American Journal of Respiratory and Critical Care Medicine

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome represent two of the most prevalent chronic respiratory disorders in clinical practice, and cardiovascular diseases represent a major comorbidity in each disorder. The two disorders coexist (overlap syndrome) in approximately 1% of adults but asymptomatic lower airway obstruction together with sleep-disordered breathing is more prevalent. Although obstructive sleep apnea syndrome has similar prevalence in COPD as the general population, and vice versa, factors such as body mass index and smoking influence relationships. Nocturnal oxygen desaturation develops in COPD, independent of apnea/hypopnea, and is more severe in the overlap syndrome, thus predisposing to pulmonary hypertension. Furthermore, upper airway flow limitation contributes to nocturnal desaturation in COPD without apnea/hypopnea. Evidence of systemic inflammation in COPD and sleep apnea, involving C-reactive protein and IL-6, in addition to nuclear factor-κB–dependent pathways involving tumor necrosis factor-α and IL-8, provides insight into potential basic interactions between both disorders. Furthermore, oxidative stress develops in each disorder, in addition to activation and/or dysfunction of circulating leukocytes. These findings are clinically relevant because systemic inflammation may contribute to the pathogenesis of cardiovascular diseases and the cell/molecular pathways involved are similar to those identified in COPD and sleep apnea. However, the pathophysiological and clinical significance of systemic inflammation in COPD and sleep apnea is not proven, and thus, studies of patients with the overlap syndrome should provide insight into the mechanisms of systemic inflammation in COPD and sleep apnea, in addition to potential relationships with cardiovascular disease.

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSAS) represent two of the most prevalent chronic respiratory disorders in clinical practice, and the term “overlap syndrome” is commonly used to describe the two disorders, when coexisting. Epidemiological studies (1, 2) indicate a prevalence of approximately 1% for the overlap syndrome in adult males, but the coexistence of asymptomatic lower airway obstruction with sleep-disordered breathing is considerably higher. Overlap patients develop more pronounced nocturnal oxygen desaturation (NOD) than COPD or OSAS alone, which predisposes to pulmonary hypertension (3).

The possible coexistence of COPD with OSAS is important because systemic inflammation develops in each disorder (4, 5) and may contribute to the pathogenesis of associated comorbidities, particularly cardiovascular. Inflammation plays an important role in atherosclerosis and cardiovascular disease (6), which represent the principal comorbidity in COPD (7) and OSAS (8, 9). However, putative causative links between OSAS- or COPD-induced systemic inflammation and cardiovascular disease remain unproven. Furthermore, no study has evaluated potential interactions between these disorders in the development of systemic inflammation or cardiovascular disease.

The objectives of this Pulmonary Perspective are, first, to review the relationships of COPD and OSAS with cardiovascular disease from the perspective of systemic inflammation and hypoxia; second, to review the epidemiology of the overlap syndrome and related factors that may influence prevalence; third, to review pathophysiological interactions between COPD, sleep, and OSAS; fourth, to review the evidence for shared systemic inflammatory pathways in COPD and OSAS; and finally, to propose future research directions, particularly where studies of overlap patients may provide insight into systemic manifestations of COPD and OSAS, in addition to potential relationships with cardiovascular disease.

Inflammation plays a key role in atherosclerotic plaque formation, from initiation of the fatty streak to the later stages of plaque rupture (6). In brief summary, endothelial dysfunction develops at an early stage in response to oxidized lipids, inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1 and IL-6, and other factors including reactive oxygen species (ROS). This process leads to up-regulation of intercellular adhesion molecules, which promote rolling and adherence of leukocytes to the endothelium. Monocytes and T cells penetrate the vascular wall, where monocytes transform into macrophages, which ingest oxidized lipids to form foam cells. These cells accumulate to form a lipid pool, which is a central component of the early atherosclerotic plaque. As the plaque develops, a fibrous cap forms that separates the plaque from the vascular lumen. The ongoing inflammatory response, matrix degradation, and cell apoptosis lead to thinning of the fibrous cap and enlargement of the lipid core, ultimately resulting in plaque rupture.

Inflammatory mediators participate in all stages of atherosclerosis and the detailed mechanisms are reviewed elsewhere (6, 10). However, there is no current evidence that targeted antiinflammatory therapy such as TNF-α antagonists ameliorate this process. Both COPD and OSAS are associated with increased activation of many inflammatory cell and molecular mechanisms associated with atherosclerosis (8, 11), which provide basic mechanisms to support the clinical and epidemiological data demonstrating COPD and OSAS as independent risk factors for cardiovascular disease (79).

Hypoxia plays an important role in the progression of atherosclerosis by stimulating angiogenesis within the atherosclerotic plaque (12), principally via activation of the adaptive hypoxia-responsive transcription factor, hypoxia-inducible factor (HIF)-1. Inflammation within the plaque is a key factor in generating hypoxia by increasing metabolic demand. Intraplaque microvessels facilitate plaque progression and ultimate rupture by providing an entry point for inflammatory cells, red blood cells, and lipoproteins (12). Furthermore, important interactions occur between lipids and hypoxia in the development of atherosclerosis. In particular, chronic intermittent hypoxia together with a high-fat diet promotes atherosclerosis in male C57BL/6 mice, whereas hypoxia or a high-fat diet alone does not (13). These findings suggest that the greater hypoxia in the overlap syndrome might predispose to atherosclerosis more than COPD or OSAS alone, but this possibility is unproven.

