Pulmonary Hypertension in Patients with Bronchiolitis Obliterans Syndrome Listed for Retransplantation

Bronchiolitis Obliterans Syndrome (BOS) is a major cause of morbidity and mortality post-lung transplantation. Pulmonary hypertension (PH) may complicate the course of patients with advanced lung disease. We sought to characterize the prevalence of PH in patients with BOS.
We performed a retrospective analysis of lung transplant recipients with BOS relisted for transplantation with the United Network for Organ Sharing (UNOS). Right heart catheterization (RHC) data were required for analysis. Eighty patients with BOS qualified for the analysis. PH was present in 32.5% of patients with an average mean pulmonary artery pressure (mPAP) of 32.3 mmHg (range: 26–63 mmHg). Of these, 42.3% had an elevated pulmonary capillary wedge pressure. There was no difference in PH prevalence between bilateral (26.5%) and single lung recipients (41.9%), nor did it differ by primary disease. There was no correlation between pulmonary function data and the presence or severity of PH. There was no difference in oxygen requirements or 6-min walk distance between patients with and without PH. This is the first report of PH in patients with BOS. Many of these cases occur in association with diastolic dysfunction. Although no impact on functional status or outcomes was discerned, further studies appear warranted.     

Posttransplant Bronchiolitis Obliterans Syndrome Is Associated with Bronchial Epithelial to Mesenchymal Transition

Bronchiolitis obliterans syndrome (BOS) compromises lung transplant outcomes and is characterised by airway epithelial damage and fibrosis. The process whereby the normal epithelial configuration is replaced by fibroblastic scar tissue is poorly understood, but recent studies have implicated epithelial mesenchymal transition (EMT). The primary aim of this study was to assess the utility of flow cytometry in detecting and quantifying EMT in bronchial epithelial cells.
Large airway brushings were obtained at 33 bronchoscopies in 16 BOS-free and 6 BOS grade 1–3 patients at 2–120 months posttransplant. Flow cytometry was used to assess expression of the mesenchymal markers αSMA, S100A4 and ED-A FN and HLA-DR. TGF β1 and HGF were measured in Bronchoalveolar lavage (BAL). Expression of all three mesenchymal markers was increased in BOS, as was HLA-DR. BAL HGF, but not TGF β1 was increased in BOS. Longitudinal investigation of one patient revealed a 100% increase in EMT markers concurrent with a 6-fold increase in BAL TGF β1 and the diagnosis of BOS at 17 months posttransplant.
Flow cytometric evaluation of bronchial epithelium may provide a novel and rapid means to assess lung allografts at risk of BOS.     

Follicular Bronchiolitis: A Rare Cause of Bronchiolitis Obliterans Syndrome After Lung Transplantation: A Case Report

This case report is the first confirmed case of follicular bronchiolitis (FB), a rare bronchiolar disorder characterized by peribronchiolar lymphoid follicles, in a series of over 400 lung transplantations performed in our center. It is to our knowledge, the first publication describing FB after lung transplantation (LTx), presenting as chronic allograft dysfunction or bronchiolitis obliterans syndrome (BOS).     

Aspergillus Colonization of the Lung Allograft Is a Risk Factor for Bronchiolitis Obliterans Syndrome

Multiple infections have been linked with the development of bronchiolitis obliterans syndrome (BOS) post-lung transplantation. Lung allograft airway colonization by Aspergillus species is common among lung transplant recipients. We hypothesized that Aspergillus colonization may promote the development of BOS and may decrease survival post-lung transplantation. We reviewed all lung transplant recipients transplanted in our center between January 2000 and June 2006. Bronchoscopy was performed according to a surveillance protocol and when clinically indicated. Aspergillus colonization was defined as a positive culture from bronchoalveolar lavage or two sputum cultures positive for the same Aspergillus species, in the absence of invasive pulmonary Aspergillosis. We found that Aspergillus colonization was strongly associated with BOS and BOS related mortality in Cox regression analyses. Aspergillus colonization typically preceded the development of BOS by a median of 261 days (95% CI 87–520). Furthermore, in a multivariate Cox regression model, Aspergillus colonization was a distinct risk factor for BOS, independent of acute rejection. These data suggest a potential causative role for Aspergillus colonization in the development of BOS post-lung transplantation and raise the possibility that strategies aimed to prevent Aspergillus colonization may help delay or reduce the incidence of BOS.     

