Pathogenesis and treatment of acute exacerbations of chronic obstructive pulmonary disease

Once thought to be a mere nuisance, exacerbations are now recognized as a major contributor to the morbidity and mortality associated with chronic obstructive pulmonary disease. This recognition has led to research using new investigative tools that has substantially enhanced our understanding of the pathogenesis of exacerbations. Several overlapping etiologies can precipitate the symptom complex of an exacerbation. Treatment of exacerbations requires the use of several therapeutic modalities with the goal of restoring the patient to baseline. Results of recent clinical trials and observational studies have allowed a refinement of the approach to treatment of exacerbations. These include a rational, stratified approach to the use of antibiotics and several trials substantiating the use of systemic corticosteroids. Relapse or failure rates of 20 to 33% have been described in the treatment of acute exacerbation, with these treatment failures contributing substantially to the costs associated with exacerbations. Improved treatment based on enhanced understanding and good clinical evidence should lead to better outcomes in this common clinical entity.     

Pathophysiology of exacerbations of chronic obstructive pulmonary disease

Smokers with stable chronic obstructive pulmonary disease have a chronic inflammation of the entire tracheobronchial tree characterized by an increased number of macrophages and CD8 T lymphocytes in the airway wall and of neutrophils in the airway lumen. Exacerbations of chronic obstructive pulmonary disease are considered to reflect worsening of the underlying chronic inflammation of the airways, caused mainly by viral and bacterial infections and air pollution. During exacerbations, the inflammatory cellular pattern changes, with a further increase of eosinophils and/or neutrophils and various inflammatory mediators--for example, cytokines (tumor necrosis factor-alpha, RANTES [regulated upon activation normal T cell-expressed and secreted], and eotaxin-1), chemokines (CXCL5 [ENA-78], CXCL8), chemokine receptors (CCR3, CXCR1, and CXCR2), adhesion molecules (E-selectin and ICAM-1), and markers of oxidative stress (H(2)O(2) and 8-isoprostane, glutathione depletion). Worsening of inflammation is considered responsible for the deterioration of lung function and clinical status during exacerbations.     

N-acetylcysteine and exacerbations of chronic obstructive pulmonary disease

Oxidative stress may play a role in chronic obstructive pulmonary disease (COPD) exacerbations. There is heterogeneity in the literature with regard to the impact of antioxidant therapy on COPD exacerbation frequency. Clinical trials of N-acetylcysteine in COPD were identified in unrestricted searches of MEDLINE, CINAHL, International Pharmaceutical Abstracts and the Cochrane Register. Randomized, controlled trials which reported exacerbations over a treatment period > or =3 months were selected. Two observers independently extracted data regarding exacerbation number over the treatment period in subjects allocated to either N-acetylcysteine or placebo. Data were analyzed using inverse-variance weighted random effects meta-analysis methodology. Meta-analysis of data from 8 trials (randomized n = 2,214) indicated that N-acetylcysteine significantly reduced the odds of experiencing one or more exacerbations over the treatment period (odds ratio = 0.49, 95% confidence interval [0.32-0.74], p = 0.001). Treatment effect was not reduced in studies which enrolled >50% active smokers (odds ratio = 0.36 [0.24-0.55], p < 0.001), although a greater effect was observed with exclusion of subjects using concurrent inhaled corticosteroids (odds ratio = 0.42 [0.32-0.54], p < 0.0001), suggesting that inhaled steroids attenuate the effect of N-acetylcysteine. The use of N-acetylcysteine significantly reduces the odds of exacerbation in patients with COPD, an effect possibly attenuated by inhaled steroids but not smoking. This analysis suggests treatment with N-acetylcysteine may be beneficial in a subset of patients with COPD.     

