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The Proceedings of the American Thoracic Society 5:237-241 (2008)
© 2008 The American Thoracic Society
doi: 10.1513/pats.200706-077MG
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Overlap Syndrome

Obstructive Sleep Apnea in Patients with Chronic Obstructive Pulmonary Disease

Emmanuel Weitzenblum1, Ari Chaouat2, Romain Kessler1 and Matthieu Canuet1

1 Département de Pneumologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; and 2 Service des Maladies Respiratoires et Réanimation Respiratoire, Centre Hospitalier Universitaire de Nancy, Vandoeuvre les Nancy, Nancy, France

Correspondence and requests for reprints should be addressed to Emmanuel Weitzenblum, Professor of Medicine and Pulmonology, Hôpital de Hautepierre, 67098 Strasbourg, France. E-mail: emmanuel.weitzenblum{at}chru-strasbourg.fr

ABSTRACT

Chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome (SAHS) are both common diseases affecting respectively 10 and 5% of the adult population over 40 years of age, and their coexistence, which is denominated overlap syndrome, can be expected to occur in about 0.5% of this population. A recent epidemiologic study has shown that the prevalence of SAHS is not higher in COPD than in the general population, and that the coexistence of the two conditions is due to chance and not through a pathophysiologic linkage between these two diseases. Patients with overlap have a more important sleep-related O2 desaturation than do patients with COPD with the same degree of bronchial obstruction. They have an increased risk of developing hypercapnic respiratory insufficiency and pulmonary hypertension when compared with patients with SAHS alone and with patients with "usual" COPD. In patients with overlap, hypoxemia, hypercapnia, and pulmonary hypertension can be observed in the presence of mild to moderate bronchial obstruction, which is different from "usual" COPD. Therapy of the overlap syndrome consists of nasal continuous positive airway pressure or nocturnal noninvasive ventilation (NIV), with or without associated nocturnal O2. Patients who are markedly hypoxemic during daytime (PaO2 < 55–60 mm Hg) should be given conventional long-term O2 therapy in addition to nocturnal ventilation.

Key Words: chronic obstructive pulmonary disease • sleep apnea-hypopnea syndrome • overlap syndrome • noninvasive ventilation • nasal continuous positive airway pressure

Both chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome (SAHS) are common diseases, and many individuals would be expected to have both conditions by chance alone (1). It has been believed that the presence of COPD could predispose to the development of SAHS (2), since the two conditions share some etiologic factors such as tobacco smoking. In fact, this remained an unresolved question (3) up to very recent years. In 2003 the Sleep Heart Health Study (SHHS) provided us with solid epidemiologic data about the coexistence of COPD and SAHS (4).

DEFINITIONS

The combination of chronic obstructive pulmonary disease and sleep apnea-hypopnea syndrome has been denominated "overlap syndrome" by the late David Flenley (5). In his opinion the term "overlap syndrome" could apply as well to the coexistence of SAHS and any chronic respiratory disease such as idiopathic pulmonary fibrosis or cystic fibrosis (5), but the use of this term is generally limited to the association of SAHS and COPD.

COPD is presently defined by the presence of an obstructive ventilatory defect characterized by an FEV1/FVC ratio less than 70% in patients not exhibiting any other chronic respiratory disease (6). There is presently no standardized definition of SAHS. Generally, both a given level of respiratory disturbance index or apnea-hypopnea index (>= 10/h, >= 15/h, etc.) and the presence of symptoms (daytime sleepiness, poor quality of sleep, etc.) are required (7).

PREVALENCE OF THE OVERLAP SYNDROME: IS SAHS MORE PREVALENT IN COPD THAN IN THE GENERAL POPULATION?