Lung Transplant Metalloproteinase Levels Are Elevated Prior to Bronchiolitis Obliterans Syndrome

Parenchymal disease in the allograft lung is associated with interstitial remodeling believed to be mediated by matrix metalloproteinases (MMPs). Recent studies suggest high levels of MMP-9 are associated with bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. Since BOS occurs late in the posttransplant period and may be preceded by episodes of acute rejection or infection, which are associated with interstitial remodeling, we examined MMP profiles in allograft bronchoalveolar lavage (BAL) fluid in the early posttransplant period (preceding BOS). Gelatin zymography, protein array analysis and specific ELISA on BAL fluids from transplanted lungs indicated that MMP-8, MMP-9 and TIMP-1 were strongly expressed in allograft BAL fluid from stable patients, or those with infection or rejection compared to BAL fluid from normal volunteers. Elevated expression of MMP-8, MMP-9 and TIMP-1 occurred early, and was sustained for the 3.2 years covered in this study. Elevations of MMP-8, MMP-9 and TIMP-1 in the first 2 years posttransplant appear to be associated with lung transplantation itself, and not infection or rejection. These data suggest that ongoing and clinically silent MMP activity could perpetuate progressive disease in the allograft lung.     

慢性阻塞性肺疾病病人饮食指导的效果观察

探讨慢性阻塞性肺疾病（COPD）病人合理的营养疗法,为饮食指导提供依据,将稳定期的40例病人随机分为观察组（20例）和对照组（20例）,观察组病人出院时制订每日摄入总热量,提供常见食物成分表,并进行学知识教育;对照组按病人的饮食习惯进食,3个月后观察两组营养指标及饮食构成,结果观察组理想体重（NW、）上臂中部臂围（MAC）明显高于对照组,差异有显著性意义（P＜0．05）,两组摄入总热量、脂肪和蛋白质量比较,差异极有显著性意义（P＜0．01）。提示合理的营养疗法可以改善COPD病人的营养状况,饮食指导应根据不同病人的状况予以个体化和量化。     

Targeting Allograft Injury and Inflammation in the Management of Post-Lung Transplant Bronchiolitis Obliterans Syndrome

Chronic allograft dysfunction, manifesting as bronchiolitis obliterans syndrome (BOS), is the major cause of morbidity and mortality in human lung transplant recipients. While alloimmunity has a definite role, there is increasing interest in overall allograft injury and subsequent inflammation and remodeling. This review deals with nonalloimmune factors that may potentiate alloimmune injury. We discuss infection and reflux/aspiration as examples of allograft injury, which may lead to chronic loss of graft function and BOS. Surgical and nonsurgical treatments aimed at preventing these insults and improving survival are considered. The need for further evidence, including randomized-controlled trials, to evaluate the role of medical and surgical therapies is emphasized by the current literature.     

Worse Prognosis for Stage IA Lung Cancer Patients with Smoking History and More Severe Chronic Obstructive Pulmonary Disease

Purpose: This retrospective study examined whether the severity of chronic obstructive lung disease (COPD) affects surgical outcomes.Methods: The subjects were 243 consecutive patients who underwent lobectomy for clinical stage IA lung cancer from 1999 to 2008 in our hospital. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) grading system was used to classify the severity of COPD in smokers.Results: Among the 149 smokers, 62 were diagnosed with COPD (25 as GOLD 1, 33 as GOLD 2, and 4 as GOLD 3). In univariate analysis, postoperative pulmonary complications were associated with male sex and more severe COPD. The frequencies were 17.1% in non-COPD, 24.0% in GOLD 1-COPD, and 46.0% in GOLD 2/3-COPD smokers (p = 0.0006). In univariate analysis, older age, smoking history, higher smoking pack-years and more severe COPD were associated with poor relapse-free survival. Relapse-free survival at five years was 80.7%, 66.9%, and 61.3% in non-COPD, GOLD 1-COPD, and GOLD 2/3-COPD smokers, respectively (p = 0.0005). Multivariate analyses showed that only GOLD 2/3-COPD was associated with postoperative pulmonary complications and relapse-free survival. Inhaled bronchodilators were prescribed preoperatively to 24.3% of the GOLD 2/3-COPD group.Conclusion: Smokers with GOLD 2/3-COPD are at high risk for pulmonary complications and have an unfavorable long-term prognosis.     

