Future directions in the pharmacologic therapy of chronic obstructive pulmonary disease

Current therapy for chronic obstructive pulmonary disease (COPD) fails to alter its relentless progression. This remains a significant challenge and unmet need. A recent advance is the demonstration that treatment with a fixed dose of an inhaled corticosteroid and a long-acting beta2-agonist in COPD improves lung function and quality of life, and reduces exacerbation more effectively than either drug alone. Other improvements include the introduction of tiotropium, a once-daily anticholinergic. In advanced clinical development are other once-daily bronchodilators and combinations of anticholinergic drugs and beta2-agonists. Increased understanding of the pathogenesis of COPD has led to novel drugs aimed at inhibiting targets, including phosphodiesterase 4, proteases, and various inflammatory mediators. Furthermore, COPD is increasingly seen as a systemic disorder or, indeed, may be a pulmonary manifestation of a complex pathophysiologic response to chronic inhalation of toxic irritants and associated with aging. Future therapy may involve better understanding of how best to target existing drugs used to treat cardiovascular disorders associated with smoking, such as atherosclerosis and hypercoagulability, and the development of new drugs that target systemic and metabolic manifestations that either result from or coexist with chronic lung inflammation, hypoxia, and cardiovascular disease in COPD.     

肺部微生态在慢性阻塞性肺疾病中的研究进展

慢性阻塞性肺疾病是一种常见的、可以防治的疾病,但由于其患病人数多,病死率高,目前仍然受到人们的高度重视。虽然近年来对于慢性阻塞性肺疾病的发生及发展演变机制研究逐步深入,但仍无法完全揭示其疾病本质,所以目前迫切需要从新的角度来探索,以此制订新的治疗方法。随着分子生物学的发展,人们逐渐认识到肺部微生态这一概念,相关研究也在进一步探索。未来对肺部微生态的研究将为慢性阻塞性肺疾病的防治提供新的有效治疗手段。     

深入进行慢性阻塞性肺疾病的研究

近10年来，慢性阻塞性肺疾病(COPD)研究受到全世界呼吸病学界的重视，取得了令人瞩目的进步。我国对COPD的研究工作也有不小的进展。近来开展的COPD流行病学研究及人群干预也将得到预期的结果。然而，与国际COPD的研究水平比较，我们的差距仍然很大。现在此谈一些粗浅的看法。     

Future treatment to lessen exacerbations of chronic obstructive pulmonary disease

Therapies currently used to reduce exacerbations of chronic obstructive pulmonary disease (COPD) are compounds used almost entirely for asthma therapy. A notable exception is tiotropium, a long-acting parasympatholytic agent. This compound and its precursor, iprotropium, are only occasionally used for asthma therapy. Likewise, leukotriene-modifying drugs are used occasionally for the treatment of COPD. In neither circumstance is there agency-approved indication for these particular cross-over therapies, but the use of long-acting beta(2)-adrenergic compounds and high-solubility inhaled steroids is a mainstay for therapy in both asthma and COPD. Similarly, theophylline, although less often used for either process, is therapeutically applicable to both asthma and COPD. Although overlap syndromes point to the occurrence of a common pathway in some cases, the inflammatory process for asthma and chronic obstructive pulmonary disease (COPD) differs substantially in most cases. Hence, the application of therapies designed to relax airway smooth muscle and ameliorate asthmatic inflammation lacks a therapeutic rationale for a disease characterized by predominant neutrophilic inflammation occurring in the small airways and alveoli. By definition, COPD is poorly reversible airflow obstruction; hence, the use of drugs designed to relax airway smooth muscle is somewhat counterintuitive and does not address the pathophysiological process of the disease.     

