Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are pathologically distinct in terms of their predominant inflammatory cells and structural alterations (i.e., remodeling). However, there are many cases of functional and pathologic overlap, supporting the author's view that use of the terms asthma or COPD is oversimplistic and fails to identify the range of phenotypes that exist. In general, there is epithelial fragility and thickening of the reticular basement membrane, even in mild asthma; increased airway smooth muscle mass, hypertrophy of mucus-secreting glands, increased vascularity, greater numbers of fibroblasts, and increased deposition of collagen in severe asthma and COPD; and mucous metaplasia, squamous metaplasia, and parenchymal destruction in COPD. Because of increased neutrophilia, patterns of inflammation become similar when exacerbations of asthma and COPD result in hospitalization. Moreover, in mild COPD, exacerbations of bronchitis are associated with mucosal eosinophilia and upregulation of RANTES, two features normally associated with asthma. The overlap may also be seen in intermediate thickening of the reticular basement membrane and eosinophilia in patients with COPD who demonstrate reversibility to oral steroid. Importantly, a recent study of "eosinophilic bronchitis" demonstrates a thickened reticular basement membrane and challenges our current concept of the histopathologic distinctions between asthma and COPD.     

The Airway Pathophysiology of COPD: Implications for Treatment

The pathophysiology of chronic obstructive pulmonary disease (COPD) is complex and can be attributed to multiple components: mucociliary dysfunction, airway inflammation and structural changes, all contributing to the development of airflow limitation, as well as an important systemic component. Current pharmacotherapies vary in their ability to address the underlying multi-component nature of COPD. Long-acting anticholinergics and long-acting β₂-agonists (LABAs) can both provide effective and convenient bronchodilation in moderate COPD (Stage II–GOLD) and are recommended as regular therapy in global treatment guidelines. However, there is evidence to suggest that LABAs can mediate additional benefits independent of their bronchodilatory effects and may help address the multi-component nature of COPD. Effects on mucociliary dysfunction and reduced bacterial-induced damage have been experimentally proven with LABAs, and anti-inflammatory activity and structural effects have also been suggested. The use of inhaled corticosteroids (ICSs) is now recommended for the treatment of COPD patients with frequent exacerbations. In addition, ICSs provide a range of anti-inflammatory effects in COPD and thus have effects that are complementary to those of LABAs. Recent data indicate that LABA/ICS combinations produce wide-ranging clinical benefits that are greater than with either agent alone. Other new strategies include selective phosphodiesterase 4 (PDE4) inhibitors, which in addition to anti-inflammatory activity, have been shown to provide bronchodilation in COPD. In summary, the potential to address the multicomponent nature of COPD with strategies such as LABA/ICS combination therapy, and the development of new treatments directed at novel targets means that the future for sufferers of COPD can be more optimistic.     

The airway pathophysiology of COPD: implications for treatment

The pathophysiology of chronic obstructive pulmonary disease (COPD) is complex and can be attributed to multiple components: mucociliary dysfunction, airway inflammation and structural changes, all contributing to the development of airflow limitation, as well as an important systemic component. Current pharmacotherapies vary in their ability to address the underlying multi-component nature of COPD. Long-acting anticholinergics and long-acting beta2-agonists (LABAs) can both provide effective and convenient bronchodilation in moderate COPD (Stage II-GOLD) and are recommended as regular therapy in global treatment guidelines. However, there is evidence to suggest that LABAs can mediate additional benefits independent of their bronchodilatory effects and may help address the multi-component nature of COPD. Effects on mucociliary dysfunction and reduced bacterial-induced damage have been experimentally proven with LABAs, and anti-inflammatory activity and structural effects have also been suggested. The use of inhaled corticosteroids (ICSs) is now recommended for the treatment of COPD patients with frequent exacerbations. In addition, ICSs provide a range of anti-inflammatory effects in COPD and thus have effects that are complementary to those of LABAs. Recent data indicate that LABA/ICS combinations produce wide-ranging clinical benefits that are greater than with either agent alone. Other new strategies include selective phosphodiesterase 4 (PDE4) inhibitors, which in addition to anti-inflammatory activity, have been shown to provide bronchodilation in COPD. In summary, the potential to address the multicomponent nature of COPD with strategies such as LABA/ICS combination therapy, and the development of new treatments directed at novel targets means that the future for sufferers of COPD can be more optimistic.     

