Lung transplantation for chronic obstructive pulmonary disease

Lung transplantation is able to provide dramatic gains in pulmonary function to patients with advanced pulmonary emphysema. At the present time, however, transplantation is available to a strictly defined pool of candidates, and outcomes are limited by numerous respiratory and nonrespiratory postoperative complications. Further progress is needed in expanding the supply of donor lungs, minimizing perioperative complications, and optimizing postoperative immunologic management.     

Analysis of referrals for lung transplantation. The Washington University Lung Transplantation Group

In the first year of our lung transplantation program, 211 patients with end-stage pulmonary disease were referred for consideration. Over 50 percent of the patients had chronic obstructive pulmonary disease, and almost 20 percent had idiopathic pulmonary fibrosis. The referrals were screened according to predefined criteria of eligibility for single and double lung transplantation. After screening, 46 of the referred patients were admitted for an extensive inpatient evaluation, and 18 of these were accepted as candidates for transplantation. Although interest in lung transplantation is growing in both the medical and lay communities, a significant number of patients with endstage pulmonary disease were ineligible by our current criteria. As experience with these procedures is gained, criteria for selection may become less restrictive, and more patients may be candidates for transplantation.     

Lung transplantation and lung volume reduction surgery versus transplantation in chronic obstructive pulmonary disease

Lung transplantation and lung volume reduction surgery are surgical options for patients with advanced chronic obstructive pulmonary disease that is refractory to medical treatment. In this review, we discuss the differential indications for each procedure, as well as compare their risks and benefits. We also present an algorithm for selecting the most appropriate procedure for individual patients. Finally, we discuss the feasibility and role of lung transplantation after lung volume reduction surgery in the management of selected patients with chronic obstructive pulmonary disease.     

Lung transplantation for chronic obstructive pulmonary disease at St Vincent's Hospital

BACKGROUND: Lung transplantation (LTx) offers selected patients with end-stage chronic obstructive pulmonary disease (COPD) an improved quality of life and possibly enhanced survival. AIM: To determine local outcomes of LTx for COPD we analysed 173 consecutive heart-LTx (n = 8), single LTx (SLTx; n = 99) and bilateral LTx (BLTx; n = 66) carried out at a single institution during 1989-2003 for smoking-related emphysema (E) (n = 112) and emphysema related to alpha-1 antitrypsin deficiency (AATD) (n = 61). METHODS: There were 98 men and 75 women with a mean age of 50 +/- 6 years (standard deviation) (range 32-63 years). Median waiting time was 113 days (interquartile range (IQR) 50-230 days), and median inpatient stay was 13 days (IQR 9-21 days). RESULTS: Perioperative survival (30 days) was 95% with deaths from sepsis (n = 5), cerebrovascular accident (n = 3) and multiorgan failure (n = 1). Mean follow-up period was 1693 +/- 1302 days (2-4,805 days). The 1-, 5- and 10-year survivals (%) were similar for patients with E and AATD (P = 0.480 log rank) at 86 +/- 5, 57 +/- 7 and 31 +/- 11, respectively, but 1- and 5-year survivals for E were higher after BLTx than after SLTx (97 +/- 2 and 81 +/- 8 vs 85 +/- 4 and 47 +/- 6) (P = 0.015). Pretransplant body mass index, forced expiratory volume in 1 second, forced vital capacity, PaCO(2), PaO(2), six-minute walk distance, home oxygen use, age, sex, cytomegalovirus donor-recipient mismatch, cardiopulmonary bypass use, year of transplant and ischaemic time did not influence survival after LTx. Increasing donor age was a survival risk factor for patients with E but not for those with AATD (hazard ratio 1.043; 95%confidence interval 1.014-1.025). CONCLUSION: Survival after LTx for COPD is similar to survival for other forms of solid organ transplantation, in part reflecting risk factor management.     

Lung transplantation of ventilator-dependent patients. The Washington University Lung Transplantation Group.

During the last few years, lung transplantation has been extended to patients with a variety of end-stage lung diseases, but recipient selection guidelines have remained relatively strict. Ventilator-dependent patients have traditionally been considered poor candidates for transplantation. However, patients who have been thoroughly evaluated and accepted for transplantation and subsequently develop respiratory failure caused by progression and/or exacerbation of their underlying disease and recipients who experience respiratory failure caused by graft failure may be suitable candidates while ventilator-dependent if no other major complications or contraindications arise before a donor organ becomes available.     