Previous studies have suggested that the prevalence of SAHS in patients with COPD, and of COPD in patients with SAHS, was high (2, 3, 8, 9)—sometimes unexpectedly high (2). The earliest report suffered from methodologic biases, since the 26 patients with COPD investigated by Guilleminault and coworkers (2) had been in fact referred to a sleep clinic because they complained of excessive daytime somnolence. This probably explains why sleep apneas were found in as many as 22/26 patients. In studies by Bradley and colleagues (8, 9) and by Chaouat and coworkers (3) in which consecutive patients with SAHS were investigated (n = 50 and 265, respectively) the prevalence of an associated COPD, defined by the presence of bronchial obstruction (either FEV1/FVC < 70% [8, 9] or FEV1/VC < 60% [3]) was, respectively, of 14% (9) and 11% (3). These figures were considered as high, suggesting that the prevalence of COPD in SAHS exceeded that observed in the general population (3), but it must be underlined that at that time there were very few reliable epidemiologic studies about the prevalence of COPD in the general population (10, 11). We presently know that the prevalence of COPD, defined by an FEV1/FVC ratio less than 70% (GOLD stages I–IV [12]) is over 10% in adults 40 years of age or older, and may exceed 20% (13–16). The 265 patients with SAHS investigated by Chaouat and colleagues (3) had a mean age of 54 ± 10 years; 92% were males, and 66% were current smokers or ex-smokers. In such a cohort a prevalence of COPD greater than 10% may be expected. Thirty out of 265 patients had COPD (3). Accordingly, it does not appear that the prevalence of COPD is increased in patients with SAHS, when compared with the general population.

A putative association between SAHS and COPD could be explained by the fact that the two conditions are favored by a common etiologic factor, namely smoking. In fact, if the role of smoking is well established in COPD (6, 17), on the contrary smoking is not presently considered as a documented risk factor for SAHS, even if earlier studies (18) have suggested that smoking could favor the occurrence of obstructive sleep apneas.

The only way to assess the prevalence of SAHS in COPD, and to confirm whether this prevalence is higher or not than in the general population, is to undertake a large epidemiologic study. It should be emphasized that earlier studies on the overlap syndrome (2, 3, 8, 9) have evaluated relatively small samples and have included patients referred to Sleep Laboratories or Respiratory Disease Clinics, which results in a selection bias (4). The Sleep Heart Health Study (SHHS) is a prospective multicenter cohort study that was designed to assess whether SAHS is a risk factor for hypertension and cardiovascular diseases (19).

It is the largest study to date but it must be underlined that it focused on a population enriched for cardiovascular risk profiles (including smoking).

Participants were recruited from ongoing cohort studies. They were at least 40 years old and had not received positive airway pressure treatment for sleep apnea nor supplemental oxygen. They underwent unattended home polysomnography, and spirometry was performed in all subjects (4). A total of 5,954 participants had complete spirometric data. Obstructive airway disease (OAD), which is synonymous of COPD, was defined by an FEV1/FVC ratio less than 70% (20), which is in agreement with the present consensual definition of COPD (6).

The main results of the SHHS are the following (4): the average FEV1/FVC of the cohort was 75.5 ± (SD) 7.9%. Subjects with OAD(n = 1,138, 19%) had a mean FEV1/FVC of 63.8 ± 6.6%, and those without OAD (n = 4,816, 81%) had a mean FEV1/FVC of 78.3 ± 5.3%. Only a small number of participants (n = 226, 3.8%) had an FEV1/FVC ratio less than 60%. The respiratory disturbance index (RDI), that is, the average number of apneas plus hypopneas per hour of sleep, was not higher in subjects with OAD than in subjects without OAD. On the contrary, participants with OAD had significantly lower mean and median RDI than those without OAD (4) (Table 1). However, after stratification by BMI quartile, RDI values were similar in the participants with and without OAD (4).


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  		TABLE 1. RESPIRATORY DISTURBANCE INDEX ACCORDING TO THE PRESENCE OR NOT OF OBSTRUCTIVE PULMONARY DISEASE

 
Thus, the prevalence of SAHS, defined either as an RDI greater than 10 or greater than 15, is not greater in subjects with COPD than in those without COPD among the general population. It ensues that the coexistence of COPD and SAHS is due to chance rather than through a pathophysiologic linkage between the two conditions (4).

