Wilkinson TM, Patel IS, Wilks M, et al. Airway bacterial load and FEV1 decline in patients with chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2003,167(8):1090-1095
25 Hill AT, Campbell EJ, Hill SL, et al. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis[J]. Am J Med, 2000,109(4):288-295
26 Patel IS, Seemungal TA, Wilks M, et al. Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations[J]. Thorax, 2002,57(9):759-764
27 Bresser P, Out TA, van AL, et al. Airway inflammation in nonobstructive and obstructive chronic bronchitis with chronic haemophilus influenzaeairway infection. Comparison with noninfected patients with chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2000,162(3 Pt 1):947-952
28 Sethi S, Maloney J, Grove L, et al. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2006,173(9):991-998
29 Soler N, Ewig S, Torres A, et al. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease[J]. Eur Respir J, 1999,14(5):1015-1022
30 Sethi S, Sethi R, Eschberger K, et al. Airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2007,176(4):356-361
31 Murphy TF, Brauer AL, Eschberger K, et al. Pseudomonas aeruginosa in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2008,177(8):853-860
32 Starner TD, Zhang N, Kim G, et al. Haemophilus influenzae forms biofilms on airway epithelia: implications in cystic fibrosis[J]. Am J Respir Crit Care Med, 2006,174(2):213-220
33 Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2001,164(9):1618-1623
34 McManus TE, Marley AM, Baxter N, et al. High levels of Epstein-Barr virus in COPD[J]. Eur Respir J, 2008,31(6):1221-1226
35 Ishii M, Teramoto S. [Childhood respiratory infection in the pathogenesis of COPD][J]. Nippon Rinsho, 2007,65(4):617-622
36 Higashimoto Y, Keicho N, Elliott WM, et al. Effect of adenovirus E1A on ICAM-1 promoter activity in human alveolar and bronchial epithelial cells[J]. Gene Expr, 1999,8(5-6):287-297
37 Yamada K, Elliott WM, Brattsand R, et al. Molecular mechanisms of decreased steroid responsiveness induced by latent adenoviral infection inallergic lung inflammation[J]. J Allergy Clin Immunol, 2002,109(1):35-42
38 McManus TE, Marley AM, Baxter N, et al. Acute and latent adenovirus in COPD[J]. Respir Med, 2007,101(10):2084-2090
39 Gwaltney JM Jr, Hendley JO, Patrie JT. Symptom severity patterns in experimental common colds and their usefulness in timing onset of illness in natural colds[J]. Clin Infect Dis, 2003,36(6):714-723
40 Monto AS, Bramley TJ, Sarnes M. Development of a predictive index for picornavirus infections[J]. Clin Infect Dis, 2003,36(3):253-258
41 Gompertz S, O'Brien C, Bayley DL, et al. Changes in bronchial inflammation during acute exacerbations of chronic bronchitis[J]. Eur Respir J, 2001,17(6):1112-1119
42 Sethi S, Muscarella K, Evans N, et al. Airway inflammation and etiology of acute exacerbations of chronic bronchitis[J]. Chest, 2000, 118 (6): 1557-1565
43 Hurst JR, Perera WR, Wilkinson TM, et al. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2006,173(1):71-78
44 Seemungal TA, Harper-Owen R, Bhowmik A, et al. Detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease[J]. Eur Respir J, 2000,16(4):677-683
45 Nylen E, Muller B, Becker KL, et al. The future diagnostic role of procalcitonin levels: the need for improved sensitivity[J]. Clin Infect Dis, 2003,36(6):823-4; author reply 826-827
46 Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial[J]. Lancet, 2004,363(9409):600-607
47罗君,杨新.特种蛋白检测在老年肺炎中的临床意义[J].实用医技杂志, 2004,11(3):167-168
2 Soler N, Ewig S, Torres A, et al. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease[J]. Eur Respir J, 1999,14:1015-1022
3 Sethi S. Bacterial infection and the pathogenesis of COPD[J]. Chest, 2000,117:286S-91S
4 Bellau-Pujol S, Vabret A, Legrand L, et al. Development of three multiplex RT-PCR assays for the detection of 12 respiratory RNA viruses[J]. J Virol Methods, 2005,126:53-63
5 Chun JY, Kim KJ, Hwang IT, et al. Dual priming oligonucleotide system for the multiplex detection of respiratory viruses and SNP genotyping of CYP2C19 gene[J]. Nucleic Acids Res, 2007,35:e40
6中华医学会呼吸病分会慢性阻塞性肺疾病学组.慢性阻塞性肺疾病诊治指南(2007年修订版)[J].中华结核和呼吸杂志, 2007,30:8-17
7 Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system[J]. Crit Care Med, 1985,13:818-829