Risk factors of chronic obstructive pulmonary disease exacerbations

Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disease characterised by persistent respiratory symptoms and airflow limitation. COPD has a major impact on public health, mainly because of its increasing prevalence, morbidity and mortality. The natural course of COPD is aggravated by episodes of respiratory symptom worsening termed exacerbations that contribute to disease progression. Acute Exacerbations of COPD (AECOPD) can be triggered by a multitude of different factors, including respiratory tract infections, various exposures, prior exacerbations, non‐adherence to treatment and associated comorbidities. AECOPD are associated with an inexorable decline of lung function and a significantly worse survival outcome. This review will summarise the most important aspects regarding the impact of different factors that contribute to COPD exacerbations.     

莫西沙星治疗慢性阻塞性肺疾病急性加重最新临床试验(MAESTRAL研究)结果解读

慢性阻塞性肺疾病(COPD)急性加重(AECOPD)是COPD自然病程中的重要事件,不但可导致肺功能进行性下降,而且还是与病死率和病残率升高、生活质量下降相关的主要因素。此外,因AE-COPD住院治疗可明显增加医疗费用。目前AECO-     

Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease

The effects of broad-spectrum antibiotic and placebo therapy in patients with chronic obstructive pulmonary disease in exacerbation were compared in a randomized, double-blinded, crossover trial. Exacerbations were defined in terms of increased dyspnea, sputum production, and sputum purulence. Exacerbations were followed at 3-day intervals by home visits, and those that resolved in 21 days were designated treatment successes. Treatment failures included exacerbations in which symptoms did not resolve but no intervention was necessary, and those in which the patient's condition deteriorated so that intervention was necessary. Over 3.5 years in 173 patients, 362 exacerbations were treated, 180 with placebo and 182 with antibiotic. The success rate with placebo was 55% and with antibiotic 68%. The rate of failure with deterioration was 19% with placebo and 10% with antibiotic. There was a significant benefit associated with antibiotic. Peak flow recovered more rapidly with antibiotic treatment than with placebo. Side effects were uncommon and did not differ between antibiotic and placebo.     

Pharmacotherapeutic approaches to preventing acute exacerbations of chronic obstructive pulmonary disease

The significance of acute exacerbations in chronic obstructive pulmonary disease (AECOPDs) is increasingly appreciated. AECOPDs result in significant morbidity and mortality and are a significant driver of health care costs. Frequent AECOPDs are associated with poor quality of life and more rapid decline in lung function. As such, reducing their frequency or severity is a key paradigm of COPD therapy. Bronchodilators alone and in combination with inhaled corticosteroids are the current standards of care and decrease AECOPDs. Prevention of infection with chronic macrolide antibiotics or pulsed quinolones has demonstrated some promise. Vaccination against Streptococcus pneumonia and influenza is likely beneficial. Therapeutics with antiinflammatory properties, including phosphodiesterase enzyme 4 inhibitors and HMG-CoA reductase inhibitors, may reduce AECOPD frequency. Inhibiting the formation of reactive oxidant species has also been studied, with varying results. Antioxidants, including N-acetylcysteine and S-carbomethylcysteine, may reduce exacerbation frequency, but further investigation is needed. As new therapies are developed, it will be helpful to know in which patient phenotypes they are most effective and how they compare in efficacy and side-effect profiles with inhaled coricosteroids, bronchodilators, or their combination.     

Management of acute exacerbations in chronic obstructive pulmonary disease

An acute exacerbation of chronic obstructive pulmonary disease (COPD) is characterized by an acute worsening of symptoms accompanied by lung infection. In severe cases, an acute exacerbation may cause respiratory failure and death. Successful management of acute exacerbation of COPD in either the inpatient or outpatient setting requires attention to a number of key issues. In this review, issues regarding the management of acute exacerbations of COPD are discussed. An inhaled beta-2 agonist along with the inhaled anticholinergic bronchodilator are recommended. Antibiotic therapy has been demonstrated to improve clinical recovery and physical outcomes. It should be directed against the most commonly occurring pathogens and, in more severe cases, coverage against Gram-negative bacteria is considered. Short course of systemic steroids does provide benefit in hospitalized patients. Supplemental oxygen is appropriate for all patients with hypoxemia. Ventilatory support treatment may be necessary, noninvasive ventilatory assistance being preferable early in the course of the acute episode. In a high number of cases, endotracheal intubation may be avoided. Promoting smoking cessation and the use of influenzae and pneumococcal vaccination may help decrease frequency of episodes of these exacerbations.     