Hypercapnia also modulates inflammatory responses in a variety of settings including sepsis and ischemia–reperfusion. Hypercapnic acidosis has been demonstrated to have antiinflammatory effects through inhibition of the proinflammatory transcription factor nuclear factor (NF)-κB in an in vitro model using endothelial cells (14), and hypercapnia was associated with reduced TNF-α levels in an in vivo animal model of ischemia–reperfusion (15). Furthermore, hypercapnia depresses both pro- and antiinflammatory cytokine production in endotoxin-stimulated whole blood cultures taken from normal human subjects (16). These findings underline the complexity of potential interactions between hypoxia and hypercapnia in the inflammatory response.

The mechanisms of cardiovascular disease in COPD and OSAS are multifactorial, but both disorders involve systemic inflammation. Whether systemic inflammation is an independent entity or largely a spillover of pulmonary inflammation in COPD (5), or upper airway inflammation in OSAS (17), is unclear. However, circulating levels of cytokines such as TNF-α and IL-8 correlate poorly with sputum levels in COPD, which argues against a simple spillover effect (18). Intermediate factors are also important because smoking (19) and obesity (20) are associated with increased systemic inflammatory markers such as IL-6, TNF-α, and ROS.

COPD

In COPD, mechanisms of cardiovascular disease include hypoxia, systemic inflammation, and oxidative stress, together with sympathetic nervous system overactivity and vascular dysfunction (11), and are summarized in Figure 1. Vascular dysfunction in COPD relates to inflammatory cytokines such as IL-6, endothelial dysfunction, and connective tissue degradation, the latter involving increased elastolytic activity and collagen deposition. Genetic factors, lung hyperinflation, and skeletal muscles (19, 21) also contribute to systemic inflammation.

COPD is a major, but underrecognized, risk factor for cardiovascular morbidity and mortality, even after adjustment for confounding risk factors such as age, smoking, and body mass index (BMI) (7, 11). Several population studies have demonstrated that cardiovascular morbidity and mortality progressively increase with declining FEV1/FVC ratio, and this relationship is present even in nonsmokers. Other prospective cohort studies indicate that cardiovascular disease represents the leading cause of mortality in patients with COPD (7). Apart from the well-recognized cor pulmonale, cardiovascular diseases independently associated with COPD include coronary artery disease, congestive heart failure, and arrhythmias (11). Nocturnal hypoxemia and hypercapnia in COPD predispose to pulmonary hypertension and sleep-related cardiac arrhythmias (22), in addition to nocturnal death during exacerbations (23).

OSAS

In OSAS, mechanisms of cardiovascular disease include increased sympathetic and reduced parasympathetic nervous system activity, systemic inflammation, oxidative stress, endothelial dysfunction, and metabolic dysregulation, the latter involving insulin resistance and disordered lipid metabolism. Intermittent hypoxia is a key feature in systemic inflammation and oxidative stress in OSAS because of the associated intermittent reoxygenation (24), which has been compared with reperfusion injury, and activates the inflammatory transcription factor NF-κB with increased production of related cytokines including TNF-α and IL-8 (25). The repetitive generation of negative intrathoracic pressure during obstructive apneas may also adversely affect cardiac function (26). The putative mechanisms of cardiovascular disease associated with intermittent hypoxia and/or sleep fragmentation in OSAS are outlined in Figure 2.

OSAS is independently associated with systemic hypertension, and there is growing evidence of independent associations with coronary artery disease, congestive heart failure, arrhythmia, and stroke (8, 9). Pulmonary hypertension may also develop in patients with severe OSAS and/or gross obesity, in whom oxygen desaturation is most pronounced, and such patients may also develop daytime hypercapnia, particularly if there is associated lower airway obstruction (27). Data from the Wisconsin Sleep Cohort Study indicate a higher all-cause and cardiovascular mortality among patients with severe OSAS (28) and observational long-term follow-up studies indicate a lower cardiovascular morbidity and mortality among patients with OSAS treated with continuous positive airway pressure (CPAP) compared with those untreated (29, 30).

Overlap Syndrome

Although systemic inflammation develops in both COPD (5, 31) and OSAS (4, 24), no study has investigated possible interactions between the disorders in these developments. Furthermore, few data exist concerning morbidity and mortality in patients with the overlap syndrome. NOD is greater in patients with the overlap syndrome than with COPD or OSAS alone (3) and apnea-associated desaturation is more pronounced. Daytime hypercapnia is also more common in overlap patients (27). This more pronounced hypoxemia and hypercapnia might result in greater cardiovascular morbidity and mortality, and there is some evidence to support this possibility. Pulmonary hypertension is more prevalent in overlap patients (3) and a preliminary report indicates that overlap patients have a higher mortality than those with COPD alone (32).

The prevalence of OSAS and COPD is reviewed elsewhere (33, 34); this review discusses the prevalence of the overlap syndrome, in addition to factors that influence prevalence such as definitions, obesity, and cigarette smoking. For clarity, the term OSAS refers to the clinical syndrome, whereas OAH refers to obstructive apneas/hypopneas alone without reference to symptoms.