慢性阻塞性肺疾病患者血清IL-6与FEV1相关性研究

目的探讨稳定期COPD患者血清IL-6与FEV1的关系。方法选择稳定期COPD患者60例,测定肺功能,ELISA法检测COPD患者和健康志愿者血清IL-6,分析COPD患者血清IL-6与FEV1之间的相关性。结果logIL-6与FEV1呈负相关（r值为-0．602,P〈0．01）。结论血清IL-6在稳定期COPD患者中增高,可在一定程度上反映COPD患者的全身炎症程度,并且与FEV1呈负相关,可作为预测稳定期COPD患者病情及预后的有效指标。     

Alemtuzumab in the Treatment of Refractory Acute Rejection and Bronchiolitis Obliterans Syndrome After Human Lung Transplantation

Despite substantial improvements in early survival after lung transplantation, refractory acute rejection (RAR) and bronchiolitis obliterans syndrome (BOS) remain major contributors to transplant-related morbidity and mortality. We have utilized alemtuzumab, a humanized anti-CD52 antibody which results in potent lymphocyte depletion, in consecutive patients with RAR (n = 12) or BOS (n = 10). All patients failed conventional treatment with methylprednisolone and antithymocyte globulin and received strict infection prophylaxis. Alemtuzumab significantly improved histological rejection scores in RAR. Total rejection grade/biopsy was 1.98 +/- 0.25 preceding alemtuzumab versus 0.33 +/- 0.14 posttreatment, p-value <0.0001 (with a similar number of biopsies/patient per respective time interval). Freedom from BOS was observed in 65% of RAR patients 2 years after alemtuzumab treatment. Although there was no statistically significant change in forced expiratory volume in 1 second (FEV1) before and after alemtuzumab treatment in patients with BOS, a stabilization or improvement in BOS grade occurred in 70% of patients. Patient survival 2 years after alemtuzumab for BOS was 69%. Despite a dramatic decline in CD4 counts in alemtuzumab-treated patients, only one patient developed a lethal infection. Thus, we provide the first evidence that alemtuzumab is a potentially useful therapy in lung transplant recipients with RAR or BOS.     

Pulmonary Hypertension Associated with Lung Transplantation Obliterative Bronchiolitis and Vascular Remodeling of the Allograft

Pathologic obliterative bronchiolitis (OB)/Bronchiolitis obliterans syndrome (pathologic OB/BOS) is the major obstacle to long-term survival post-lung transplantation (LT). Our group has demonstrated that pulmonary hypertension (PH) complicates the course of chronic inflammatory lung diseases that have similarities to pathologic OB/BOS and that vascular remodeling of the bronchial circulation occurs during BOS. Consequently, we hypothesized that PH is associated with pathologic OB/BOS and may result from a vasculopathy of the allograft pulmonary circulation.
We conducted a single-center, retrospective study and examined the presence of PH and vasculopathy in patients with pathologic OB/BOS. Fifty-two pathologic specimens post-LT were recovered from January 10, 1997 to January 5, 2007 and divided into two groups, those with and without pathologic OB/BOS.PH was defined as a mean pulmonary artery pressure (mPAP) > 25 mmHg by right heart catheterization (RHC) or right ventricular systolic pressure (RVSP) ≥45 mmHg by transthoracic echocardiogram (TTE).
PH was more prevalent in those LT recipients with pathologic OB/BOS (72% vs. 0%, p = 0.003). Furthermore, pulmonary arteriopathy and venopathy were more prevalent in patients with pathologic OB/BOS (84% vs. 4%, p < 0.0001, and 77% vs. 35%, p = 0.004, respectively).
PH is common in LT recipients with pathologic OB/BOS and is associated with a vasculopathy of the allograft pulmonary circulation.     

