COPD and Sleep Apnea Syndrome – Impact and Interaction of Coexisting Disease

COPD includes heterogeneous lesions that variably affect the airways, lung parenchyma and systemic structures. COPD is caused by various pathogenic mechanisms and does not present a uniform histological substrate. Patients with this disease present with different clinical features: non-exacerbator with emphysema or chronic bronchitis; mixed COPD-asthma; exacerbator with emphysema and exacerbator with chronic bronchitis (Miravitlles et al., 2013). In addition to affecting the lungs, the disease presents significant systemic consequences including skeletal muscle dysfunction, nutritional disorders and weight loss (Andreassen &


Introduction
Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases (Global Strategy for the Diagnosis, 2013).
The chronic airflow limitation characteristic of COPD is caused by a mixture of small-airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema). The relative contributions of each vary from person to person. Chronic inflammation causes structural changes and narrowing of the small airways.
Symptoms of COPD include sputum production, cough and dyspnea. These respiratory symptoms are chronic and progressive over time. As a result, subjects increasingly experience deterioration in their health-related quality of life, in their capacity to work and reduced participation in social and physical activities (Rabe et al., 2007).
COPD includes heterogeneous lesions that variably affect the airways, lung parenchyma and systemic structures. COPD is caused by various pathogenic mechanisms and does not present a uniform histological substrate. Patients with this disease present with different clinical features: non-exacerbator with emphysema or chronic bronchitis; mixed COPD-asthma; exacerbator with emphysema and exacerbator with chronic bronchitis (Miravitlles et al., 2013). In addition to affecting the lungs, the disease presents significant systemic consequences including skeletal muscle dysfunction, nutritional disorders and weight loss (Andreassen & Treatment with continuous positive airway pressure (CPAP) has been shown to decrease the frequency and severity of sleep disturbances and associated symptoms (Kiely et al., 1999). Other treatments include mandibular advancement prosthesis (Doff et al., 2013) or surgery (Tuncel et al., 2012).
OSAS may coexist with COPD and this combination has been the focus of extensive study. Fenley referred to it as ''overlap syndrome" (Flenley, 1985). Recently, to encourage further research in this area, another terminology has been proposed to integrate OSAS in the setting of obstructive lung disease, which is called OLDOSA (obstructive lung disease and obstructive sleep apnea) (Ioachimescu & Teodorescu, 2013).
The aim of the present review is to analyse the association and interaction of obstructive sleep apnea syndrome and chronic obstructive lung disease.

Epidemiology
There have been a number of studies evaluating the presence of OSAS among COPD patients. Chaouat et al. found a 14% prevalence of OSAS among patients with mild COPD (Chaouat et al., 1995), and O'Brien found overlap syndrome in 11.9% of COPD patients (O'Brien & Whitman, 2005).
On the other hand, there have also been studies evaluating the presence of COPD among patients with OSAS. In a group of 265 OSAS patients, Chaouat found that 11% also had COPD (Chaouat et al., 1995). Sanders et al. found 11% of overlap syndrome among patients with OSAS (Sanders et al., 2003). Nevertheless, a very large study including 5,954 participants done in conjunction with the Sleep Heart Health Study found no significant difference in the prevalence of OSAS, defined as apnea hypopnea index greater than 10, among COPD subjects (14.0%) and those without COPD (18.6%) (Sanders et al., 2003). A study involving 356 males and 320 females with OSAS found a lower prevalence of overlap syndrome (9.2%) (Bednarek et al., 2005). Recently, in 524 male subjects with OSAS diagnosed by the prevalence rate of COPD was 12% (Shiina et al., 2012).
All of this suggests that the coexistence of COPD and OSAS is due more to chance than a pathophysiologic link between the two conditions.
Among the different phenotypes that constitute COPD, OSAS is preferably associated to chronic bronchitis. Study results COPDGene showed that patients with chronic bronchitis phenotype showed prevalence of OSAS 22.4% versus 14.4% in those who did not meet this criterion (Kim et al., 2011). These findings are consistent with the idea that the chronic bronchitis patient may present episodic nocturnal desaturations during REM sleep. Izquierdo et al. also found that the prevalence of OSAS is more prevalent in the phenotype chronic bronchitis and emphysema, compared to COPD and asthma (23.6, 4.9% and 12.5%, respectively (Izquierdo-Alonso et al., 2013).