Regulation of inflammatory cell function by corticosteroids

Different inflammatory cell profiles are observed in the lungs of patients with asthma versus those with chronic obstructive pulmonary disease (COPD). In asthma, several key mediators have been implicated, including tumor necrosis factor-alpha and interleukin (IL)-1beta, together with cytokines derived from type 2 T-helper lymphocytes, such as IL-4, IL-5, and IL-13. In fact, inhibitors of IL-4 and IL-5 show promise as therapeutic agents. In COPD, the predominant inflammatory cell types are CD8(+) T lymphocytes, macrophages, and neutrophils. Glucocorticoids inhibit eosinophils in asthma, neutrophils in COPD and severe asthma, mast cells and basophils in asthma and COPD, and macrophages in COPD. However, it is generally assumed that neutrophils are less sensitive to glucocorticoids than are eosinophils and T cells, and that macrophages from patients with COPD are less sensitive to steroid treatment under certain circumstances. These differences in the responsiveness of activated inflammatory cells may help to explain why inhaled corticosteroid treatment has been more beneficial for patients with asthma than for patients with COPD.     

Airway inflammation in childhood asthma

Airway pathology has been extensively investigated in adulthood asthma, whereas only few studies examined bronchial biopsies in childhood asthma. To evaluate the airway pathology in children with asthma, we analyzed bronchial biopsies obtained from 23 children undergoing bronchoscopy for clinical indications other than asthma. Nine had mild/moderate asthma. Six had atopy without asthma, and eight had no atopy or asthma. We measured basement membrane thickness and quantified the number of eosinophils, mast cells, neutrophils, macrophages, T lymphocytes, and positive cells for transforming growth factor-beta1 (TGF-beta1) and its receptors I and II (TGFbeta-RI and TGFbeta-RII) in subepithelium. Children with asthma had an increase in basement membrane thickness and in the number of eosinophils compared with control subjects, but not compared with children with atopy. They also had a decreased expression of TGFbeta-RII compared with both those with atopy and control subjects. In children with asthma, the number of eosinophils correlated negatively with TGFbeta-RII and positively with symptom duration. In conclusion, airway eosinophilia and basement membrane thickening, which are the pathologic features that are characteristic of adulthood asthma, are already present in children with mild asthma, and even in children with atopy without asthma. Moreover, in children with asthma but not in children with atopy without asthma, there is a downregulation of TGFbeta-RII.     

Mast cells in COPD airways: relationship to bronchodilator responsiveness and angiogenesis

We have investigated whether mast cells are associated with bronchodilator responsiveness and airway vascular changes in chronic obstructive pulmonary disease (COPD) airways. We have previously shown that the reticular basement membrane is hypervascular and the lamina propria is hypovascular in COPD. Bronchial biopsies from 32 COPD subjects, 15 smokers with normal lung function and 17 controls, were immunostained for factor VIII, mast cell tryptase and chymase antibodies. Mast cells in the airway smooth muscle, the reticular basement membrane and the underlying lamina propria were quantitated. 41% of COPD subjects had significant bronchodilator responsiveness, but this was not related to smooth muscle mast cell numbers. The reticular basement membrane had greater mast cell density in all groups compared with controls (p<0.01). In this compartment, perivascular mast cell density was related to hypervascularity. Lamina propria mast cell density was increased only in COPD (p<0.05). Perivascular mast cell density in the lamina propria was not related to its decreased vessel density. Bronchodilator responsiveness in COPD is not related to large airway smooth muscle mast cells of either type; both reticular basement membrane and lamina propria mast cells are increased in COPD patients, and perivascular mast cells may be involved in increased angiogenesis in the reticular basement membrane.     

Genetic risk factors for the development of pulmonary disease identified by genome‐wide association