慢性阻塞性肺疾病与勃起功能障碍

慢性阻塞性肺疾病(COPD)不仅是肺疾病,而且是一种全身疾病,ED是COPD的肺外表现之一,随着COPD患者病情的加重,ED的发病率增加,但是COPD患者发生ED的机制至今尚未完全明确。探讨COPD患者ED的发生情况及影响因素,有助于提高COPD患者对发生ED的早期认识,预防ED的发生、发展,对改进COPD患者的生活质量具有重要意义。     

两种雾化吸入方法治疗慢性阻塞性肺疾病患者临床效果的对比研究

目的观察不同雾化吸入方法对慢性阻塞性肺疾病(COPD)患者肺功能及血气的影响。方法将40例COPD患者随机分为观察组和对照组,各20例,用相同剂量异丙托溴铵,观察组用压缩雾化吸入法,对照组用超声雾化吸入法。比较两组治疗前、后第1秒钟用力呼气容积(FEV1)、最大呼气峰流速(PEF)及PaO2、PaCO2的变化。结果两组治疗前FEV1、PEF与治疗后比较,差异有显著意义(P<0.01,P<0.05);观察组PaO2、PaCO2治疗前、后差异有显著意义(均P<0.05);治疗后观察组各观察指标较对照组显著改善(均P<0.05)。结论压缩雾化吸入法能降低COPD患者的呼吸道阻力,改善肺功能,其治疗效果优于超声雾化吸入法。     

术前肺康复对肺癌合并中一重度慢性阻塞性肺疾病患者运动耐力的影响

目的评估术前肺康复（PR）对肺癌合并中一重度慢性阻塞性肺疾病（COPD）患者运动耐力的影响。方法选择2009年3月至20lO年8月华西医院胸外科收治32例肺癌伴中重度COPD患者作为研究对象,其中30例完成术前为期2周的肺康复训练并接受手术治疗,男18例,女12例;年龄62．5±7．7岁。中度C（）PD12例,重度COPD18例;康复前后均进行心、肺功能评估,并分析这些患者的术后肺部并发症发生情况及住院时间。结果（1）静态肺功能试验中第1秒用力肺活量（FEV1）、第1秒用力肺活量百分比（FEV,％）、第1秒用力肺活量与用力肺活量比（FEV1／FVC）、最大通气量（MVV）康复后较康复前（1．30±0．30I,VS．1．24±0．40L,59．19±18．00LVS．51．89±14．00L,47．74±12．00LVS．46．59±10．00L,56．63±13．00LVS．49．67±13．00L）增加不显著（P〉0．05）;一氧化碳弥散能力（DLco）康复前和康复后（19．38±18．00LVS．15．38±4．10L）变化不明显（P〉0．05）。（2）6-分钟步行距离（6-MwD）在肺康复后显著高于康复前（594．87±116．00mvs．502．67±157．00m,P〈0．05）;呼吸困难指数（Borg指数）在康复后显著低于康复前（o．12±0．10VS．0．26±0．20,P〈0．05）;疲劳指数在康复后显著低于康复前（0．12±0．10VS．0．24±0．20,P〈0．05）。（3）呼气峰流速（PEF）在康复后显著高于康复前（255．33±70．00L／minVS．209．33±66．00L／min,P〈0．05）。（4）30例接受手术治疗患者,围手术期无死亡（术后30d内）,术后出现肺部并发症（PPC）8例,术后平均住院时间为8．0±2．4d。结论术前肺康复可提高肺癌伴中一重度COPD患者的运动耐力,可能对肺癌伴中重度COPD患者降低术后肺部并发症有所帮助。     

Parametric Response Mapping of Bronchiolitis Obliterans Syndrome Progression After Lung Transplantation