Influence of Definitions on the Prevalence of Overlap Syndrome

Although COPD and OSAS are prevalent, the reported prevalence is influenced by definitions. In the National Health and Nutrition Examination Survey (NHANES III), involving 9,838 normal subjects (35), COPD prevalence ranged from 7.7% for GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage IIa (FEV1/FVC ratio <70% with FEV1 <80% and >50% predicted) to 16.8% for GOLD stage I (FEV1/FVC ratio <70% and FEV1 >80%). The prevalence of obstructive sleep apnea is also influenced by definitions. In the Wisconsin Sleep Cohort Study of 602 middle-aged working adults (36), 4% of males and 2% of females had an apnea–hypopnea frequency (AHI) of at least 5/hour together with daytime sleepiness, which are the minimal criteria for the clinical syndrome (37). However, an AHI of at least 5/hour alone without daytime symptoms occurred in 24% of males and 9% of females. The widely accepted definition of OSAS by an international task force (37) requires obstructed breathing events and compatible daytime symptoms for diagnosis. Thus, the lower prevalence in the Wisconsin Sleep Cohort Study refers to OSAS. However, pathophysiological interactions between COPD and OSAS relate more to sleep-disordered breathing than daytime symptoms; thus, the higher prevalence figures previously cited for OAH alone may be more relevant in this context. Thus, a prevalence for subclinical forms of the overlap of 4% in males could be speculated from a simple calculation based on the prevalence of 16.8% for GOLD stage I in the NHANES Study and 24% among males for an AHI of at least 5/hour in the Wisconsin Sleep Cohort Study. Although the clinical relevance of an isolated AHI of at least 5/hour is uncertain, this finding has been independently associated with hypertension in the Wisconsin Sleep Cohort Study (34).

Prevalence of Overlap Syndrome

Several reports have assessed the epidemiological relationships between COPD and OSAS (3) (13, 38), and details are presented in Table 1. Overall, the data support a similar prevalence of OSAS in patients with COPD as in an equivalent general population. Data from the Sleep Heart Health Study (1) indicate that the respiratory disturbance index (RDI) was less in subjects with lower airway obstruction, largely as a consequence of lower BMI, because RDI values were similar when stratified for BMI. In the World Health Organization (Geneva, Switzerland)-sponsored MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) II project (2), OSAS prevalence was relatively high at 11.3%, but lower airway obstruction did not predispose to OSAS, or OSAS to lower airway obstruction. The overlap syndrome occurred in 1% of subjects, but an AHI of at least 5/hour alone with FEV1/FVC less than 70% occurred in 3%, which approximates the prevalence speculated previously. Overlap patients had lower nocturnal SaO2 levels than those with COPD or OSAS. Although Larsson and coworkers (38) reported a higher OSAS prevalence in subjects with chronic bronchitis than in control subjects, data were from only 52 subjects undergoing home-based studies without sleep staging.

TABLE 1. PREVALENCE OF OVERLAP SYNDROME


Author (Ref. No.)

Study Details

Findings
Sanders et al. (1)Prospective community sample of 5,964 adults ≥40 yr undergoing spirometry and polysomnography; sample enriched for cardiovascular risk factors including smoking19% had FEV1/FVC ratio <70%; 3.8% had FEV1/FVC ratio 60%. This group had lower AHI, largely as a consequence of lower BMI
Bednarek et al. (2)Prospective community sample of 356 adult males and 320 females aged 41–72 yr11.3% had AHI ≥5 with sleepiness; 31.8% had AHI ≥5 alone; 10.7% had FEV1/FVC ratio <70%. Overlap syndrome in 1% but FEV1/FVC <70% and AHI ≥5 alone in 3%
Chaouat et al. (3)265 sleep clinic patients with established OSAS (AHI ≥20/h)11% had FEV1/FVC ratio <60%; this group was all male, had lower PaO2, higher PaCO2, and pulmonary artery pressures
Larsson et al. (37)
471 adults with chronic bronchitis and 108 without; 52 subjects had home-based limited sleep studies (type 3 monitor)
7.4% of patients with bronchitis and 3.1% of control subjects had OSAS (AHI >5 with sleepiness); difference not statistically significant

Definition of abbreviations: AHI = apnea–hypopnea index; BMI = body mass index; OSAS = obstructive sleep apnea syndrome.

Influence of Body Mass Index, Smoking, and Age on Prevalence

Several confounding factors may influence relationships between COPD and OSAS, particularly BMI and smoking. Obesity is a key factor in OSAS (26), yet low BMI is common in COPD, especially in patients with advanced disease (39). This feature may protect against OAH, and is supported by the finding of a lower RDI in subjects with airflow obstruction, relating to lower BMI (1). On the other hand, many other patients with COPD have elevated BMI, thus predisposing to OAH, and the finding of a higher RDI in overweight patients with airflow obstruction supports this possibility (1).

Smoking is a risk factor for COPD and OSAS, and several reports found a higher AHI in smokers than nonsmokers (34). A report based on the Wisconsin Sleep Cohort including 811 adults (40) found that an AHI of at least 5/hour was three times more likely in current smokers than in never-smokers. Heavy smokers (≥40 cigarettes/d) had an odds ratio of 6.74 for AHI of at least 5/hour. OSAS and COPD are more common in the elderly (41, 42) and Chaouat and coauthors (3) reported that overlap patients in their sleep clinic cohort were older than patients with OSAS alone.

This perspective focuses on interactions of COPD, sleep, and upper airway obstruction in the pathophysiology of sleep-related breathing disturbances.

Sleep-related Effects in COPD

Sleep quality is impaired in COPD (43), with sleep fragmentation and, as a result, diminished slow-wave and REM sleep. Sleep disturbance is largely a consequence of COPD, not coexisting OAH (22), although cigarette smoking also impairs sleep quality (44). This reduction in REM sleep protects against OAH in COPD, because apneas are more pronounced in OSAS during REM sleep (26). The effects of chronic sleep disturbance on pulmonary function in COPD are unknown, but an early report found lower FVC and FEV1 (5 and 6%, respectively) in the morning after one night's sleep deprivation in 15 adult males with stable COPD when compared with measurements after a night of normal sleep (45). However, the mechanisms of this effect were unclear.