Physiopatological consequences
Sleep has profound effects on ventilation (Douglas et al., 1982), partly because it is accompanied by a fall in metabolic rate (White et al., 1985). Sleep represents a challenge to the respiratory system, especially in patients debilitated by respiratory disease. As occurs in some respiratory diseases, patients affected by respiratory failure while awake, are even more seriously affected during sleep.
In overlap syndrome, ventilatory response may be disturbed by lung mechanics and gas exchange. Radwan et al. studied breathing pattern and CO 2 response in obese patients with overlap syndrome and obese patients with OSAS only. The OSAS group presented similar values to non-obese controls in ventilatory response to CO 2 and occlusion pressure responses. The overlap group had a higher breathing frequency and lower tidal volume than the OSASonly group. This author concluded that overlap patients with hypercapnia had both blunted ventilatory and mouth occlusion pressure responses during CO 2 . In patients with chronic hypercapnia, there is an increased blood bicarbonate concentration, which may inhibit CO 2 sensitivity and decreases mouth occlusion pressure response (Radwan et al., 1995).
In patients with overlap syndrome, sleep-related hypoventilation is associated to a reduction in respiratory drive, loss of accessory muscle activity and ventilation perfusion mismatch. Hypoventilation in such patients is due to an increased breathing effort, related to upper and lower airway obstruction. Respiratory muscles may also fatigue which is related to the mechanical disadvantage of chest wall hyperinflation. Moreover, there is also a reduction in functional residual capacity which is related to supine posture and sleep state (McNicholas, 1997). Kwon et al. suggest that increased severity of hyperinflation is associated with worse sleep efficiency, independent of apnea and nocturnal hypoxemia. The mechanisms underlying this observation are uncertain. These authors speculate that therapies aimed at reducing lung hyperinflation may improve sleep quality in patients with overlap syndrome (Kwon et al., 2009).
Overlap patients present more nocturnal desaturation than patients with either OSAS or COPD alone (Chaouat et al., 1995;Sanders et al., 2003). Sanders examined the degree to which COPD and OSAS independently and jointly contribute to desaturation during sleep. After adjusting for age, sex, height, weight, race, smoking status, and awake oxygen saturation, the OR for nocturnal oxyhemoglobin desaturation was found to be considerably increased in OSAS patients (Sanders et al., 2003). Furthermore, Lacedonia suggest that day-time hypoxemia in overlap patients is largely determined by the increase of body weight and severity of nocturnal hypoxia (Lacedonia et al., 2013).

Pulmonary hypertension
Patients with overlap syndrome are more likely to develop daytime pulmonary hypertension (Weitzenblum et al., 1988) and right heart failure (Bradley & Phillipson, 1985) than patients with either condition alone. COPD patients are affected by pulmonary hypertension secondary to alveolar hypoxia (Bonsignore et al., 1994), which is associated to increased morbidity and mortality (Chaouat et al., 2005). In these patients, pulmonary hypertension is primarily observed in those with severe disease, when the FEV 1 is lower than 50% predicted and diurnal PaO 2 is less than 60 mm Hg (Ashutosh et al., 1983).
OSAS patients may also be affected by pulmonary hypertension (Bady et al., 2000). However, this impact is higher when associated with COPD. In fact, Hawrylkiewicz et al. found a prevalence of pulmonary hypertension among overlap patients of 80% compared to 16% among individuals with OSAS alone (Hawrylkiewicz et al., 2004).
Patients with simultaneous COPD and OSAS have a more serious sleep related oxygen desaturacion than patients with COPD alone and the same degree of bronchial obstruction. Chaouat et al. reported a PaO2 ≤ 65 mm Hg in 54 (23%) out of 235 non-OSAS COPD patients and compared to 17 (57%) out of 30 patients with overlap syndrome (Chaouat et al., 1995). In the same report, right-heart catheterization identified pulmonary hypertension in 7% of patients with COPD and 36% of those with overlap syndrome. In fact, hypoxemia, hypercapnia, and pulmonary hypertension were observed in the presence of even mild to moderate bronchial obstruction in overlap patients (Fletcher et al., 1987). When COPD reaches an advanced-stage, concomitant OSAS is likely to cause significant adverse clinical consequences (Hiestand & Phillips, 2008).