Bronchiolitis obliterans syndrome (BOS) remains a major complication after lung transplantation. Air trapping and mosaic attenuation are typical radiological features of BOS; however, quantitative evaluation remains troublesome. We evaluated parametric response mapping (PRM, voxel‐to‐voxel comparison of inspiratory and expiratory computed tomography [CT] scans) in lung transplant recipients diagnosed with BOS (n = 20) and time‐matched stable lung transplant recipients (n = 20). Serial PRM measurements were performed prediagnosis, at time of BOS diagnosis, and postdiagnosis (T_pre, T₀, and T_post, respectively), or at a postoperatively matched time in stable patients. PRM results were correlated with pulmonary function and confirmed by microCT analysis of end‐stage explanted lung tissue. Using PRM, we observed an increase in functional small airway disease (fSAD), from T_pre to T₀ (p = 0.006) and a concurrent decrease in healthy parenchyma (p = 0.02) in the BOS group. This change in PRM continued to T_post, which was significantly different compared to the stable patients (p = 0.0002). At BOS diagnosis, the increase in fSAD was strongly associated with a decrease in forced expiratory volume in 1 s (p = 0.011). Micro‐CT confirmed the presence of airway obliteration in a sample of a BOS patient identified with 67% fSAD by PRM. We demonstrated the use of PRM as an adequate output to monitor BOS progression in lung transplant recipients.     

Indirect Allorecognition of Mismatched Donor HLA Class II Peptides in Lung Transplant Recipients with Bronchiolitis Obliterans Syndrome

A correlation between indirect allorecognition of mismatched donor HLA class I peptides and development of bronchiolitis obliterans syndrome (BOS) after lung transplantation has been previously observed. The aim of this study was to determine whether there was a correlation between indirect allorecognition of mismatched donor HLA class II peptides and development of BOS after lung transplantation. Peripheral blood mononuclear cells from nine BOS+ and nine BOS-lung transplant recipients were cultured with synthetic peptides corresponding to the beta-chain hypervariable region of a mismatched donor HLA-DR molecule. Then, proliferative alloreactivity as well as frequency of alloreactive T cells were determined. In addition, the immunodominant epitopes from the donor HLA-DR molecules were identified in selected patients. T cells from BOS+ patients showed a dose-dependent proliferative alloreactivity against donor HLA-DR peptides that was significantly higher than that observed in BOS- patients (p=0.001). Similarly, the frequency of HLA-DR alloreactive T cells was significantly higher in BOS+ patients than in BOS- patients (p=0.001). This T-cell alloreactivity was directed against a single immunodominant HLA-DR peptide. These results suggest that indirect alloreactivity to donor HLA class II molecules may play a role in the pathogenesis of BOS after lung transplantation.     

Clinical Impact of Community-Acquired Respiratory Viruses on Bronchiolitis Obliterans After Lung Transplant

Community-acquired viral respiratory tract infections (RTI) in lung transplant recipients may have a high rate of progression to pneumonia and can be a trigger for immunologically mediated detrimental effects on lung function. A cohort of 100 patients was enrolled from 2001 to 2003 in which 50 patients had clinically diagnosed viral RTI and 50 were asymptomatic. All patients had nasopharyngeal and throat swabs taken for respiratory virus antigen detection, culture and RT-PCR. All patients had pulmonary function tests at regular intervals for 12 months. Rates of rejection, decline in forced expiratory volume (L) in 1 s (FEV-1) and bacterial and fungal superinfection were compared at the 3-month primary endpoint. In the 50 patients with RTI, a microbial etiology was identified in 33 of 50 (66%) and included rhinovirus (9), coronavirus (8), RSV (6), influenza A (5), parainfluenza (4) and human metapneumovirus (1). During the 3-month primary endpoint, 8 of 50 (16%) RTI patients had acute rejection versus 0 of 50 non-RTI patients (p=0.006). The number of patients experiencing a 20% or more decline in FEV-1 by 3 months was 9 of 50 (18%) RTI versus 0 of 50 non-RTI (0%) (p=0.003). In six of these nine patients, the decline in FEV-1 was sustained over a 1-year period consistent with bronchiolitis obliterans syndrome (BOS). Community-acquired respiratory viruses may be associated with the development of acute rejection and BOS.     