The principal basis for disturbances in ventilation and gas exchange during sleep in COPD, independent of OAH, relates to augmented physiological adaptations (22). Respiratory center responses to chemical and other inputs are diminished during sleep (46) and respiratory muscle responses to respiratory center outputs are diminished, particularly during REM sleep, and especially involving accessory muscles of respiration. Minute ventilation falls during non-REM and more so during REM sleep, even in normal subjects, predominantly because of a reduction in tidal volume due to increased upper airway resistance and diminished inspiratory drive, with a slight fall in SaO2 that is not clinically significant in normal subjects (47). In COPD, this reduction in ventilation is augmented, resulting in greater falls in SaO2 during sleep with associated hypercapnia. Because many such patients have awake hypoxemia, they are especially prone to nocturnal oxygen desaturation (NOD) by being on the steep portion of the oxyhemoglobin dissociation curve. Furthermore, SaO2 falls more during sleep in COPD patients without OAH than during maximal exercise (48).

The ribcage contribution to breathing is reduced, particularly during REM sleep, because of reduced accessory muscle contraction, which particularly affects the intercostal muscles, whereas diaphragmatic contraction is spared. This reduction is important in COPD, where lung hyperinflation may reduce diaphragmatic efficiency (49), thus necessitating an increased accessory muscle contribution to breathing. Skeletal muscle atrophy and dysfunction is common in advanced COPD (39), which may further compromise the contribution made by accessory muscles. A small reduction in FRC occurs during sleep, principally because of a reduction in tonic muscle activity, which may augment ventilation–perfusion mismatching.

Pathophysiological Interactions of COPD and OSAS

Several pathophysiological factors influence the relationship between COPD and OSAS (Figure 3). COPD-related factors that may predispose to OAH include rostral shift of peripheral edema when supine, resulting in fluid accumulation in the neck, thus contributing to pharyngeal narrowing (50). Although there are no data for COPD, this phenomenon might be particularly expected in patients with cor pulmonale, among whom peripheral edema is a major feature. Body mass and cigarette smoking also affect pathophysiological relationships. Neck obesity contributes to upper airway narrowing, which is of key importance in OAH pathophysiology (26), and a preliminary report found that such narrowing predisposes to NOD in COPD, independent of OAH (51). Truncal obesity promotes ventilatory disturbances by reduced chest wall compliance and respiratory muscle strength (52). Furthermore, truncal obesity is associated with reduced FRC, which contributes to ventilation–perfusion mismatching. However, many patients with advanced COPD have low BMI, which protects against OSA. Cigarette smoking predisposes to OAH by increasing upper airway resistance due to local inflammation and edema (26).

Medications used in COPD may influence interactions between COPD and OSAS. Theophyllines (53), inhaled anticholinergic agents (54), and inhaled long-acting β-agonists (55) ameliorate NOD, likely because of reductions in both gas trapping and lower airway obstruction. Corticosteroids may predispose to OAH by promoting central obesity and fluid retention with associated upper airway narrowing, in addition to myopathy and metabolic alkalosis.

The mechanisms of systemic inflammation in COPD and OSAS are reviewed elsewhere (4, 5, 8, 39, 56); this perspective concentrates on overlapping mechanisms, thus highlighting possible interactions, as outlined in Figure 4.

C-reactive Protein and IL-6

The acute-phase inflammatory protein CRP (C-reactive protein) is produced by the liver in response to IL-6 and contributes to atherosclerosis by promoting adhesion molecule expression. CRP levels correlate with future cardiovascular events (57, 58), although conventional cardiovascular risk factors such as obesity may be largely responsible for this association (59).

In OSAS, CRP levels are elevated (60, 61), but obesity is an important confounding factor in this relationship (62). The Wisconsin Sleep Cohort Study of 907 adults failed to detect an independent association between CRP and OSAS after adjustment for BMI (63), and a randomized control trial found no difference in CRP and IL-6 levels between therapeutic and sham CPAP after 4 weeks of therapy (64). In COPD, CRP levels are elevated in patients with stable disease (31) and correlate with pulmonary artery pressures (65). The NHANES III study of 6,629 subjects reported a correlation of CRP with airflow obstruction and myocardial ischemia (66). CRP was an independent predictor of future outcomes in some (67) but not other studies (68, 69), and appears to be a sensitive biomarker of exacerbations (70).

IL-6 levels predict future cardiovascular disease (58) and adipose tissue is a major site of production. In OSAS, early studies found increased IL-6 levels (61), but more recent reports of patients with OSAS and matched control subjects found no differences (71), and CPAP therapy had no effect on IL-6 levels (64, 71). Furthermore, the Cleveland Family Study of 385 adults found no association between circulating IL-6 levels and OSAS after adjustment for BMI (72), although an independent association was found between OSAS and soluble IL-6 receptor levels. In COPD, IL-6 levels are increased (69), particularly during exacerbations (73), and IL-6 levels parallel CRP.

Thus, there is evidence of increased circulating CRP and IL-6 levels in COPD whereas in OSAS obesity is a major confounding variable and the evidence of an independent relationship between OSAS and CRP/IL-6 levels is less clear. Furthermore, the precise role of CRP and IL-6 in the pathogenesis of cardiovascular disease in these disorders is not fully established.