The very low percentage of subjects with severe COPD may limit the bearing of these results, which cannot be automatically transposed to patients with advanced COPD. Nevertheless, the findings of Sanders and coworkers (4) do not support the hypothesis that the presence of COPD favors the coexistence of SAHS and vice versa. If the overlap syndrome is observed in a relatively high number of subjects (or patients), it is simply because COPD and SAHS are both frequent conditions. If COPD is present in about 10% of the adult population 40 years of age or older (13–15), and if the prevalence of SAHS in the same population is in the range of 5 to 10% (21–24), overlap syndrome can be expected to be present in 0.5 to 1% of the population over 40 years of age, which is a far from being negligible.

CLINICAL AND PULMONARY FUNCTION FEATURES IN THE OVERLAP SYNDROME

Quality of Sleep
Many patients with COPD complain of poor-quality sleep, and objective evidence of disturbed sleep in COPD has been demonstrated by adequate EEG studies (25–29): sleep efficiency is reduced, sleep onset is delayed, total sleep time is reduced, and periods of wakefulness are frequent and sometimes prolonged. The causes of this poor-quality sleep are probably multifactorial and include nocturnal cough, nocturnal dyspnea, use of drugs, and the effects of ageing on sleep. In fact, these earlier studies (25–29) have included patients with severe COPD with marked daytime hypoxemia. On the other hand, the SHHS (4) mentioned above, where 1,138 participants with mild COPD were investigated, has shown that in the absence of sleep apnea, sleep was minimally perturbed. No significant differences were observed in sleep architecture in the subjects with the lowest compared with the highest FEV1 quartile (4). Thus, COPD per se does not affect the quality of sleep. Sanders and colleagues (4) have observed that subjects with overlap, compared with subjects who had only obstructive airway disease, had higher Epworth sleepiness scores, lower total sleep time, lower sleep efficiency, and higher arousal index. Only small differences were found between subjects with SAHS alone and those with both disorders (subjects with overlap) (4). Thus, the quality of sleep in COPD is influenced by the presence of SAHS but not by the severity of airway obstruction (4).

Severity of Respiratory Events and of Nocturnal Desaturation
Having prospectively investigated a series of 265 patients who were selected on the basis of a confirmed diagnosis of SAHS (apnea-hypopnea index > 20/h), Chaouat and coworkers (3) have found an obstructive spirographic pattern (FEV1/VC ratio <= 60%) in 30/265 patients. These patients with overlap did not differ from the remainder by their apnea index or apnea-hypopnea index (Table 2), but nocturnal hypoxemia was more important in patients with overlap than in patients with SAHS alone (P < 0.05). The average FEV1/VC of the 30 overlap patients was 50 ± 6% (Table 3) (3), which is lower than the average FEV1/FVC of 63.8 ± 6.6% in the SHHS (4), a difference that can be explained by the fact that Chaouat and colleagues (3) have investigated consecutive patients, whereas the SHHS (4) has enrolled participants from the general population. In spite of these differences, the SHHS (4) has also clearly demonstrated that subjects with both SAHS and COPD had greater sleep desaturation than those with only one disorder. After adjusting for age, sex, height, race, smoking status, and awake SpO2, the OR for oxyhemoglobin saturation below levels of 90 and 85% for more than 5% of total sleep time was 20-fold greater in participants with SAHS alone compared with those who had neither disorder and 30-fold greater in participants with both disorders (subjects with overlap) (4).


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  		TABLE 2. APNEAS, HYPOPNEAS, AND NOCTURNAL OXYGEN SATURATION IN A SERIES OF 265 CONSECUTIVE PATIENTS WITH SAHS: COMPARISON OF PATIENTS WITH SAHS ALONE (N=235) TO PATIENTS WITH OVERLAP (SAHS + COPD)

 

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  		TABLE 3. PULMONARY FUNCTION DATA AND ARTERIAL BLOOD GASES IN PATIENTS WITH OVERLAP COMPARED WITH PATIENTS WITH SAHS ALONE AND WITH PATIENTS WITH THE OBESITY-HYPOVENTILATION SYNDROME

 
Consequently the risk of significant nocturnal desaturation is clear in patients who exhibit some degree of daytime hypoxemia, which is the case of the patients with overlap investigated by Chaouat and coworkers (3), but is also present in subjects with less severe overlap, as those recruited in the SHHS (4).