嗜酸性粒细胞在慢性阻塞性肺疾病中的临床研究进展

嗜酸性粒细胞在慢性阻塞性肺疾病(简称慢阻肺)患者中的作用近年来备受关注。研究发现在部分慢阻肺稳定期和急性加重期患者的循环血、气道、肺组织中均可发现嗜酸性粒细胞增高。近期的研究显示嗜酸性粒细胞与慢阻肺患者急性加重风险升高、病死率升高、肺功能下降有关,并可预测慢阻肺患者对糖皮质激素的治疗反应。该文主要综述嗜酸性粒细胞在慢阻肺患者中作为生物标志物的研究进展。     

Cardiac disease in chronic obstructive pulmonary disease

The cardiac manifestations of chronic obstructive pulmonary disease (COPD) are numerous. Impairments of right ventricular dysfunction and pulmonary vascular disease are well known to complicate the clinical course of COPD and correlate inversely with survival. The pathogenesis of pulmonary vascular disease in COPD is likely multifactorial and related to alterations in gas exchange and vascular biology, as well as structural changes of the pulmonary vasculature and mechanical factors. Several modalities currently exist for the assessment of pulmonary vascular disease in COPD, but right heart catheterization remains the gold standard. Although no specific therapy other than oxygen has been generally accepted for the treatment of pulmonary hypertension in this population, there has been renewed interest in specific pulmonary vasodilators. The coexistence of COPD and coronary artery disease occurs frequently. This association is likely related to shared risk factors as well as similar pathogenic mechanisms, such as systemic inflammation. Management strategies for the care of patients with COPD and coronary artery disease are similar to those without COPD, but care must be given to address their respiratory limitations. Arrhythmias occur frequently in patients with COPD, but are rarely fatal and can generally be treated medically. Use of beta-blockers in the management of cardiac disease, while a theoretical concern in patients with increased airway resistance, is generally safe with the use of cardioselective agents.     

Cardiovascular disease in chronic obstructive pulmonary disease

Smoking is a major cause of chronic obstructive pulmonary disease (COPD) and cardiovascular disorders, including coronary heart disease (CHD) and peripheral arterial disease. Smoking-induced inflammation and other risk factors like dyslipidemia cause vascular endothelial damage via oxidative stress, and a vicious cycle with the characteristics of atherosclerosis ensues. Inflammatory cytokines stimulate hepatic acute-phase protein production, and C-reactive protein is now used widely to assess inflammation in the arterial wall. Smoking is associated with many alterations in lipids and lipoproteins, and is also prothrombotic. Global risk assessment, which determines the absolute risk for developing CHD in 10 years, is used widely to determine who should receive lipid-lowering therapy. Major CHD risk factors include age, sex, smoking, blood pressure, lipoproteins, and cholesterol, but COPD is not among them. Future studies should determine the absolute risk for developing CHD in patients with COPD. The 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are used widely to treat and prevent cardiovascular disease. The statins may also produce other beneficial pleiotropic effects, including increased nitric oxide and prostacyclin, antithrombosis, and decreased inflammation, perhaps indicating utility in the therapy for COPD. Efforts are currently underway to determine if such antiinflammatory effects are independent of or in addition to simply lowering low-density lipoprotein cholesterol.     

Clinical research in chronic obstructive pulmonary disease: needs and opportunities

Chronic obstructive pulmonary disease (COPD) is a common condition, and one difficult to manage. Available treatments, other than smoking cessation, are only minimally effective, and the knowledge basis for clinical decision making is limited. To identify areas in which further clinical research may lead to significant improvements in the care of patients with COPD, the National Heart, Lung, and Blood Institute convened a Working Group, entitled "Clinical Research in COPD: Needs and Opportunities," on March 21-22, 2002. This group of experts identified important questions in the field and made the following recommendations: (1) establish a multicenter Clinical Research Network to perform multiple, short-term clinical trials of treatments in patients with moderate-to-severe COPD; (2) create a system for the standardized collection, processing, and distribution of lung tissue specimens and associated clinical and laboratory data; (3) develop standards for the classification and staging of COPD; (4) characterize the development and progression of COPD using measures and biomarkers that relate to current concepts of pathogenesis; and (5) evaluate indications for long-term oxygen therapy for patients with COPD.     