NF-κB and Related Cytokines

The transcription factor NF-κB is a master regulator of inflammatory gene expression and regulates cytokines such as TNF-α and IL-8 that contribute to atherosclerosis by inducing adhesion molecule expression (6). Hypoxia induces NF-κB activation and also activation of the adaptive transcription factor HIF-1, which regulates many genes that promote tissue perfusion and oxygenation (74). NF-κB and HIF-1 pathways also interact in the hypoxic response (75). We demonstrated in an in vitro model of hypoxia a preferential activation of NF-κB over HIF-1 pathways during intermittent hypoxia, whereas sustained hypoxia resulted in preferential activation of HIF-1 (Figure 5) (25). These findings imply that intermittent hypoxia preferentially up-regulates inflammatory pathways, which particularly applies to the hypoxic pattern in OAH but may also apply to patients with COPD during sleep and exercise. The findings also suggest that disorders associated with chronic sustained hypoxia, such as hypoventilation syndromes or COPD patients with chronic hypoxemia, may invoke an HIF-1–mediated response more so than OSAS, in which intermittent hypoxemia is the dominant pattern, although persistent hypoxemia may also occur in OSAS especially in severely obese patients. In COPD, there is NF-κB activation in skeletal muscles (76), which may contribute to skeletal muscle wasting.

Tumor Necrosis Factor-α and IL-8

Circulating TNF-α and IL-8 levels correlate with early atherosclerosis, and are predictive of coronary heart disease and congestive heart failure (77). In COPD, TNF-α and IL-8 levels are elevated compared with control subjects (31, 78) and TNF-α elevation is associated with muscle wasting, likely relating to TNF-α accumulation in muscle tissue (79). Systemic hypoxemia contributes to TNF-α elevation in COPD (80), which is particularly relevant in the overlap syndrome where hypoxemia is more pronounced. Furthermore, circulating TNF-α levels are higher in COPD patients with pulmonary hypertension, who are also more hypoxemic (65).

In OSAS, circulating TNF-α and IL-8 levels are elevated in patients compared with control subjects, independent of obesity, and fall with CPAP therapy (71). The oxygen desaturation index is the strongest predictor of TNF-α and IL-8 levels in OSAS, and T cells and monocytes are potential sources of TNF-α (81). Unlike COPD, TNF-α elevation does not appear to be associated with muscle wasting in OSAS.

Overall, the data indicate activation of TNF-α in COPD and OSAS with hypoxemia being a key factor. Thus, TNF-α and related cytokine levels should be particularly elevated in patients with the overlap syndrome, and studies of this pathway in overlap patients may provide insight into the role of NF-κB–dependent pathways in cardiovascular disease.

Oxidative Stress

Oxidative stress occurs in COPD (82) and OSAS (24) and is associated with increased ROS production, principally from leukocytes. Although ROS serve important physiological roles in signal transduction and as second messengers in signaling pathways, excessive production may damage cellular components and biomolecules including lipids, proteins, and DNA (83) and contribute to vascular endothelial dysfunction.

In COPD, oxidative stress occurs in the lungs and systemically (82) with increased ROS production from both intrapulmonary and circulating leukocytes, particularly during exacerbations. Oxidative stress in COPD may also result from reduced antioxidant capacity and mechanisms include reduced levels of the transcription factor nuclear factor erythroid 2-related factor 2 in lung tissue, which is a master regulator of antioxidant gene production.

In patients with OSAS, ROS production by circulating leukocytes is increased and reduced after CPAP therapy (84), and is also increased in rodents exposed to intermittent hypoxia (85). Patients with OSAS also demonstrate oxidation of macromolecules, particularly lipid peroxidation (86). Intermittent hypoxia may particularly promote oxidative stress because the associated intermittent reoxygenation has been compared with reperfusion injury where increased ROS production is evident (24).

However, confounding factors such as cigarette smoking and obesity also promote oxidative stress (19, 87). Furthermore, interactions of oxidative stress with pathways of systemic inflammation in response to hypoxia, such as those involving NF-κB, are complex and not fully elucidated. Evidence supporting a causal association include reports that ROS up-regulates mitogen-activated protein kinase pathways, which then activate inflammatory transcription factors such as NF-κB; and by reports that TNF-α stimulation results in increased intracellular ROS production (83). However, NF-κB can also be activated in an ROS-independent fashion and several signal cascades activate NF-κB without ROS involvement (88).

Circulating Inflammatory Cells

There is evidence of activation/dysfunction of circulating leukocytes in COPD and OSAS, which has particular relevance because leukocyte accumulation and adhesion to the endothelium are of key importance to atherosclerotic plaque formation (6).

In OSAS, circulating neutrophil numbers are elevated compared with matched control subjects (25) and impaired neutrophil apoptosis occurs together with increased adhesion molecule expression (89). Recurrent obstructive apneas in rats lead to increased leukocyte–endothelial cell interactions such as leukocyte rolling and adhesion (90). Cytotoxic T-cell lymphocytes in patients with OSAS acquire an activated phenotype resulting in cytotoxicity against endothelial cells (91). Furthermore, monocytes from patients with OSAS adhere more firmly to endothelial cells than do those from control subjects, which is decreased by CPAP therapy (92).

In stable COPD, circulating neutrophil numbers are elevated (31). Abnormalities of circulating neutrophils have been reported in patients with COPD that facilitate recruitment into the lungs, such as increased expression of the surface adhesion molecule CD11b and elevated circulating levels of intercellular adhesion molecule-1 (93). Increased surface expression of CD11b/CD18 has also been demonstrated on circulating neutrophils during apoptosis in patients with stable COPD (94). Lymphocyte abnormalities reported in COPD include higher numbers of circulating cytotoxic CD8+ lymphocytes and higher cytochrome oxidase activity in circulating lymphocytes of patients with COPD than in control subjects (95). However, cigarette smoking may be an important confounding variable in these changes (39).