New drugs for exacerbations of chronic obstructive pulmonary disease

Tobacco smoking is the dominant risk factor for chronic obstructive pulmonary disease (COPD), but viral and bacterial infections are the major causes of exacerbations in later stages of disease. Reactive oxygen species (ROS), pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs) activate families of pattern recognition receptors (PRRs) that include the toll-like receptors (TLRs). This understanding has led to the hypothesis that COPD is an archetypal disease of innate immunity. COPD is characterised by abnormal response to injury, with altered barrier function of the respiratory tract, an acute phase reaction, and excessive activation of macrophages, neutrophils, and fibroblasts in the lung. The activated non-specific immune system then mediates the processes of inflammation and repair, fibrosis, and proteolysis. COPD is also associated with corticosteroid resistance, abnormal macrophage and T-cell populations in the airway, autoinflammation and autoimmunity, aberrant fibrosis, accelerated ageing, systemic and concomitant disease, and defective regeneration. Such concepts have been used to generate a range of molecular targets, and clinical trials are taking place to identify effective drugs for the prevention and treatment of COPD exacerbations.     

What is the optimal treatment strategy for chronic obstructive pulmonary disease exacerbations?

The present study aims to determine whether treating chronic obstructive pulmonary disease (COPD) exacerbations with intravenous steroids and aerosol bronchodilators (group I) is superior to oral steroids and multiple dose inhaler (MDI) bronchodilators with a spacer (group II). Group I received 40 mg methylprednisolone x day(-1) intravenously with a decrease to 20 mg after 10 days and a further decrease of 4 mg x 4 days(-1). Aerosol therapy consisted of 10 mg salbutamol and 1 mg ipratropiumbromide x day(-1). Group II received 32 mg methylprednisolone orally for 1 week followed by 24 mg x day(-1) for 4 days and a subsequent decrease of 4 mg x week(-1). Duovent MDI with a spacer was given at a dose of 1.6 mg fenoterol and 640 microg ipratropiumbromide x day(-1). In group I (n=19) forced expiratory volume in one second (FEV1) rose from 0.82+/-0.46 to 0.91+/-0.47 L and average dyspnoea decreased from 6.0+/-1.9 to 4.1+/-2.6 within 10 days. The Chronic Respiratory Disease Index Questionnaire (CRQ) score increased from 78+/-24 to 90+/-24 points after 4 weeks. In group II (n=18) FEV1 increased from 0.70+/-0.27 to 0.90+/-0.29 L, dyspnoea regressed from 6.2+/-2.4 to 2.7+/-2.6 and CRQ from 67+/-17 to 86+/-20. Both groups showed similar results in dropout rate, length of hospital stay and patient satisfaction. In conclusion, the two treatment strategies appear equally effective in treating chronic obstructive pulmonary disease exacerbations, although oral steroids and metered dose inhaler bronchodilators appear associated with a higher risk of hospital re-admission.     

Inflammation and infection in exacerbations of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a common disorder with symptoms of chronic cough and progressive dyspnea caused by chronic bronchitis or emphysema. Acute exacerbations of COPD contribute to the accelerated decline in lung function characteristic of this disease and are associated with significant cost, morbidity, and mortality for patients. Controversy exists as to whether exacerbations are caused primarily by inflammation, infection, or perhaps a combination of both conditions. Advances in the pathogenesis of COPD have shed light on the role of inflammation in this condition and highlighted the differences in the inflammatory response present in COPD compared with asthma. Infectious agents often are suspected as causing acute exacerbations of COPD, and antibiotics are frequently prescribed empirically to patients. We review the evidence for an inflammatory and infectious etiology for exacerbations of COPD and compare and contrast how each impacts on this disease.