茶碱在慢性阻塞性肺疾病中的抗炎作用研究进展

茶碱因其支气管扩张作用而应用于临床多年,目前对其抗炎作用及机制有了一些新认识.茶碱可提高细胞内的磷酸腺苷浓度、拮抗腺苷受体、抑制炎症因子释放等.茶碱可恢复组蛋白去乙酰化酶的活性,抑制炎症基因的表达,增强糖皮质激素的敏感性.     

慢性阻塞性肺疾病患者骨代谢研究进展

COPD是一种以气流持续受限为特征的慢性呼吸系统疾病,其患病率、致残率、病死率高.骨质疏松是以骨量减少、骨结构退化和骨折风险增加的骨代谢性疾病,是COPD的重要合并症之一,但在临床中常被忽视.当COPD合并骨折时,可引起患者肺功能下降、急性加重频率及病死率增加,因此及早诊治COPD合并的骨质疏松能有效预防骨折的发生,改善患者预后.因此,早期发现、早期诊治骨质疏松,预防骨质疏松相关的骨折对于COPD患者具有重要意义.     

Imaging in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is divided into pulmonary emphysema and chronic bronchitis (CB). Emphysema is defined patho-anatomically as "permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls, and without obvious fibrosis" (1). These lesions are readily identified and quantitated using computed tomography (CT), whereas the accompanying hyperinflation is best detected on plain chest X-ray, especially in advanced disease. The diagnosis of CB is clinical and relies on the presence of productive cough for 3 months in 2 or more successive years. The pathological changes of mucosal inflammation and bronchial wall thickening have been more difficult to identify with available imaging techniques. However, recent studies using Multi-detector row CT (MDCT) reported more reproducible assessment of air wall thickening.     

Cough in chronic obstructive pulmonary disease

Patients with chronic obstructive pulmonary disease (COPD) most commonly complain of cough, production of phlegm and breathlessness. The cough reflex sensitivity is heightened compared with that in healthy volunteers and is similar to that in subjects with asthma. The degree of airflow obstruction does not predict cough reflex sensitivity or objective cough counts, implying an independent process. Objective cough rates seem to be relatively low in COPD, despite frequent reporting of the symptom by patients. The relative contribution of cough to disability in COPD seems to be small, if assessed by subjective reporting. Effective treatments for cough in COPD have not yet been identified. Improved outcome measures of cough, a better understanding of the mechanisms underlying cough, and the importance of cough to patients is required to progress in this field.     

Osteoporosis in chronic obstructive pulmonary disease

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of osteoporosis because of their age, limited physical activity, low body mass index, smoking, hypogonadism, malnutrition, and use of corticosteroids. Systemic inflammation represents an additional pathomechanism contributing to the development of osteoporosis in COPD patients. Males in their mid to late 60s with a smoking history of greater than 60 pack-years have a prevalence rate of vertebral fractures similar to, and possibly greater than, postmenopausal women greater than or equal to 65 years old: in patients with severe COPD, up to 50-70% have osteoporosis or osteopenia, and up to 24-30% have compression vertebral fractures. Correlates of osteoporosis in COPD are mainly measures of body composition, disease severity and the use of corticosteroids, although causality has not been proven. Systemic corticosteroids remain the most common cause of drug-related osteoporosis, and a meta-analysis concluded that the use of more than 6.25 mg prednisone daily led to decreased bone mineral density (BMD) and increased fracture risk. In contrast, the effects of the long-term use of inhaled corticosteroids on BMD remain debatable. Effects of treatment of osteoporosis have not been investigated in samples consisting of COPD patients only but the recommendations follow the general recommendations for the diagnosis and treatment of osteoporosis. Early recognition of BMD loss is essential, and assumes close interdisciplinary cooperation between respirologists and reumatologists. Longitudinal follow-up to assess determinants of osteoporosis in COPD and randomised placebo-controlled trials on the effects of treatment of osteoporosis in patients with COPD only are warranted. In the future, novel therapeutical strategies such as monoclonal antibodies against osteoclasts activators may prove their beneficial effects in the treatment of COPD-related osteoporosis.     