Despite the high prevalence of overlap syndrome, few data are available on its pathophysiological and clinical consequences. Most information relates to cross-sectional analysis of selected clinic cohorts and there are no long-term follow-up studies. The finding that NOD in COPD relates mainly to upper airway narrowing without OAH requires confirmation. The association of systemic inflammation with COPD and OSAS indicates that the possibility of an overlap is relevant to protocols evaluating pathophysiological mechanisms in each disorder. Because polysomnography may pose difficulties in COPD-related studies, ambulatory monitoring systems are available that record cardiorespiratory variables suited to evaluating sleep-related breathing disturbances (96).

Although there is evidence in COPD and OSAS of overlapping mechanisms relating to inflammation, oxidative stress, and leukocyte dysfunction, there may be differences in the magnitude and consequences of these responses. Furthermore, the role of inflammatory markers in the prediction of cardiovascular morbidity in OSAS and COPD is unclear and long-term prospective studies are lacking. Data are particularly lacking on these responses in the overlap syndrome, and the potential relationships to cardiovascular disease. If systemic inflammation is important in COPD and OSAS, studies in overlap patients should provide insight regarding the nature and significance of these responses. Because hypoxia is greater in the overlap syndrome, evaluating the role of hypoxia in systemic inflammation among overlap patients may provide additional insights into the mechanisms involved in each disorder.

The author acknowledges with thanks the critical feedback from several expert colleagues in the preparation of this manuscript, namely William MacNee (Edinburgh), John Stradling (Oxford), Michael P. Keane (Dublin), and Peter Calverley (Liverpool).