Prognostication in chronic obstructive pulmonary disease: implications for lung transplantation

Chronic obstructive pulmonary disease (COPD) is the most common disease for which single lung transplantation (SLT) is performed and is a frequent reason for bilateral lung transplantation (BLT). Recent data suggest a favorable survival advantage for patients with COPD undergoing lung transplantation compared with other diagnoses. This has led some investigators to question whether transplantation leads to improved survival in COPD patients compared with alternative treatment and whether this surgical therapy is appropriate in these individuals. These viewpoints may reflect the difficulties inherent in accurately predicting short- and long-term survival in patients with advanced COPD. Our review of the available data suggests that clinical, physiological, and radiographic features allow the identification of COPD patients with increased mortality despite maximal medical therapy. In these high risk individuals transplantation remains a viable therapeutic option.     

Treatment of end-stage chronic obstructive pulmonary disease with double lung transplantation.

Six patients with end-stage emphysema (age 44 +/- 2 years) underwent double lung transplantation (Tx) from June 1988 through May 1990. All suffered from severe inanition and required oxygen therapy. The ischemic time was 193 +/- 28 minutes. Post-Tx immune suppression was OKT3 (14 days), cyclosporine (trough levels of 150 +/- 25 ng/ml), azathioprine to keep WBC at 3,000 to 5,000/cu mm (1 to 3.0 mg/kg/day) and following OKT3, a tapering prednisone regimen. Two rejection episodes that occurred in two patients on post-Tx day 5 and 10 were treated with bolus doses of methylprednisolone. The mean hospital stay was 32 +/- 7 days (range, 20 to 69 days). Four patients required treatment of cytomegalovirus (CMV) infection: gastritis (+donor, +recipient) in one and CMV pneumonia in two (+donor, -recipient). A fourth (+donor, -recipient) had right-sided Candida empyema six weeks post-Tx, developed CMV and staphylococcal sepsis, and died 64 days post-Tx. One patient required pyloroplasty eight weeks post-Tx and one patient underwent tracheal suture line repair at eight weeks. During a follow-up of 81 patients months (range, 8 to 24 months), one patient had developed Epstein-Barr viral (EBV) induced lymphoproliferative disease in the lung and one patient had developed EBV lymphoma. Three patients are at work, one is continuing rehabilitation, and one is at home. Double lung Tx offers a definitive benefit to patients with emphysema; however, a prolonged postoperative course can be expected. Viral infections remain serious but treatable problems.     

Prognosis in severe chronic obstructive pulmonary disease.

A long-term prognostic study of 129 patients with severe chronic obstructive pulmonary disease (initial value for forced expiratory volume in 1 sec [FEV1] smaller than or equal to 1,000 ml) is reported. Data from the patients (72 per patient) were obtained in a clinically stable phase during the first hospital admission and subsequent regular outpatient visits; the data were processed using multiple regression and discriminant analysis. Five- and 10-year cumulative survival rates were 69 and 40 per cent, respectively. Prediction of survival rate was determined mainly by the rate of decrease in initial FEV1 per year and the degree of increase of initial FEV1 after administration of thiazinamium, a bronchodilator. Initial FEV1 values per se contributed to prediction only when they were less than 450 ml. Study of the data from the individual patients showed the presence of different types of decrease in FEV1: linear, exponential, combined linear-exponential, and phasic. FEV1 sometimes remained unchanged for several years or even showed an increase. No sudden decreases were observed. The better survival rate in patients with greater reversibility of airway obstruction after administration of thiazinamium has important bearing on treatment policy. The hypothesis is put forward that the better survival rate in the present study might be the result of continuing medical care. Comprehensive treatment, provided it includes a component directed at preventing and treating reversible airway obstruction, may be of major importance in determining survival in patients with severe chronic obstructive pulmonary disease. The value of so-called dominant, survival-predicting factors is considered to be of secondary importance; their main function is to alert the physician to the fact that prognosis as concerns survival may be unfavorable and that preventive and therapeutic measures should be taken without delay.     

慢性阻塞性肺疾病的肺减容术治疗

肺减容术(lung volume reduction surgery,LVRS)是一种治疗慢性阻塞性肺疾病(chronicobstructive pulmonary disease,COPD)的外科方法.临床实验已经证实了LVRS在经过选择的COPD患者中的治疗效果,并且对LVRS的疗效进行了多角度的研究.微创LVRS可减少并发症、降低病死率,可能是现有外科治疗方式的有益补充.     

Surgery for chronic obstructive pulmonary disease: the place for lung volume reduction and transplantation

Lung volume reduction surgery and lung transplantation have been shown to improve lung function, exercise capacity, and quality of life in patients with advanced emphysema. Because the indications for both surgical procedures overlap, lung volume reduction surgery may be used as an alternative treatment or as a "bridge" to lung transplantation. In this article, we discuss patient selection, clinical outcome parameters, and the morbidity and mortality associated with each surgical procedure. We focus on the different preoperative predictors of good and poor outcomes after lung volume reduction surgery, the role of pulmonary rehabilitation, and the preferred surgical techniques for lung volume reduction surgery. An overview of the postoperative care of emphysema patients who undergo single-lung transplantation is also discussed.     

