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 2Service des Maladies Respiratoires et Réanimation
Respiratoire, Centre Hospitalier Universitaire de Nancy, Vandoeuvre les Nancy, Nancy, France
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 com-
pared 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 ventila-
tion.
Keywords: 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 ‘‘over-
lap syndrome’’ by the late David Flenley (5). In his opinion
the term ‘‘overlap syndrome’’ could apply as well to the co-
existence of SAHS and any chronic respiratory disease such as
idiopathic pulmonary fibrosis or cystic fibrosis (5), but the use of
(Received in original form July 27, 2007; accepted in final form September 6, 2007)
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@chru-strasbourg.fr
Proc Am Thorac Soc Vol 5. pp 237–241, 2008
DOI: 10.1513/pats.200706-077MG
Internet address: www.atsjournals.org
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 co-
workers (2) had been in fact referred to a sleep clinic because
they complained of excessive daytime somnolence. This prob-
ably 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 5 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 pop-
ulation (3), but it must be underlined that at that time there
were very few reliable epidemiologic studies about the preva-
lence 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 6 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). Ac-
cordingly, 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
238
the general population, is to undertake a large epidemiologic
study. It should be emphasized that earlier studies on the over-
lap syndrome (2, 3, 8, 9) have evaluated relatively small sam-
ples 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 dis-
eases (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 6 (SD) 7.9%. Subjects
with OAD(n 5 1,138, 19%) had a mean FEV1/FVC of 63.8 6
6.6%, and those without OAD (n 5 4,816, 81%) had a mean
FEV1/FVC of 78.3 6 5.3%. Only a small number of participants
(n 5 226, 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 con-
trary, 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).
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 pop-
ulation. 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 hypoth-
esis that the presence of COPD favors the coexistence of SAHS
TABLE 1. RESPIRATORY DISTURBANCE INDEX ACCORDING TO THE
PRESENCE OR NOT OF OBSTRUCTIVE PULMONARY DISEASE
Participants Participants
without COPD with COPD
(FEV1/FVC > 70%) (FEV1/FVC , 70%)
Variables (N 5 4,816) (N 5 1,138)
RDI: mean value 6 SD 9.13 6 12.59 7.49 6 11.87*
RDI: median value (interquartile
range) 4.51 (1.36, 11.59) 3.51 (1.35, 8.81)†
Participants with RDI . 10/h (%) 28.86 22.32*
Participants with RDI . 15/h (%) 18.63 13.97‡
Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease;
RDI 5 respiratory disturbance index (events/h) (RDI is equivalent to apnea-
hypopnea index).
Results of the Sleep Heart Health Study (SHHS). Adapted by permission from
Reference 4.
* P , 0.0001.
†
P , 0.001.
‡
P , 0.0002.
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 5 2008
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 dem-
onstrated 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) men-
tioned 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 ob-
served in sleep architecture in the subjects with the lowest com-
pared 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
TABLE 2. APNEAS, HYPOPNEAS, AND NOCTURNAL OXYGEN
SATURATION IN A SERIES OF 265 CONSECUTIVE PATIENTS
WITH SAHS: COMPARISON OF PATIENTS WITH SAHS ALONE
(N5235) TO PATIENTS WITH OVERLAP (SAHS 1 COPD)
Group as Patients with Patients with t test (overlap
a Whole overlap SAHS Alone vs. SAHS
Variables (n 5 265) (n 5 30) (n 5 235) Alone)
AI, events/h 59 6 38 64 6 41 59 6 38 NS
RDI, events/h 77 6 33 89 6 37 76 6 32 NS
TSA/TST, % 24 6 17 22 6 15 24 6 18 NS
M SaO2, % 91 6 4 89 6 4 91 6 4 p , 0.05
Definition of abbreviations: AI 5 apnea index; M SaO2 5 mean nocturnal oxygen
transcutaneous saturation; RDI 5 respiratory disturbance index (5 apnea-
hypopnea index); SAHS 5 sleep apnea-hypopnea syndrome; TSA/TST 5 time
spent in apnea/total sleep time.
Data are expressed as means 6 SD. Adapted by permission from Reference 3.
Weitzenblum, Chaouat, Kessler, et al.: Association of COPD and Sleep Apnea 239

important in patients with overlap than in patients with SAHS alone (Table 3). In the study by Chaouat and colleagues (3),
alone (P , 0.05). The average FEV1/VC of the 30 overlap 17/30 (57%) patients with overlap had a PaO2 less than or equal
patients was 50 6 6% (Table 3) (3), which is lower than the to 65 mm Hg versus 54/235 (23%) of patients with SAHS alone
average FEV1/FVC of 63.8 6 6.6% in the SHHS (4), a differ- (P , 0.001); 8/30 (27%) patients with overlap were hypercapnic
ence that can be explained by the fact that Chaouat and col- (PaCO2 > 45 mm Hg) versus 19/235 (8%) patients with SAHS
leagues (3) have investigated consecutive patients, whereas the alone (P , 0.05) (3). Of interest, these arterial blood gases re-
SHHS (4) has enrolled participants from the general popula- sults are very similar to those of Alford and coworkers (PaO2 5
tion. In spite of these differences, the SHHS (4) has also clearly 65 6 6.8 mm Hg, PaCO2 5 45.2 6 6.6 mm Hg) in their 20 pa-
demonstrated that subjects with both SAHS and COPD had tients with overlap whose bronchial obstruction was less pro-
greater sleep desaturation than those with only one disorder. nounced) (31).