Pulmonary Function and Arterial Blood Gases
The results of spirography and arterial blood gases in a series of 30 patients with overlap (3) are given in Table 3. They are compared with those of patients with SAHS alone (3) and also to a series of patients with obesity-hypoventilation (30). As mentioned above, "patients" with overlap have lower pulmonary volumes and lower FEV1/VC ratio than do "subjects" with overlap enrolled in cohort studies like the SHHS (4), and these differences might be explained by the different ways of recruitment. On the other hand, the 20 patients with overlap investigated by Alford and colleagues (31) were hospitalized and had an average FEV1/FVC of 63.7 ± 10.9%, which is very similar to the average value of the SHHS participants exhibiting an OAD (63.8 ± 6.6%).

By definition, patients with overlap have an obstructive ventilatory pattern that is most often mild to moderate, with an average FEV1 of 1,580 ± 560 ml (52 ± 15% of the predicted value) in the series of Chaouat and coworkers (3) (Table 3). Total lung capacity ranges within normal limits (no static hyperinflation).

The coexistence of COPD and SAHS favors the presence of hypoxemia, which is rarely observed in patients with SAHS alone (Table 3). In the study by Chaouat and colleagues (3), 17/30 (57%) patients with overlap had a PaO2 less than or equal to 65 mm Hg versus 54/235 (23%) of patients with SAHS alone (P < 0.001); 8/30 (27%) patients with overlap were hypercapnic (PaCO2 >= 45 mm Hg) versus 19/235 (8%) patients with SAHS alone (P < 0.05) (3). Of interest, these arterial blood gases results are very similar to those of Alford and coworkers (PaO2 = 65 ± 6.8 mm Hg, PaCO2 = 45.2 ± 6.6 mm Hg) in their 20 patients with overlap whose bronchial obstruction was less pronounced) (31).

Hypoxemia and hypercapnia are more severe in patients with obesity-hypoventilation than in patients with overlap (Table 3), all patients having been investigated in a stable state of the disease, several weeks after any exacerbation (30).

Pulmonary Hypertension
Patients with overlap are at risk of developing pulmonary hypertension (PH) even though their obstructive defect is not severe. Chaouat and colleagues (3) have observed that among the 26 patients with overlap who underwent right heart catheterization, 11 had PH defined by a mean pulmonary artery pressure (Formula) greater than 20 mm Hg (Table 4). The prevalence of PH was of 36% in patients with overlap, much higher than in "usual" SAHS (19/181 = 9%), but somewhat lower than in the obesity-hypoventilation syndrome (Table 4) (30).


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  		TABLE 4. PULMONARY HEMODYNAMICS IN PATIENTS WITH OVERLAP COMPARED WITH PATIENTS WITH SAHS ALONE AND WITH PATIENTS WITH THE OBESITY-HYPOVENTILATION SYNDROME

 
Patients with overlap can develop PH even if they do not exhibit a marked degree of bronchial obstruction. In "usual" COPD, PH is generally observed in the case of severe bronchial obstruction (FEV1 < 50% of the predicted value, and generally <= 1,000 ml) leading to significant hypoxemia. This discordance has been emphasized by several authors (2, 3, 8, 9, 31–35). The hypoxemic–hypercapnic SAHS investigated by Bradley and colleagues (8, 9) exhibited cor pulmonale. The subjects from that study were patients with overlap, but their average FEV1 (2.0 ± 0.31 l) and FEV1/FVC (59 ± 5%) did not indicate severe bronchial obstruction. Similarly, the FEV1/FVC of the patients with overlap investigated by Fletcher and coworkers (34) was close to 60%, which contrasted with marked hypoxemia and PH. This can be explained by the synergistic effects of the diseases on gas exchange and pulmonary hemodynamics (3, 32, 34, 35).