Chronic respiratory diseases are a major cause of morbidity and mortality. Asthma and chronic obstructive pulmonary disease (COPD) combined affect over 500 million people worldwide. While environmental factors are important in disease progression, asthma and COPD have long been known to be heritable with genetic components playing an important role in the risk of developing disease. Identification of genetic variation contributing to disease progression is important for a number of reasons including identification of risk alleles, understanding underlying disease mechanisms and development of novel therapies. Genome‐wide association studies (GWAS) have been successful in identifying many loci associated with lung function, COPD and asthma. In recent years, meta‐analyses and improved imputation have facilitated the growth of GWAS in terms of numbers of subjects and the number of single nucleotide polymorphisms (SNP) that can be interrogated. As a consequence, there has been a significant increase in the number of signals associated with asthma, COPD and lung function. SNP that have shown association with lung function reassuringly show a significant overlap with SNP associated with COPD giving a glimpse at pathways that may be involved in COPD mechanisms including genes in, for example, developmental pathways. In asthma, association signals are often in or near genes involved in both adaptive and innate immune response pathways, epithelial cell homeostasis and airway structural changes. The challenges now are translating these genetic signals into a new understanding of lung biology, understanding how variants impact health and disease and how they may provide opportunities for therapeutic intervention.     

Similarities and differences in asthma and chronic obstructive pulmonary disease exacerbations

There is no generally accepted definition of an exacerbation either for asthma or for chronic obstructive pulmonary disease. There is little consistency among the symptomatic or functional criteria used in different studies. The most consistent criterion is the introduction of systemic corticosteroids for the acute worsening of the disease. The time course of an exacerbation does not seem to differ very much between asthma and chronic obstructive pulmonary disease (COPD). The decrease in peak flow rate is more pronounced in asthma than in COPD. The frequency of exacerbations is linked to disease severity both in asthma and COPD. Common causes are viral infections and increased environmental air pollution, whereas allergen exposure and bacterial infections are more specific for asthma and COPD exacerbations, respectively. Few data are available about the airway pathology of asthma or COPD exacerbations. Eosinophilia and/or neutrophilia have been associated with exacerbations in both diseases. Avoidance of the causal factors decreases exacerbation rate in both diseases. Pharmacologic prevention of exacerbations in asthma has been shown for inhaled corticosteroids, combination therapy with long-acting inhaled beta(2)-agonists and inhaled corticosteroids, and monoclonal anti-IgE. Inhaled corticosteroids, long-acting inhaled beta(2)-agonists, combination therapy with both, and the long-acting inhaled anticholinergic tiotropium decrease the exacerbation rate in COPD.     

Prospective study of inhaled corticosteroid use, cardiovascular mortality, and all-cause mortality in asthmatic women

BACKGROUND: Therapy with inhaled corticosteroids (ICSs) decreases the risk of asthma exacerbations. Recent studies have suggested that ICS therapy also may decrease the risk of cardiovascular disease, and perhaps of all-cause mortality. We examined this hypothesis in a large, well-characterized cohort of asthmatic women. METHODS: In 1976, the Nurses' Health Study enrolled 121,700 registered nurses, who were 30 to 55 years of age. Participants were asked about "physician-diagnosed asthma" on biennial questionnaires. In 1998, asthmatic participants were sent a supplementary questionnaire on asthma diagnosis and management, including ICS use. Mortality was assessed through 2003, without knowledge of the 1998 (baseline) ICS status. The odds ratios (ORs) for death were adjusted for age, asthma severity, smoking, heart disease, cancer, stroke, aspirin, and statin use. RESULTS: Among 2,671 eligible women (ie, those who responded to the 1998 supplement [85%], met criteria for persistent asthma, and had not received a prior diagnosis of COPD), 54% reported ICS use. Over the next 5 years, 87 women (3.3%) died (cardiovascular deaths, 22; cancer deaths, 31; other, 34 [including 4 from asthma]). Compared to asthmatic women who did not use ICSs, those receiving therapy with ICSs had lower all-cause mortality (OR, 0.58; 95% confidence interval [CI], 0.36 to 0.92). ICS users were at significantly lower risk of cardiovascular death (OR, 0.35; 95% CI, 0.13 to 0.93), but not of death from cancer (OR, 0.66; 95% CI, 0.32 to 1.38) or other causes (OR, 0.62; 95% CI, 0.30 to 1.27). CONCLUSIONS: ICS use was associated with significantly lower cardiovascular and all-cause mortality in women with asthma. These observational data suggest that ICSs may indeed have antiinflammatory benefits beyond the airway, which is a possibility that merits further study.     