Cardiopulmonary exercise responses after single lung transplantation for severe obstructive lung disease

The purpose of this study was to characterize cardiovascular and ventilatory responses to exercise in single lung transplantation (SLT) recipients with nonseptic, severe obstructive lung disease (SLT-OB). We also investigated whether the hyperinflated native lung in SLT-OB recipients could limit normal increases in tidal volume by mechanically constraining the transplanted lung, resulting in ventilation-perfusion imbalance in the lung graft. Data from six SLT-OB recipients (five women, one man) and six age-matched SLT recipients (two women, four men) with severe interstitial lung disease (SLT-IN) were compared. Resting arterial O2 and CO2 tensions were normal and comparable between the SLT groups. Spirometry results were reduced but comparable between SLT groups. Total lung capacity was significantly larger in patients with SLT-OB than in patients with SLT-IN. Diffusion capacity was not different between SLT groups when differences in alveolar volume were accounted for. Quantitative perfusion to the lung graft was comparable between the SLT groups, but quantitative ventilation was greater in patients with SLT-OB than in patients with SLT-IN. Maximum exercise capacity following SLT-OB was decreased, but was comparable to that of SLT-IN recipients. None of the SLT-OB recipients reached predicted maximum minute ventilation and only one experienced mild arterial O2 desaturation, suggesting peripheral muscle abnormalities from corticosteroid use and deconditioning as limiting factors rather than a ventilatory limitation. Tidal volumes at end exercise in the SLT-OB recipients were normal. Our quantitative lung scan and exercise testing data suggest that ventilation-perfusion imbalance and resulting gas exchange abnormalities from lung graft constraint and compression do not occur at rest or with exercise after SLT for obstructive lung disease.     

Helium-oxygen breathing in severe chronic obstructive pulmonary disease

The effect of breathing helium-oxygen (He-O2) mixtures was evaluated in 15 patients with severe chronic obstructive pulmonary disease (COPD). Gas exchange was assessed during quiet breathing at rest before and after 15 minutes of breathing 80 percent He-20 percent O2 mixtures in all patients. Functional residual capacity (FRC) determined during argon (Ar) washing studies fell significantly while breathing He-O2, but we did not find significant changes in minute ventilation, tidal volume, respiratory frequency, or inspiratory or expiratory timing. Eleven patients showed decreases in arterial PCO2 and CO2 excretion during resting breathing on He-O2. Expiratory flows were increased at a given lung volume during He-O2 breathing as expected. Apparently, mechanical work of breathing was decreased in patients with severe COPD while breathing He-O2, leading to a reduction in VCO2 and improvement in overall alveolar ventilation. These findings lend support to the therapeutic use of He-O2 under some conditions in patients with severe COPD.     

肺移植对5例慢性阻塞性肺疾病患者肺功能的影响

目的研究单肺移植手术治疗慢性阻塞性肺疾病(COPD)对呼吸生理及肺功能的影响。方法5例患者均为Ⅳ级COPD男性患者,年龄51～63岁。术前2周测定患者用力肺活量(FVC)、第一秒用力呼气容积(FEV1)、FEV1/FVC、最大通气量(MVV)、残气容积(RV)、肺总量(TLC)、残总比(RV/TLC)、深吸气量(IC)、胸腔气体容积(TGV)、呼气峰流量(PEF)、总气道阻力(Rawtotal)、肺一氧化碳弥散量(DLCO)、每升肺泡容积肺一氧化碳弥散量(DLCO/V·A)、6分钟行走距离(6MWD)、动脉血氧分压(PaO2)、肺泡气动脉血氧分压差[P(Aa)O2]、动脉血氧饱和度(SaO2)、动脉血二氧化碳分压(PaCO2)及平均肺动脉压(mPAP)等参数。术后2个月再行上述测定。结果5例患者术前2周、术后2个月检测的参数为MVV(23.6±5.8)、(71.6±21.8)L,FEV1(0.68±0.21)、(1.85±0.46)L,FEV1/FVC(37.4±8.3)、(75.6±13.9)%,PaO2(60.0±9.1)、(86.2±2.9)mmHg(1mmHg=0.133kPa),SaO2(90.0±4.6)%、(96.8±0.5)%及mPAP(31.2±5.5)、(16.6±1.8)mmHg,均有显著改善(P均<0.05);3例患者IC[(1.16±0.26)、(1.83±0.35)L]、TGV[(6.52±0.27)、(4.52±0.29)L]、RV[(5.12±0.39)、(3.20±0.32)L]、RV/TLC[(71.0±5.6)、(51.3±2.5)%]及Rawtotal[(6.62±0.99)、(2.48±0.87)cmH2O·L-1·s-1]改善显著(P均<0.05);4例患者PEF[(1.65±0.40)、(3.92±1.63)L/s]、DLCO[(8.5±3.0)、(21.0±6.2)ml·min-1·mmHg-1]及6MWD[(46.8±14.7)、(246.8±51.9)m]也显著增加(P均<0.05);FVC[(1.85±0.40)、(2.45±0.49)L]、TLC[(7.19±0.15)、(6.26±0.73)L]、DLCO/V·A[(2.90±1.50)、(5.41±0.87)L·min-1·mmHg-1]、P(Aa)O2[(37.6±16.3)、(17.8±6.3)mmHg]及PaCO2[(44.6±7.7)、(37.4±3.4)mmHg]有所改善,但差异无统计学意义(P均>0.05)。结论COPD患者肺移植术后肺通气、气道阻力、残气、弥散、运动耐力及气体交换功能均明显改善。     