In patients with COPD, PH is generally observed when daytime PaO2 is less than 55 to 60 mm Hg (36). The average daytime PaO2 of the patients with overlap in the study by Chaouat and colleagues (3) was higher (66 ± 10 mm Hg) (Table 3) and only 8/30 had a PaO2 less than 60 mm Hg. It must be kept in mind that if the daytime PaO2 of these patients is about 65 mm Hg, the mean PaO2 during sleep is certainly lower because of the repetition of apneas and hypopneas (the time spent in apnea represented 22 ± 15% of the total sleep time in the overlap group [3]). Thus, the combination of marked nocturnal hypoxemia with a mild to moderate diurnal hypoxemia could explain the occurrence of pulmonary hypertension.

PRINCIPLES OF TREATMENT OF THE OVERLAP SYNDROME

Long-term nasal continuous positive airway pressure (nCPAP) is the first line treatment of SAHS (37). This treatment is efficient in suppressing apneas and hypopneas and sleep-related hypoxemia in patients with SAHS. However, adherence to therapy is poor in some patients and this will negatively influence the long-term results of this treatment. To our knowledge, there are no data about the adherence to treatment in a population with COPD compared with a population without COPD. In our experience, the follow-up of patients with COPD when given nCPAP does not differ from that of "usual" COPD, and we are not aware of outcome studies in this subpopulation.

nCPAP may be inefficient for correcting nighttime hypoxemia in patients with an associated COPD (38, 39). In these patients some degree of sleep-related hypoxemia may persist, particularly during REM sleep. Consequently, it is necessary to add supplementary O2 (1.5–3 L/min) to nCPAP when the mean nocturnal SaO2 under nCPAP alone is less than 90%. It is also possible in these cases to shift to another mode of nocturnal ventilation, such as bilevel positive airway pressure, which is also called nocturnal noninvasive ventilation (NIV) or nocturnal noninvasive positive pressure ventilation. In patients with severe hypercapnic COPD without associated SAHS, the long-term effects of NIV have not been so far convincingly demonstrated (40–42), whereas the results of NIV are excellent in the obesity-hypoventilation syndrome (43–46). To our knowledge there has been no controlled study on the effects of NIV in patients with overlap.

The efficiency of NIV (abolition of apneas and correction of hypoxemia) must be assessed by nocturnal oximetry and, whenever possible, by polysomnography.

Finally, in the most severe overlap patients, a marked daytime hypoxemia may persist in spite of the efficient treatment of nocturnal apneas-hypopneas. These patients require conventional long-term oxygen therapy (LTOT) (>= 16–18 h/d) in addition to nCPAP or NIV, when the standard criteria for oxygen therapy are fulfilled (47)—namely, a daytime PaO2 regularly less than 55 to 60 mm Hg. These patients are the most likely to develop PH (34), and LTOT may help to decrease or at least stabilize PAP (48).

CONCLUSIONS

Overlap syndrome is not a rare condition, due to the high prevalence of both COPD and SAHS. A recent epidemiologic study has clearly shown that the presence of COPD does not favor the occurrence of SAHS and vice versa.

Patients with overlap have a more important sleep-related O2 desaturation than patients with COPD with the same degree of bronchial obstruction. They have an increased risk of developing hypercapnic respiratory insufficiency and pulmonary hypertension when compared with patients with SAHS alone. In patients with overlap, hypoxemia, hypercapnia, and pulmonary hypertension can be observed in the presence of mild to moderate bronchial obstruction, which is quite different from "usual" COPD.

Therapy of the overlap syndrome consists of nCPAP or nocturnal NIV with or without associated nocturnal O2. Patients who are markedly hypoxemic during daytime (PaO2 < 55–60 mm Hg) should receive conventional LTOT in addition to nocturnal ventilation.

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form July 27, 2007; accepted in final form September 6, 2007)

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