8 Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2001,164:1618-1623
9 Wilkinson TM, Donaldson GC, Johnston SL, et al. Respiratory syncytial virus, airway inflammation, and FEV1 decline in patients with chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2006,173:871-876
10 Pichler M, Herrmann G, Schmidt H, et al. Persistent adenoviral infection and chronic obstructive bronchitis in children: is there a link[J]. Pediatr Pulmonol, 2001,32:367-371
11 Matsuse T, Matsui H, Shu CY, et al. Adenovirus pulmonary infections identified by PCR and in situ hybridisation in bone marrow transplant recipients[J]. J Clin Pathol, 1994,47:973-977
12 den Hoogen BG v, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease[J]. Nat Med, 2001,7:719-724
13 Rohde G, Borg I, Arinir U, et al. Relevance of human metapneumovirus in exacerbations of COPD[J]. Respir Res, 2005,6:150
14 Martinello RA, Esper F, Weibel C, et al. Human metapneumovirus and exacerbations of chronic obstructive pulmonary disease[J]. J Infect, 2006,53:248-254
15 Sivaprakasam V, Collins TC, Aitken C, et al. Life-threatening human metapneumovirus infections in West of Scotland[J]. J Clin Virol, 2007,39:234-237
16 Zhao Q, Li S, Xue F, et al. Structure of the main protease from a global infectious human coronavirus, HCoV-HKU1[J]. J Virol, 2008, 82: 8647-8655
17陈杭薇.成人呼吸道病毒、肺炎衣原体、支原体感染研究[J].中华医院感染学杂志, 2003:12-14
18周一平,陆学东,陈小可,等.呼吸道病毒与成人下呼吸道感染相关性探讨[J].中华实用诊断与治疗杂志, 2010:121-124
19 Beckham JD, Cadena A, Lin J, et al. Respiratory viral infections in patients with chronic, obstructive pulmonary disease[J]. J Infect, 2005,50:322-330
20 Krug RM, Aramini JM. Emerging antiviral targets for influenza A virus[J]. Trends Pharmacol Sci, 2009,30:269-277
21区映研,秦笙,杨子峰,等.广州市不同时段成人上呼吸道感染病毒鉴定与临床分析[J].中国实用内科杂志, 2009:707-709+713
22 Wongsurakiat P, Maranetra KN, Wasi C, et al. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study[J]. Chest, 2004,125:2011-2020
23 Wang CS, Wang ST, Lai CT, et al. Impact of influenza vaccination on major cause-specific mortality[J]. Vaccine, 2007,25:1196-1203
24 Laitinen LA, Elkin RB, Empey DW, et al. Bronchial hyperresponsiveness in normal subjects during attenuated influenza virus infection[J]. Am Rev Respir Dis, 1991,143:358-361
25 Roger T, Bresser P, Snoek M, et al. Exaggerated IL-8 and IL-6 responses to TNF-alpha by parainfluenza virus type 4-infected NCI-H292 cells[J]. Am J Physiol Lung Cell Mol Physiol, 2004,287:L1048-1055
26 Hacievliyagil SS, Gunen H, Mutlu LC, et al. Association between cytokines in induced sputum and severity of chronic obstructive pulmonary disease[J]. Respir Med, 2006,100:846-854
27 Wilkinson TM, Hurst JR, Perera WR, et al. Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD[J]. Chest, 2006,129:317-324
28王永兴,郭梅,刘德江.慢性阻塞性肺病急性加重期呼吸道病原菌分布及耐药性分析[J].第四军医大学学报, 2004:1874-1876
29周志祥,周洋,陈宗宁,等.慢性阻塞性肺疾病急性加重期痰致病菌检测及其临床意义[J].临床医药实践杂志, 2008:955-956
30 Murphy TF, Brauer AL, Schiffmacher AT, et al. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2004,170:266-272
31 Banerjee D, Khair OA, Honeybourne D. Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD[J]. Eur Respir J, 2004,23:685-691
32 Sethi S, Maloney J, Grove L, et al. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2006,173:991-998
33倪安平,王辉,董平,等.肺炎、支气管炎和急性上呼吸道感染患者肺炎衣原体感染的研究[J].中华内科杂志, 1995:388-391
34 Hewlett EL, Edwards KM. Clinical practice. Pertussis--not just for kids[J]. N Engl J Med, 2005,352:1215-1222
35徐少华,柏玉红,邵红艳.病毒感染对慢性阻塞性肺疾病患者气道炎症的作用[J].中华医院感染学杂志, 2004:13-15
1 Hewlett EL, Edwards KM. Clinical practice. Pertussis--not just for kids[J]. N Engl J Med, 2005,352(12):1215-1222
2 Ko FW, Ng TK, Li TS, et al. Sputum bacteriology in patients with acute exacerbations of COPD in Hong Kong[J]. Respir Med, 2005,99(4):454-460
3 Ko FW, Ip M, Chan PK, et al. A one-year prospective study of infectious etiology in patients hospitalized with acute exacerbations of COPD and concomitant pneumonia[J]. Respir Med, 2008,102(8):1109-1116
4 Lieberman D, Lieberman D, Gelfer Y, et al. Pneumonic vs nonpneumonic acute exacerbations of COPD[J]. Chest, 2002,122(4):1264-1270
5 Miravitlles M, Espinosa C, Fernandez-Laso E, et al. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD[J]. Chest, 1999,116(1):40-46
6 Borg I, Rohde G, Loseke S, et al. Evaluation of a quantitative real-time PCR for the detection of respiratory syncytial virus in pulmonary diseases[J]. Eur Respir J, 2003,21(6):944-951