Sleep apnea syndrome and COPD association and vascular disease
COPD is a systemic disease with multiple effects on target-organs including cardiovascular system. Until recently, exacerbations of disease and progression of respiratory insufficiency have been the focus of mortality studies in COPD, however, a number of epidemiologic reports have shown that significant morbidity and mortality in COPD involves cardiovascular diseases.
In France, Fuhrman et al found that cardiovascular disease accounted for 32% of deaths in COPD patients (Fuhrman et al., 2006). Similar results were obtained in previous retrospective studies conducted in Canada (Huiart et al., 2005;Curkendall et al., 2006). In these reports, cardiovascular morbidity and mortality were higher in the COPD group than in the general population.
Moreover, some prospective reports have shown that FEV 1 is a factor that predicts mortality risk from all causes and specifically mortality from ischemic heart disease in both genders independently of the smoking habit (Schunemann et al., 2000). In Spain, De Lucas-Ramos et al. in a cross sectional multicentre study of 572 COPD patients found a prevalence of 16.4% of ischemic heart disease (De Lucas-Ramos et al., 2008). In a subsequent paper of 1200 COPD patients and 300 control subjects, these authors found that COPD was an independent risk factor for cardiovascular disease with an odds ratio of 2.23 (1.18 to 4.24) (De Lucas-Ramos et al., 2012). However, Izquierdo et al, in another case-control study found no association between ischemic heart disease and COPD and concluded that the higher prevalence of traditional cardiovascular risk factors in patients with COPD may explain the higher incidence of ischemic heart disease in these patients (Izquierdo et al., 2010). It has also been found that homocysteine in blood, another marker for cardiovascular disease, was elevated in severe stable COPD patients (Seemungal et al., 2007). In a three-year followup study of a cohort of 3247 subjects, Nunomiya  Systemic inflammation is increasingly being recognized as a risk factor for a number of complications including atherosclerosis (Ross, 1999) and is a well-established factor in the pathogenesis of cardiovascular disease (Hansson, 2005). C-reactive protein is an important serum marker of inflammation with major implications for cardiovascular morbidity and atherogenesis (Rutter et al., 2004). C-reactive protein levels are increased in OSAS in accordance with disease severity ( As inflammatory diseases, both OSAS and COPD are associated to higher cardiovascular risk. The mechanisms that may be involved different factors and include vascular inflammation, endothelial dysfunction, and tonic elevation of sympathetic neural activity (Figure 1).

Clinical characteristics
The most common symptoms of OSAS patients include chronic loud snoring, excessive daytime sleepiness, personality changes, depression, impairment of thinking and deterioration of quality of life ( In fact, significant differences were only found with respect to healthy subjects (Weitzenblum et al., 2008).
In addition, some studies have shown that overlap syndrome has a major impact on quality of life. Mermigkis studied 30 subjects with overlap syndrome and 15 control subjects. Quality of life was determined by St George's Respiratory Questionnaire. The control group included subjects with COPD and no evidence of OSAS by polysomnography. All subjects were habitual snorers with normal Epworth Sleepiness Scale scores. Significant differences were found in total score and in each of the three questionnaire components suggesting worse quality of life in overlap patients. It is fair to say that OSAS has a major impact on quality of life in patients with overlap syndrome and can exist in COPD patients with habitual snoring even in the absence of daytime sleepiness (Mermigkis et al., 2007).

Diagnostic procedures
The diagnosis of OSAS should be based on clinical findings and confirmed by polysomnography which has traditionally been regarded as the gold standard for diagnosis (Kushida et al., 2005