1. Sanders MH, Newman AB, Haggerty CL, Redline S, Lebowitz M, Samet J, O'Connor GT, Punjabi NM, Shahar E. Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med 2003;167:7–14.
2. Bednarek M, Plywaczewski R, Jonczak L, Zielinski J. There is no relationship between chronic obstructive pulmonary disease and obstructive sleep apnea syndrome: a population study. Respiration 2005;72:142–149.
3. Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler R. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med 1995;151:82–86.
4. Gozal D, Kheirandish-Gozal L. Cardiovascular morbidity in obstructive sleep apnea: oxidative stress, inflammation, and much more. Am J Respir Crit Care Med 2008;177:369–375.
5. Wouters EFM. Local and systemic inflammation in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:26–33.
6. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–1695.
7. Sin DD, Man SFP. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc 2005;2:8–11.
8. McNicholas WT, Bonsignore MR. Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;29:156–178.
9. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation scientific statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 2008;52:686–717.
10. Lusis AJ. Atherosclerosis. Nature 2000;407:233–241.
11. MacNee W, Maclay J, McAllister D. Cardiovascular injury and repair in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008;5:824–833.
12. Sluimer JC, Daemen MJ. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol 2009;218:7–29.
13. Savransky V, Nanayakkara A, Li J, Bevans S, Smith PL, Rodriguez A, Polotsky VY. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 2007;175:1290–1297.
14. Takeshita K, Suzuki Y, Nishio K, Takeuchi O, Toda K, Kudo H, Miyao N, Ishii M, Sato N, Naoki K, et al. Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-κB activation. Am J Respir Cell Mol Biol 2003;29:124–132.
15. Laffey JG, Tanaka M, Engelberts D, Luo X, Yuan S, Keith Tanswell A, Post M, Lindsay T, Kavanagh BP. Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir Crit Care Med 2000;162:2287–2294.
16. Kimura D, Totapally BR, Raszynski A, Ramachandran C, Torbati D. The effects of CO2 on cytokine concentrations in endotoxin-stimulated human whole blood. Crit Care Med 2008;36:2823–2827.
17. Boyd JH, Petrof BJ, Hamid Q, Fraser R, Kimoff RJ. Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:541–546.
18. Vernooy JH, Kucukaycan M, Jacobs JA, Chavannes NH, Buurman WA, Dentener MA, Wouters EF. Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. Am J Respir Crit Care Med 2002;166:1218–1224.
19. Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EFM. Systemic effects of smoking. Chest 2007;131:1557–1566.
20. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2007;92:347–355.
21. Yanbaeva DG, Dentener MA, Creutzberg EC, Wouters EF. Systemic inflammation in COPD: is genetic susceptibility a key factor? COPD 2006;3:51–61.
22. McNicholas WT. Impact of sleep in COPD. Chest 2000;117:48S–53S.
23. McNicholas WT, Fitzgerald MX. Nocturnal deaths among patients with chronic bronchitis and emphysema. Br Med J (Clin Res Ed) 1984;289:878.
24. Lavie L. Obstructive sleep apnoea syndrome: an oxidative stress disorder. Sleep Med Rev 2003;7:35–51.
25. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660–2667.
26. Deegan PC, McNicholas WT. Pathophysiology of obstructive sleep apnoea. Eur Respir J 1995;8:1161–1178.
27. Bradley TD, Rutherford R, Lue F, Moldofsky H, Grossman RF, Zamel N, Phillipson EA. Role of diffuse airway obstruction in the hypercapnia of obstructive sleep apnea. Am Rev Respir Dis 1986;134:920–924.
28. Young T, Finn L, Peppard PE, Szklo-Coxe M, Austin D, Javier Nieto F, Stubbs R, Hla KM. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin Sleep Cohort. Sleep 2008;31:1071–1078.
29. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046–1053.
30. Doherty LS, Kiely JL, Swan V, McNicholas WT. Long-term effects of nasal continuous positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest 2005;127:2076–2084.
31. Gan WQ, Man SFP, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004;59:574–580.
32. Marin JM, DeAndres R, Alonso J, Sanchez A, Carrizo S. Long term mortality in the overlap syndrome. Eur Respir J 2008;32:865.
33. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007;370:765–773.
34. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165:1217–1239.
35. Celli BR, Halbert RJ, Isonaka S, Schau B. Population impact of different definitions of airway obstruction. Eur Respir J 2003;22:268–273.
36. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230–1235.
37. Flemons WW, Buysse D, Redline S, Pack A, Strohl K, Wheatley J, Young T, Douglas N, Levy P, McNicholas W, et al. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999;22:667–689.
38. Larsson LG, Lindberg A, Franklin KA, Lundbäck B. Obstructive sleep apnoea syndrome is common in subjects with chronic bronchitis: report from the Obstructive Lung Disease in Northern Sweden Studies. Respiration 2001;68:250–255.
39. Agusti AGN. Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:367–370.
40. Wetter DW, Young TB, Bidwell TR, Badr MS, Palta M. Smoking as a risk factor for sleep-disordered breathing. Arch Intern Med 1994;154:2219–2224.
41. Stepnowsky CJ, Ancoli-Israel S. Sleep and its disorders in seniors. Sleep Med Clin 2008;3:281–293.
42. Anto JM, Vermeire P, Vestbo J, Sunyer J. Epidemiology of chronic obstructive pulmonary disease. Eur Respir J 2001;17:982–994.
43. Cormick W, Olson LG, Hensley MJ, Saunders NA. Nocturnal hypoxaemia and quality of sleep in patients with chronic obstructive lung disease. Thorax 1986;41:846–854.
44. Zhang L, Samet J, Caffo B, Bankman I, Punjabi NM. Power spectral analysis of EEG activity during sleep in cigarette smokers. Chest 2008;133:427–432.
45. Phillips BA, Cooper KR, Burke TV. The effect of sleep loss on breathing in chronic obstructive pulmonary disease. Chest 1987;91:29–32.
46. Phillipson EA. Control of breathing during sleep. Am Rev Respir Dis 1978;118:909–939.
47. Douglas NJ, White DP, Pickett CK, Weil JV, Zwillich CW. Respiration during sleep in normal man. Thorax 1982;37:840–844.
48. Mulloy E, McNicholas WT. Ventilation and gas exchange during sleep and exercise in severe COPD. Chest 1996;109:387–394.
49. Johnson MW, Remmers JE. Accessory muscle activity during sleep in chronic obstructive pulmonary disease. J Appl Physiol 1984;57:1011–1017.
50. Redolfi S, Yumino D, Ruttanaumpawan P, Yau B, Su M-C, Lam J, Bradley TD. Relationship between overnight rostral fluid shift and obstructive sleep apnea in nonobese men. Am J Respir Crit Care Med 2009;179:241–246.
51. Novali M, Piana GL, Montemurro LT, Bertella E, Redolfi S, Corda L, Tantucci C. Predictive factors of sleep oxygen desaturation in COPD patients without daytime respiratory failure and OSAH [abstract]. Am J Respir Crit Care Med 2008;177:A935.
52. Poulain M, Doucet M, Major GC, Drapeau V, Series F, Boulet L-P, Tremblay A, Maltais F. The effect of obesity on chronic respiratory diseases: pathophysiology and therapeutic strategies. Can Med Assoc J 2006;174:1293–1299.
53. Mulloy E, McNicholas WT. Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1993;148:1030–1036.