Endothelial cell activity in chronic obstructive pulmonary disease without severe pulmonary hypertension.

Pulmonary hypertension is common in patients with chronic obstructive pulmonary disease (COPD), but the precise mechanism of vascular impairment in these patients is unknown. We, therefore, decided to investigate whether endothelial cell dysfunction is present in patients with COPD with a wide range of chronic airflow obstruction before the development of severe pulmonary hypertension. Selected plasma markers of endothelial cell activity were studied: nitrate+nitrite (NO-(2)/NO-(3)), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), soluble selectins (endothelium sES, leukocyte sLS, platelet sPS), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1). Twenty-five patients with COPD (forced expiratory volume in one second/vital capacity [FEV(1)/VC] < 88% predicted) and 29 healthy control subjects were recruited to the study. Among patients nine had a pulmonary artery systolic pressure (PASP) between 15 and 30 mmHg, 13 between 32 and 38 mmHg, 2 had a PASP of 41 and 42 mmHg, respectively. One patient had severe pulmonary hypertension with a PASP of 70 mmHg. The average FEV(1) of patients with COPD was 46 +/- 4% predicted. As compared to control subjects, patients with COPD showed a significant increase in plasma levels of TM and TFPI, indicating that their endothelial cells are still able to produce potent coagulation inhibitors. Levels of NO-(2)/NO-(3) were similar in the two groups of subjects examined, further suggesting preserved endothelial function in patients with COPD. In regard to adhesion molecules, patients with COPD showed a reduction in sLS, sPS, and sPECAM-1, and an increase in sICAM-1. This study shows that endothelial cell activity is largely preserved in patients with COPD without severe pulmonary hypertension, suggesting that these patients, despite quite severe airway obstruction, retain reasonably normal endothelial function until they develop severe pulmonary hypertension.     

Lung development and susceptibility to chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease with emphysema has been considered to be an accelerated involutional disease of aging smokers. However, because only a proportion ( approximately 15%) of smokers develop chronic obstructive pulmonary disease with emphysema, clearly genetic susceptibility must play a significant part in determining both the age of onset and the rapidity of decline in lung function. In mice, interference with key genes, either by null mutation, hypomorphism, or gain or loss of function, results in phenotypes comprising either neonatal lethal respiratory distress if the structural effect is severe, or reduced alveolarization and/or early-onset emphysema if the effect is milder. Likewise, null mutants that interfere with matrix assembly and/or integrity, such as elastin, lysyl oxidase, or fibrillin, also result in alveolar dysplasia. Importantly, null mutation of Smad3, which encodes a receptor-activated Smad in the transforming growth factor-beta signaling pathway, results in a more subtle failure to correctly organize the alveolar matrix, which is in turn antecedent to early-onset emphysema mediated by matrix metalloproteinase-9. Furthermore, exposure to side-stream smoke profoundly exacerbates and accelerates alveolar destruction, leading to more severe early-onset emphysema in young Smad3-null mice (unpublished data). Interestingly, polymorphisms in the fibrillin, transforming growth factor-beta type II receptor, and matrix metalloproteinase-9 genes have been described in humans with emphysema. Thus, dysplastic or degraded matrix cannot provide the structural niche for alveolar stem/progenitor cells to assume the correct phenotype and/or repair the alveolar cell lineage niche. The hope is that providing the correct exogenous signals can coax them into doing so.     

New therapies for chronic obstructive pulmonary disease,lung regeneration

Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow limitations that are not fully reversible and is a major cause of chronic morbidity and mortality worldwide. Although there has been extensive research examining the molecular mechanisms underlying the development of COPD, there is no proven clinically effective treatment for promoting recovery from established COPD. At present, regeneration is the only hope for a cure in patients with COPD. In this article, we review current treatments for COPD, focusing particularly on recent advances in lung regeneration based on two major approaches: regeneration-promoting agents and cell therapy. Retinoic acids are the major focus among regeneration-promoting agents, while mesenchymal stem cells are the main topic in the field of cell-based therapy. This article aims to provide valuable information for developing new therapies for COPD.