Treatment
Conventional oxygen therapy is prescribed to stable COPD patients who exhibit marked and persistent hypoxemia. This therapy is sufficient to correct even severe nocturnal desaturation and has favourable effects on the observed hypoxemia-related peaks in pulmonary hypertension (Boysen et al., 1979). Furthermore, some authors report that oxygen therapy improves the quality of sleep by shortening latency to sleep, increasing REM sleep as well as stages III and IV, and by decreasing number of arousals (Calverley et al., 1982).
All patients with OSAS should be counselled about the potential benefits of therapy and the risks of going without treatment as well as the value of avoiding factors that increase the severity of upper-airway obstruction, such as sleep deprivation; the use of alcohol, sedatives, and hypnotic agents; and excessive weight (Haynes, 2005). CPAP therapy is a well-established, widely used treatment (Giles et al., 2006), but, it is not suitable for all patients.
The coexistence of OSAS and COPD defines a high-risk group of patients because their awake and sleep related hypoxemia and hypoxemic cardiovascular consequences are more marked.
Although the natural history of overlap syndrome is not well-known, a major aim of therapy should be to correct both upper airway obstructive episodes and sleep hypoxemia. Sampol studied a group of overlap patients over three consecutive nights. This study found that the application of CPAP corrected apneas and hypopneas, but not oxygen desaturation.
With the addition of oxygen at a flow of 1.5 L.min-1 at suboptimal CPAP levels, they observed an increase in apnea frequency, persistence of apneas at CPAP levels which eliminated them when no supplemental oxygen was administered, and longer duration of apneas and hypopneas. However, when the effective CPAP level was reached with supplemental oxygen, its efficacy in eliminating apneas and hypopneas was maintained and, furthermore, oxygen desaturation was corrected. The authors conclude that CPAP with supplemental oxygen constitutes a practical therapeutic alternative for hypoxic patients with overlap syndrome (Sampol et al., 1996).
De Miguel evaluated the effects of CPAP therapy on lung function in patients with overlap syndrome over two consecutive years. After six months of CPAP therapy, there were statistically significant increases in PaO 2 , FEV 1 , and FVC, accompanied by significant decreases in PaCO 2 , serum bicarbonate levels, and alveolar-arterial oxygen difference. However, these patients also had significant weight loss during this time, which may explain the benefits observed. Also, the degree of obstruction, as reflected by the FEV 1 /FVC ratio, did not change.
Interestingly, there was no improvement from six to eighteen months, a period in which there were no changes in patient weight. Response of overlap syndrome patients to CPAP therapy was greater in the hypercapnic group, particularly in relation to improvement of arterial blood gases 13 .
Mansfield and Naughton studied fourteen patients, ten of whom were able to tolerate CPAP for at least three months. They found an improvement in gas exchange and FEV 1 associated with a decrease in hospitalizations (Mansfield & Naughton, 1999). Similar results were reported by other studies (Peker et al., 1997;Marin et al., 2010).
CPAP treatment may have other potentially beneficial effects. Seeing as COPD is an inflammatory airways disorder and OSAS may act as an inflammatory stimulus, coexistent of both diseases in overlap may augment airway inflammation. Thus, the improvement in OSAS resulting from the application of CPAP may, in turn, lead to an improvement in the coexistent COPD. In some studies, the improvement in some markers of bronchial hyper responsiveness following the application of CPAP suggests the possibility that CPAP therapy may have a bronchodilator effect (Chan et al., 1988).
A decrease of serum C reactive protein in overlap patients following effective CPAP treatment shows that CPAP is an effective treatment method for systemic inflammation (Nural et al., 2013) Nocturnal oxygen attenuates sleep desaturations among stable overlap patients and does not produce clinically significant increases in PaCO2. However, hypoxemia and hipercapnic may persist in the most severe overlap patients in spite of efficient application of nocturnal CPAP and oxygen therapy. For these patients, some authors recommend nocturnal treatment with positive pressure ventilators, and the monitoring of treatment effectiveness by sleep study (Marrone et al., 2006).

Prognosis
Regarding the complications that modify the natural history of COPD, it has previously been shown that, compared to COPD-only patients, overlap syndrome patients are at an increased risk for respiratory failure, pulmonary hypertension and cor pulmonale, independently of the degree of airway obstruction ( In order to evaluate the cost-effectiveness of early interventions and disease management programs, Shaya studied the economic impact of OSAS among Medicaid beneficiaries with COPD. The diagnosis of concomitant COPD was associated with substantially higher medical utilization and cost than the diagnosis of either alone, and OSAS may add additional economic burden on beneficiaries who already have COPD or concomitant COPD (Shaya et al., 2009).
Machado carried out a prospective cohort study of 603 hypoxemic COPD patients receiving long-term oxygen therapy, 95 subjects were diagnosed with moderate-to-severe OSAS. After adjusting for several confounders, patients treated with CPAP had a significantly lower risk of death (Machado et al., 2009). This observational study indicated a positive effect of CPAP treatment on survival in moderate-to severe OSAS patients with hypoxemic COPD receiving long-term oxygen therapy. This study recommends an active search for OSAS in patients with hypoxemic COPD using a screening questionnaire and/or nocturnal oximetry.
Overlap syndrome exhibit both increased overall and cardiovascular mortality in patients with COPD. Marin et al. in a cohort of patients with SAS followed for nine years, patients with COPD and SAS had a relative risk of death of 1.79 (1.16 to 2.77), with cardiovascular and pulmonary causes the most common mortality even adjusted for the severity of COPD.
In conclusion, overlap syndrome constitutes a worsening of the complications inherent in either COPD or OSAS alone. Early identification and treatment of overlap syndrome is fundamental in order to avoid serious potential effects.