Airway Dimensions in Fatal Asthma and Fatal COPD: Overlap in Older Patients

Abstract

In some patients with chronic asthma clinical and physiological similarities with COPD may exist, such as partial reversibility to bronchodilators and persistent expiratory airflow obstruction. However, pathological data comparing both diseases in patients of similar age and disease severity are scarce. We compared large and small airway dimensions in 12 younger (mean age 32 yrs) and 15 older (mean age 65 yrs) non-smoker adult fatal asthma patients with 14 chronic smokers with severe, fatal COPD (mean age 71 yrs). Using H&E, Movat pentachrome staining and image analysis, we quantified large airway basement membrane (BM) thickness (μm), submucosal gland area and large and small airway inner wall, smooth muscle and outer wall areas. Areas were normalized by BM perimeter (μm²/μm).

Younger adult fatal asthma patients had thicker BM, smooth muscle, and outer wall areas in both small and large airways when compared to COPD patients. In older asthmatics there was an overlap in BM thickness and airway structure in small airways. Inner wall layer in large and small airway level and submucosal gland areas were similar among groups. In conclusion, there are airway histological structural similarities between fatal asthma and fatal COPD. Older fatal asthmatics present overlapping airway structural features with younger adult fatal asthmatics and severe COPD patients. Our data contributes to a better understanding of asthma pathology in the elderly.     

Differences of Inflammatory Mechanisms in Asthma and COPD

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are increasing common diseases. The major pathogenesis of both illnesses is chronic inflammation. However, the inflammatory pattern is distinct in each disease. In asthmatic airways, activated mast cells/eosinophils and T helper 2 lymphocytes (Th2) are predominant. In contrast, macrophages and neutrophils are important in COPD airways/lung. Although nitric oxide (NO) hyperproduction due to inducible NO synthase (iNOS) is observed in asthma and COPD, nitrotyro- sine formation via the reaction between NO and O2^- in addition to the myeloperoxidase-mediated pathway. These distinct inflammatory patterns in both diseases seem to cause pathological differences in asthma and COPD.     

Bronchial hyper-responsiveness and exhaled nitric oxide in chronic obstructive pulmonary disease

Several lung diseases including asthma and chronic obstructive pulmonary disease (COPD) involve chronic inflammation of the airways. Therefore, there is great interest in non-invasive methods assessing airway inflammation. Measurement of bronchial hyper-responsiveness (BHR) and exhaled nitric oxide (NO) are such indirect markers of airway inflammation. Additional information about severity of disease, prognosis and possible response to anti-inflammatory treatment with inhaled corticosteroids can be gained by these methods. However, they are not yet established in assessing patients with COPD in clinical routine. BHR has long been recognised as a hallmark of asthma. Less is known about prevalence and clinical relevance of BHR in the general population and in COPD patients. Longitudinal studies have shown that BHR in healthy persons is a risk factor for development of respiratory symptoms, asthma and COPD. BHR has also been shown to increase the detrimental effect of cigarette smoke and is associated with a decline in lung function. Furthermore, studies indicate that the presence of BHR is a prognostic factor in COPD. Increased BHR to histamine has been shown to be a predictor for mortality in COPD patients. Based on current guidelines, treatment of patients with severe COPD (GOLD stage III and IV) and regular exacerbations includes therapy with inhaled corticosteroids. Inhaled corticosteroids have been shown to reduce frequency of exacerbations but they have not been shown to modify long-term decline in FEV1. However, one small study found that BHR to inhaled mannitol could possibly predict responsiveness to inhaled corticosteroids in patients with moderately severe COPD and identify a subgroup of patients that is likely to benefit from this treatment. Exhaled NO has been shown to correlate with other inflammatory markers and to be elevated in asthma. In COPD patients, data is inconsistent. However, measuring exhaled NO may have a role in the identification of patients with severe, unstable COPD who were shown to have higher NO levels compared to patients with stable COPD. This suggests that exhaled NO might be a method to assess and monitor disease activity in COPD. Possible explanations for the contradictory results are different measurement techniques of exhaled NO and different smoking histories of patients in various studies. Smoking has been found to be a confounding factor by reducing NO levels significantly, an effect which might counteract the potentially increased exhaled NO due to airway inflammation. In conclusion, measuring BHR and exhaled NO in patients with COPD might provide additional information about disease severity, prognosis and possible response to anti-inflammatory medical treatment. However, to establish these methods in clinical routine in COPD patients, more data is clearly needed.     

Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease

To determine whether patients with fixed airflow obstruction have distinct pathologic and functional characteristics depending on a history of either asthma or chronic obstructive pulmonary disease (COPD), we characterized 46 consecutive outpatients presenting with fixed airflow obstruction by clinical history, pulmonary function tests, exhaled nitric oxide, sputum analysis, bronchoalveolar lavage, bronchial biopsy, and high-resolution computed tomography chest scans. Subjects with a history of COPD (n = 27) and subjects with a history of asthma (n = 19) had a similar degree of fixed airflow obstruction (FEV1: 56 +/- 2 versus 56 +/- 3% predicted) and airway hyperresponsiveness (PC20FEV1: 2.81 [3.1] versus 1.17 [3.3]). Subjects with a history of asthma had significantly more eosinophils in peripheral blood, sputum, bronchoalveolar lavage, and airway mucosa; fewer neutrophils in sputum and bronchoalveolar lavage fluid; a higher CD4+/CD8+ ratio of T cells infiltrating the airway mucosa; and a thicker reticular layer of the epithelial basement membrane. They also had significantly lower residual volume, higher diffusing capacity, higher exhaled nitric oxide, lower high-resolution computed tomography scan emphysema score, and greater reversibility to bronchodilator and steroids. In conclusion, despite similar fixed airflow obstruction, subjects with a history of asthma have distinct characteristics compared with subjects with a history of COPD and should be properly identified and treated.     

Evidence of mast-cell activation in a subset of patients with eosinophilic chronic obstructive pulmonary disease.

Although asthma has been viewed mainly as an eosinophilic disease, and chronic obstructive pulmonary disease (COPD) as a neutrophilic disease, recent studies have shown increased neutrophil counts in severe asthma and sputum eosinophilia in some COPD patients. In an attempt to further characterise these two syndromes according to pathology, the current authors have conducted a study of induced sputum in 15 subjects with COPD, 17 asthmatics, and 17 nonatopic healthy individuals. Sputum was analysed for cytology and levels of eosinophil cationic protein (ECP), albumin, tryptase and soluble intercellular adhesion molecule-1. The COPD subjects differed from the asthmatics as they had higher sputum neutrophil and lower columnar epithelial cell counts, but there were no differences in any soluble marker studied. When compared to control subjects, both the asthmatic and COPD subjects had raised eosinophil counts and ECP levels. In a subset of COPD subjects with sputum eosinophilia (>3% of total cells), significantly increased levels of tryptase were detected. In conclusion, although chronic obstructive pulmonary disease is a more neutrophilic disease than asthma, the two diseases are difficult to distinguish on the basis of sputum levels of the soluble markers traditionally associated with asthma. However, a subset of patients with chronic obstructive pulmonary disease with airway eosinophilia and mast-cell activation might represent a distinct pathological phenotype.     

Addressing steroid phobia: improving the risk-benefit ratio with new agents

Inhaled corticosteroids (ICSs) are the preferred first-line preventative therapy for asthma of all severity levels. Although these drugs have been proven efficacious, concerns of adverse systemic affects due to both long- and short-term use continue to limit patient compliance with dosing regimens. Deficits in bone growth, bone density, and hypothalamic-pituitary-adrenal axis function, in addition to cataract formation and elevated intraocular pressure/glaucoma, have been associated with ICS use in some studies. Although some of these studies were flawed, featured drugs that are less commonly prescribed today, or both, adverse effects from chronic ICSs use are still a cause of concern today. Current therapies are designed to be efficacious at minimal doses, limiting potential side effects, increasing adherence, and improving asthma control.     

Adherence to inhaled corticosteroids: Comparison of available therapies

Adherence to daily anti-inflammatory therapy, the cornerstone being inhaled corticosteroids (ICSs), is critical for the control of persistent asthma. Many factors, both behavioral and treatment-related, can affect treatment adherence. In the pediatric population, adherence is often the responsibility of parents/caregivers. Thus, parents may need improved awareness of the major asthma controller medications, especially regarding the efficacy and safety of ICSs; their beliefs or concerns regarding asthma therapy have a bearing on their diligence in encouraging adherence with the prescribed treatment regimen. Dosing complexity and factors relating to inhaler use are also important components of adherence. There are currently 6 ICSs (excluding nebulized ICSs) approved for children in the United States. The purpose of this review is to examine and compare the features of the available ICSs that may influence adherence in the treatment of pediatric asthma.     

Cytokine expression in peripheral blood lymphocytes before and after aspirin desensitization in aspirin-exacerbated respiratory disease.