肺癌合并慢性阻塞性肺病和手术方式对患者术后快速康复及治疗费用的影响

目的探索影响肺癌患者术后快速康复的相关临床因素及治疗费用,探讨术后快速康复的临床途径及其临床价值。方法回顾性分析华西医院同一医疗组从2010年1月至2011年3月的所有入院,连续129例行肺癌切除术患者的临床资料。按是否合并慢性阻塞性肺疾病将患者分为合并慢性阻塞性肺病组[COPD组,53例,其中男39例、女14例,平均年龄（56．3l±10．51）]岁和非慢性阻塞性肺病组[非COPD组,76例,其中男37例、女39例,平均年龄（65．92±7．85）]岁;根据手术方式不同将患者分为全胸腔镜手术组（VATS组,83例,其中男44例、女39例,平均年龄（61．62±10．80）]岁和开胸组[46例,其中男32例、女14例,平均年龄（62．95±9．97）]岁;分析不同组患者的术后并发症发生率、平均住院时间及各项费用。结果COPD组和非COPD组术后并发症发生率（53％VS．40％,P=0．134）和平均住院时间[（7．66±2．95）dVS．（7．36±2．74）d,P=0．539]差异均无统计学意义。VATS组术后并发症发生率（34％VS．65％,P〈0．001）和平均住院时间[（6．67±2．52）dVS．（8．6l±3．01）d,P〈0．001]均低于开胸组,且差异有统计学意义。VATS组平均住院总费用[（44542．26±11447．50）元VS．（23634．13±6014．35）元,P〈0．001]和材料费[（37352．53±11807．81）元VS．（12763．08±7124．76）元;P〈0．001]均显著高于开胸组,且差异有统计学意义。VATS组平均西药费显著低于开胸组[（7473．54±4523．70）元VS．（10176．7l±6371．12）元,P〈0．001],而两组其它费用差异均无统计学意义。结论VATS肺癌肺叶切除术可以促进术后快速康复,但增加了手术材料费用。而肺癌患者合并COPD与术后快速康复及费用均无关。     

慢性阻塞性肺疾病患者远程康复使用意愿量表的编制及信效度检验

目的 编制慢性阻塞性肺疾病（COPD）患者远程康复使用意愿量表,为评估COPD患者远程康复使用意愿提供测评工具。方法 以整合技术与采纳模型及健康信念模型为理论依据,结合文献回顾和德尔菲专家函询形成量表的初始条目。便利选取COPD患者156例进行问卷调查,对量表进行项目分析和信效度检验。结果 2轮专家函询的积极系数均为100%;专家权威系数分别为0.872、0.888;Kendall′s协调系数分别为0.114、0.113（均P＜0.05）;变异系数为0.08~0.23、0.05~0.22。正式量表共计26个条目,探索性因子分析提取7个公因子,累计方差贡献率为84.84%;条目水平的内容效度指数0.800~1.000,量表水平的内容效度指数为0.913;量表总的Cronbach′s α系数为0.963;分半信度为0.884。结论 慢性阻塞性肺疾病患者远程康复使用意愿量表具有良好的信效度,可作为COPD患者远程康复使用意愿的评估工具。     

慢性阻塞性肺疾病患者远程康复使用意愿量表的编制及信效度检验

目的 编制慢性阻塞性肺疾病（COPD）患者远程康复使用意愿量表,为评估COPD患者远程康复使用意愿提供测评工具。方法 以整合技术与采纳模型及健康信念模型为理论依据,结合文献回顾和德尔菲专家函询形成量表的初始条目。便利选取COPD患者156例进行问卷调查,对量表进行项目分析和信效度检验。结果 2轮专家函询的积极系数均为100%;专家权威系数分别为0.872、0.888;Kendall′s协调系数分别为0.114、0.113（均P＜0.05）;变异系数为0.08~0.23、0.05~0.22。正式量表共计26个条目,探索性因子分析提取7个公因子,累计方差贡献率为84.84%;条目水平的内容效度指数0.800~1.000,量表水平的内容效度指数为0.913;量表总的Cronbach′s α系数为0.963;分半信度为0.884。结论 慢性阻塞性肺疾病患者远程康复使用意愿量表具有良好的信效度,可作为COPD患者远程康复使用意愿的评估工具。