Comorbidities in chronic obstructive pulmonary disease

Comorbidities such as cardiac disease, diabetes mellitus, hypertension, osteoporosis, and psychological disorders are commonly reported in patients with chronic obstructive pulmonary disease (COPD) but with great variability in reported prevalence. Tobacco smoking is a risk factor for many of these comorbidities as well as for COPD, making it difficult to draw conclusions about the relationship between COPD and these comorbidities. However, recent large epidemiologic studies have confirmed the independent detrimental effects of these comorbidities on patients with COPD. On the other hand, many of these comorbidities are now considered to be part of the commonly prevalent nonpulmonary sequelae of COPD that are relevant not only to the understanding of the real burden of COPD but also to the development of effective management strategies.     

Sleep in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death, affecting 14 million adults in the United States. Symptoms related to sleep disturbances are common in moderate to severe COPD, particularly in elderly patients, in the form of morning tiredness and early awakenings. One major cause of morbidity in this population is abnormalities in gas exchange and resultant hypoxemia. Sleep has profound adverse effects on respiration and gas exchange in patients with COPD. There are several mechanisms underlying nonapneic oxygen desaturation during sleep. They include decreased functional residual capacity, diminished ventilatory responses to hypoxia and hypercapnia, impaired respiratory mechanical effectiveness, diminished arousal responses, respiratory muscle fatigue, diminished nonchemical respiratory drive, increased upper airway resistance, and the position of baseline saturation values on the oxyhemoglobin dissociation curve. Smoking cessation, bronchodilation, and pulmonary rehabilitation are cornerstones of treatment of COPD. Improvement in lung mechanics and gas exchange should lead to better sleep quality and health status.     

Definitions in chronic obstructive pulmonary disease

States of airflow obstruction are common disorders which span the spectrum from asthmatic-chronic bronchitis to emphysema. Asthmatic and chronic bronchitic states are at least potentially reversible by systematic, pharmacologically oriented therapy focusing on bronchodilators and corticosteroids. Both asthmatic bronchitis, particularly when it is not adequately treated, and emphysema result in the final common pathway of COPD. These are generally progressive states, unless smoking cessation can be achieved in early or mild stages of disease. The future focuses on the great challenge of early identification, classification, and intervention. Thus, all patients with cough, dyspnea, and wheeze should be carefully evaluated by health workers who understand the history, physical examination, and simple pulmonary function tests in the context of chest radiology. These clinical methods together can help define the disease states characterized by airflow obstruction. Often, a final definition of disease cannot be made until aggressive attempts at the treatment of the airflow obstruction and its attendant symptoms complex have been vigorously pursued by experienced clinicians.     

慢性阻塞性肺疾病的呼吸困难

呼吸困难是慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)的首要症状,也是COPD患者最痛苦的症状.COPD诊断、处理和预防全球策略2011年报告推荐采用修订版呼吸困难分级(the modified Medical Research Council Dyspnea Scale,mMRC)评估COPD患者的呼吸困难,对mMRC达到和(或)超过2分的患者积极进行药物干预,以缓解呼吸困难.指南建议转化到临床实践的过程中,医师需要认识COPD呼吸困难的发生机制;理解呼吸困难测量工具的测定原理,包括信度、效度、对呼吸困难变化的敏感度;各种新老药物缓解呼吸困难的疗效.这篇文章从呼吸困难发生机制、呼吸困难测量、呼吸困难治疗三方面,综述COPD呼吸困难的最新进展.     

Transplantation in chronic obstructive pulmonary disease

Lung transplantation is a surgical option for patients who fail optimization of medical treatment for the severe symptoms that result from COPD. This review will discuss patient selection, transplant listing, and the surgical technique for transplantation in COPD. Furthermore, it will describe transplant outcomes and its effects on recipient survival, pulmonary function, exercise capacity, respiratory muscle function, and quality of life. The respective roles of transplantation and lung volume reduction surgery as therapies for advanced disease will be outlined.     

Malnutrition in chronic obstructive pulmonary disease

Malnutrition in patients with COPD is associated with an impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rate when compared with adequately nourished individuals with COPD. Deterioration in patients with COPD may be the result of malnutrition. In addition, malnutrition could be a sign of other factors directly altered by the disease.