Aspirin intolerance is the hallmark of aspirin-exacerbated respiratory disease (AERD). Overproduction of cysteinyl-leukotrienes (Cys-LTs) has been implicated as major mediators of AERD; however, the LT receptor antagonist montelukast is only partially effective in inhibiting aspirin responses. Several studies have documented the importance of cytokine production by T lymphocytes in asthma. Peripheral blood lymphocyte (PBL) cytokine expression and its relation to aspirin desensitization in aspirin-sensitive patients with asthma have not been studied. This study was performed to examine PBL cytokine expression in aspirin-sensitive patients who have asthma before and after aspirin desensitization. A 42-year-old white woman with a history of severe asthma, nasal polyps, aspirin sensitivity, and chronic sinusitis was treated with aspirin desensitization. Blood was taken before and after aspirin desensitization, and PBL cytokine expression was studied by flow cytometry. Aspirin desensitization differentially affects interferon (IFN) gamma expression. This effect results in an increase in IFN-gamma expression by CD4(+) lymphocytes and a decrease in IFN-gamma expression by CD8(+) lymphocytes. Aspirin desensitization in an aspirin-sensitive patient with asthma resulted in an increase in IFN-gamma expression by CD4(+) lymphocytes and a decrease in IFN-gamma expression by CD8(+) lymphocytes, the significance of which needs additional investigation.     

The activity of cytochrome oxidase is increased in circulating lymphocytes of patients with chronic obstructive pulmonary disease, asthma, and chronic arthritis

We have previously shown that the activity of cytochrome oxidase (CytOx) in skeletal muscle of patients with chronic obstructive pulmonary disease (COPD) was higher than in healthy control subjects. The mechanisms and implications of this observation were unclear. In particular, it was not known if this abnormality can occur also in: (1) cell types other than muscle cells, and (2) other chronic inflammatory diseases. To obtain further insight into these questions, we measured the activity of CytOx in circulating lymphocytes in patients with stable COPD (n = 17), bronchial asthma (n = 6), or chronic arthritis (n = 5), and in healthy control subjects (n = 8). We found that, compared with healthy subjects (280 +/- 117 nKat/microg protein), patients with COPD showed increased CytOx activity (430 +/- 150 nKat/microg protein, p = 0.01) in lymphocytes. Further, this activity was negatively related to the degree of airflow obstruction present in these patients (r = -0.53, p < 0.05). We also found that the activity of CytOx in circulating lymphocytes was higher than normal in patients with chronic arthritis (411 +/- 130 nKat/microg protein, p < 0.05) and, particularly, in patients with bronchial asthma (1,667 +/- 1,027 nKat/microg protein, p < 0.001). These results show that the increased CytOx activity previously reported in skeletal muscle of patients with COPD is also detected in other cell types (such as circulating lymphocytes) and in other chronic inflammatory diseases (such as bronchial asthma and chronic arthritis). The mechanisms and implications of these findings deserve further investigation.     

Prognosis in chronic obstructive pulmonary disease

Although many factors have been shown to relate to survival in patients with COPD, the patient's age and baseline postbronchodilator FEV1 are the best predictors of mortality. The presence of mild obstructive airway disease is not indicative of a progressive downhill course and shortened survival. Mortality in patients with a baseline postbronchodilator FEV1 greater than or equal to 50% of predicted was only slightly greater than that of a group of healthy smokers. Investigators attempting to compare survival in patients with COPD should attempt to exclude patients with asthma or asthmatic bronchitis, because these individuals have a much better prognosis than those with typical COPD (emphysema and chronic bronchitis). Patients should be matched closely for age and severity of impairment, because younger individuals and those with milder impairment are likely to live longer. Other factors besides age and baseline FEV1 have been shown to affect survival. Patients who stop smoking are likely to survive longer than those who continue to smoke. The presence of malnutrition has clearly been shown to worsen survival. Further studies will be necessary to determine if corticosteroid therapy can slow down progression of disease in patients with typical COPD. Oxygen therapy improves survival in COPD patients with significant hypoxemia, many of whom also have CO2 retention, polycythemia, and cor pulmonale. There are now multiple studies in the literature suggesting that the type of comprehensive respiratory care provided by pulmonary rehabilitation programs can not only improve the quality of life but also survival in patients with chronic obstructive pulmonary disease.