7 Rohde G, Wiethege A, Borg I, et al. Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study[J]. Thorax, 2003,58(1):37-42
8 Beckham JD, Cadena A, Lin J, et al. Respiratory viral infections in patients with chronic, obstructive pulmonary disease[J]. J Infect, 2005,50(4):322-330
9 den Hoogen BG v, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease[J]. Nat Med, 2001,7(6):719-724
10 Rohde G, Borg I, Arinir U, et al. Relevance of human metapneumovirus in exacerbations of COPD[J]. Respir Res, 2005,6:150
11 Martinello RA, Esper F, Weibel C, et al. Human metapneumovirus and exacerbations of chronic obstructive pulmonary disease[J]. J Infect, 2006,53(4):248-254
12 Sivaprakasam V, Collins TC, Aitken C, et al. Life-threatening human metapneumovirus infections in West of Scotland[J]. J Clin Virol, 2007,39(3):234-237
13 Ko FW, Ip M, Chan PK, et al. Viral etiology of acute exacerbations of COPD in Hong Kong[J]. Chest, 2007,132(3):900-908
14 Hutchinson AF, Ghimire AK, Thompson MA, et al. A community-based, time-matched, case-control study of respiratory viruses and exacerbations of COPD[J]. Respir Med, 2007,101(12):2472-2481
15 McManus TE, Marley AM, Baxter N, et al. Respiratory viral infection in exacerbations of COPD[J]. Respir Med, 2008,102(11):1575-1580
16 Wilkinson TM, Hurst JR, Perera WR, et al. Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD[J]. Chest, 2006,129(2):317-324
17 Avadhanula V, Rodriguez CA, Devincenzo JP, et al. Respiratory virusesaugment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner[J]. J Virol, 2006, 80 (4): 1629-1636
18 Sajjan US, Jia Y, Newcomb DC, et al. H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression[J]. FASEB J, 2006,20(12):2121-2123
19 Barnes PJ. Chronic obstructive pulmonary disease[J]. N Engl J Med, 2000,343(4):269-280
20 Morris A, Sciurba FC, Lebedeva IP, et al. Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization[J]. Am J Respir Crit Care Med, 2004,170(4):408-413
21 Blasi F, Damato S, Cosentini R, et al. Chlamydia pneumoniae and chronic bronchitis: association with severity and bacterial clearance following treatment[J]. Thorax, 2002,57(8):672-676
22 Murphy TF, Brauer AL, Schiffmacher AT, et al. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2004,170(3):266-272
23 Banerjee D, Khair OA, Honeybourne D. Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD[J]. Eur Respir J, 2004,23(5):685-691
24 Wilkinson TM, Patel IS, Wilks M, et al. Airway bacterial load and FEV1 decline in patients with chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2003,167(8):1090-1095
25 Hill AT, Campbell EJ, Hill SL, et al. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis[J]. Am J Med, 2000,109(4):288-295
26 Patel IS, Seemungal TA, Wilks M, et al. Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations[J]. Thorax, 2002,57(9):759-764
27 Bresser P, Out TA, van AL, et al. Airway inflammation in nonobstructive and obstructive chronic bronchitis with chronic haemophilus influenzaeairway infection. Comparison with noninfected patients with chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2000,162(3 Pt 1):947-952
28 Sethi S, Maloney J, Grove L, et al. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2006,173(9):991-998
29 Soler N, Ewig S, Torres A, et al. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease[J]. Eur Respir J, 1999,14(5):1015-1022
30 Sethi S, Sethi R, Eschberger K, et al. Airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2007,176(4):356-361
31 Murphy TF, Brauer AL, Eschberger K, et al. Pseudomonas aeruginosa in chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2008,177(8):853-860
32 Starner TD, Zhang N, Kim G, et al. Haemophilus influenzae forms biofilms on airway epithelia: implications in cystic fibrosis[J]. Am J Respir Crit Care Med, 2006,174(2):213-220
33 Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 2001,164(9):1618-1623
34 McManus TE, Marley AM, Baxter N, et al. High levels of Epstein-Barr virus in COPD[J]. Eur Respir J, 2008,31(6):1221-1226
35 Ishii M, Teramoto S. [Childhood respiratory infection in the pathogenesis of COPD][J]. Nippon Rinsho, 2007,65(4):617-622
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