54. McNicholas WT, Calverley PMA, Lee A, Edwards JC. Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD. Eur Respir J 2004;23:825–831.
55. Ryan S, Doherty LS, Rock C, Nolan G, McNicholas WT. Effects of salmeterol on sleeping oxygen saturation in chronic obstructive pulmonary disease. Respiration 2009; E-pub ahead of print August 14, 2009.
56. Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204–212.
57. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979.
58. Luc G, Bard J-M, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P, Arveiler D, Fruchart J-C, Ducimetiere P. C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease: the Prime Study. Arterioscler Thromb Vasc Biol 2003;23:1255–1261.
59. Miller M, Zhan M, Havas S. High attributable risk of elevated C-reactive protein level to conventional coronary heart disease risk factors: the Third National Health and Nutrition Examination Survey. Arch Intern Med 2005;165:2063–2068.
60. Yao M, Tachibana N, Okura M, Ikeda A, Tanigawa T, Yamagishi K, Sato S, Shimamoto T, Iso H. The relationship between sleep-disordered breathing and high-sensitivity C-reactive protein in Japanese men. Sleep 2006;29:661–665.
61. Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129–1134.
62. Ryan S, Nolan GM, Hannigan E, Cunningham S, Taylor C, McNicholas WT. Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity. Thorax 2007;62:509–514.
63. Taheri S, Austin D, Lin L, Nieto FJ, Young T, Mignot E. Correlates of serum C-reactive protein (CRP): no association with sleep duration or sleep disordered breathing. Sleep 2007;30:991–996.
64. Kohler M, Ayers L, Pepperell JCT, Packwood KL, Ferry B, Crosthwaite N, Craig S, Siccoli MM, Davies RJO, Stradling JR. Effects of continuous positive airway pressure on systemic inflammation in patients with moderate to severe obstructive sleep apnoea: a randomised controlled trial. Thorax 2009;64:67–73.
65. Joppa P, Petrasova D, Stancak B, Tkacova R. Systemic inflammation in patients with COPD and pulmonary hypertension. Chest 2006;130:326–333.
66. Sin DD, Man SFP. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514–1519.
67. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:250–255.
68. Fogarty AW, Jones S, Britton JR, Lewis SA, McKeever TM. Systemic inflammation and decline in lung function in a general population: a prospective study. Thorax 2007;62:515–520.
69. de Torres JP, Pinto-Plata V, Casanova C, Mullerova H, Cordoba-Lanus E, Muros de Fuentes M, Aguirre-Jaime A, Celli BR. C-reactive protein levels and survival in patients with moderate to very severe chronic obstructive pulmonary disease. Chest 2008;133:1336–1343.
70. Hurst JR, Donaldson GC, Perera WR, Wilkinson TMA, Bilello JA, Hagan GW, Vessey RS, Wedzicha JA. Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:867–874.
71. Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factor κB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174:824–830.
72. Mehra R, Storfer-Isser A, Kirchner HL, Johnson N, Jenny N, Tracy RP, Redline S. Soluble interleukin 6 receptor: a novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med 2006;166:1725–1731.
73. Hurst JR, Perera WR, Wilkinson TMA, Donaldson GC, Wedzicha JA. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:71–78.
74. Garvey JF, Taylor CT, McNicholas WT. Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation. Eur Respir J 2009;33:1195–1205.
75. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 2008;453:807–811.
76. Agusti A, Morla M, Sauleda J, Saus C, Busquets X. NF-κB activation and i-NOS upregulation in skeletal muscle of patients with COPD and low body weight. Thorax 2004;59:483–487.
77. Cesari M, Penninx BWJH, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, Rubin SM, Ding J, Simonsick EM, Harris TB, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC Study. Circulation 2003;108:2317–2322.
78. Drost EM, Skwarski KM, Sauleda J, Soler N, Roca J, Agusti A, MacNee W. Oxidative stress and airway inflammation in severe exacerbations of COPD. Thorax 2005;60:293–300.
79. Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, Shale DJ. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1414–1418.
80. Takabatake N, Nakamura H, Abe S, Inoue S, Hino T, Saito H, Yuki H, Kato S, Tomoike H. The relationship between chronic hypoxemia and activation of the tumor necrosis factor-α system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1179–1184.
81. Dyugovskaya L, Lavie P, Lavie L. Phenotypic and functional characterization of blood γδ T cells in sleep apnea. Am J Respir Crit Care Med 2003;168:242–249.
82. MacNee W. Oxidants/antioxidants and COPD. Chest 2000;117:303S–317S.
83. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82:47–95.
84. Schulz R, Mahmoudi S, Hattar K, Sibelius ULF, Olschewski H, Mayer K, Seeger W, Grimminger F. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea: impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 2000;162:566–570.
85. Chen L, Einbinder E, Zhang Q, Hasday J, Balke CW, Scharf SM. Oxidative stress and left ventricular function with chronic intermittent hypoxia in rats. Am J Respir Crit Care Med 2005;172:915–920.
86. Lavie L, Vishnevsky A, Lavie P. Evidence for lipid peroxidation in obstructive sleep apnea. Sleep 2004;27:123–128.
87. Keaney JF Jr, Larson MG, Vasan RS, Wilson PWF, Lipinska I, Corey D, Massaro JM, Sutherland P, Vita JA, Benjamin EJ. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler Thromb Vasc Biol 2003;23:434–439.
88. Hayakawa M, Miyashita H, Sakamoto I, Kitagawa M, Tanaka H, Yasuda H, Karin M, Kikugawa K. Evidence that reactive oxygen species do not mediate NF-κB activation. EMBO J 2003;22:3356–3366.
89. Dyugovskaya L, Polyakov A, Lavie P, Lavie L. Delayed neutrophil apoptosis in patients with sleep apnea. Am J Respir Crit Care Med 2008;177:544–554.
90. Nácher M, Serrano-Mollar A, Farré R, Panés J, Seguí J, Montserrat JM. Recurrent obstructive apneas trigger early systemic inflammation in a rat model of sleep apnea. Respir Physiol Neurobiol 2007;155:93–96.
91. Dyugovskaya L, Lavie P, Lavie L. Lymphocyte activation as a possible measure of atherosclerotic risk in patients with sleep apnea. Ann N Y Acad Sci 2005;1051:340–350.
92. Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002;165:934–939.
93. Noguera A, Busquets X, Sauleda J, Villaverde JM, MacNee W, Agusti Alvar GN. Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:1664–1668.
94. Noguera A, Sala E, Pons AR, Iglesias J, MacNee W, Agusti AGN. Expression of adhesion molecules during apoptosis of circulating neutrophils in COPD. Chest 2004;125:1837–1842.
95. Sauleda J, Garcia-Palmer FJ, Gonzalez G, Palou A, Agusti AGN. The activity of cytochrome oxidase is increased in circulating lymphocytes of patients with chronic obstructive pulmonary disease, asthma, and chronic arthritis. Am J Respir Crit Care Med 2000;161:32–35.
96. McNicholas WT. Diagnosis of obstructive sleep apnea in adults. Proc Am Thorac Soc 2008;5:154–160.
Correspondence and requests for reprints should be addressed to Walter T. McNicholas, M.D., Pulmonary and Sleep Disorders Unit, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland. E-mail:

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