After adjusting for age, sex, height, race, smoking status, and Hypoxemia and hypercapnia are more severe in patients
awake SpO2, the OR for oxyhemoglobin saturation below levels with obesity-hypoventilation than in patients with overlap
of 90 and 85% for more than 5% of total sleep time was 20-fold (Table 3), all patients having been investigated in a stable state
greater in participants with SAHS alone compared with those of the disease, several weeks after any exacerbation (30).
who had neither disorder and 30-fold greater in participants
with both disorders (subjects with overlap) (4). Pulmonary Hypertension
Consequently the risk of significant nocturnal desaturation is Patients with overlap are at risk of developing pulmonary
clear in patients who exhibit some degree of daytime hypox- hypertension (PH) even though their obstructive defect is not
emia, which is the case of the patients with overlap investigated severe. Chaouat and colleagues (3) have observed that among
by Chaouat and coworkers (3), but is also present in subjects the 26 patients with overlap who underwent right heart cathe-
with less severe overlap, as those recruited in the SHHS (4). terization, 11 had PH defined by a mean pulmonary artery pres-
Pulmonary Function and Arterial Blood Gases
sure (Ppa) greater than 20 mm Hg (Table 4). The prevalence of
PH was of 36% in patients with overlap, much higher than in
The results of spirography and arterial blood gases in a series of ‘‘usual’’ SAHS (19/181 5 9%), but somewhat lower than in the
30 patients with overlap (3) are given in Table 3. They are obesity-hypoventilation syndrome (Table 4) (30).
compared with those of patients with SAHS alone (3) and also Patients with overlap can develop PH even if they do not
to a series of patients with obesity-hypoventilation (30). As exhibit a marked degree of bronchial obstruction. In ‘‘usual’’
mentioned above, ‘‘patients’’ with overlap have lower pulmo- COPD, PH is generally observed in the case of severe bronchial
nary volumes and lower FEV1/VC ratio than do ‘‘subjects’’ with obstruction (FEV1 , 50% of the predicted value, and generally
overlap enrolled in cohort studies like the SHHS (4), and these < 1,000 ml) leading to significant hypoxemia. This discordance
differences might be explained by the different ways of re- has been emphasized by several authors (2, 3, 8, 9, 31–35). The
cruitment. On the other hand, the 20 patients with overlap hypoxemic–hypercapnic SAHS investigated by Bradley and
investigated by Alford and colleagues (31) were hospitalized colleagues (8, 9) exhibited cor pulmonale. The subjects from
and had an average FEV1/FVC of 63.7 6 10.9%, which is very that study were patients with overlap, but their average FEV1
similar to the average value of the SHHS participants exhibiting (2.0 6 0.31 l) and FEV1/FVC (59 6 5%) did not indicate severe
an OAD (63.8 6 6.6%). bronchial obstruction. Similarly, the FEV1/FVC of the patients
By definition, patients with overlap have an obstructive with overlap investigated by Fletcher and coworkers (34) was
ventilatory pattern that is most often mild to moderate, with close to 60%, which contrasted with marked hypoxemia and
an average FEV1 of 1,580 6 560 ml (52 6 15% of the predicted PH. This can be explained by the synergistic effects of the
value) in the series of Chaouat and coworkers (3) (Table 3). diseases on gas exchange and pulmonary hemodynamics (3, 32,
Total lung capacity ranges within normal limits (no static 34, 35).
hyperinflation). In patients with COPD, PH is generally observed when
The coexistence of COPD and SAHS favors the presence of daytime PaO2 is less than 55 to 60 mm Hg (36). The average day-
hypoxemia, which is rarely observed in patients with SAHS time PaO2 of the patients with overlap in the study by Chaouat
and colleagues (3) was higher (66 6 10 mm Hg) (Table 3) and
only 8/30 had a PaO2 less than 60 mm Hg. It must be kept in
TABLE 3. PULMONARY FUNCTION DATA AND ARTERIAL BLOOD
mind that if the daytime PaO2 of these patients is about 65 mm
GASES IN PATIENTS WITH OVERLAP COMPARED WITH
PATIENTS WITH SAHS ALONE AND WITH PATIENTS WITH Hg, the mean PaO2 during sleep is certainly lower because of
THE OBESITY-HYPOVENTILATION SYNDROME
SAHS Alone TABLE 4. PULMONARY HEMODYNAMICS IN PATIENTS WITH
OHS SAHS Alone Overlap versus overlap OVERLAP COMPARED WITH PATIENTS WITH SAHS ALONE
Variables (n 5 34) (n 5 235) (n 5 30) (P Value) AND WITH PATIENTS WITH THE OBESITY-HYPOVENTILATION
SYNDROME
Age, yr 61 6 11 53 6 10 58 6 9 , 0.05
BMI, kg/m2 40 6 8 32 6 6 31 6 5 NS OHS SAHS Alone Overlap SAHS Alone versus
VC, % predicted 79 6 16 91 6 15 77 6 20 , 0.001 Variables (n 5 27) (n 5 180) (n 5 26) overlap (P Value)
FEV1, liters 1.85 6 0.64 2.87 6 0.74 1.58 6 0.56 , 0.001
FEV1, % predicted 70 6 17 88 6 17 52 6 15 , 0.001 Ppa, mm Hg 23 6 10 15 6 5 20 6 6 , 0.001
FEV1/VC, % 69 6 7 75 6 10 50 6 6 , 0.001 PVR, mm Hg/L/min 4.0 6 1.5 2.7 6 1.2 3.6 6 1.8 , 0.002
TLC, % predicted 78 6 11 86 6 11 88 6 13 NS Cardiac output, L/min 6.2 6 18 5.9 6 1.6 5.9 6 1.6 NS
PaO2, mm Hg 59 6 7 75 6 10 66 6 10 , 0.001 PH, n (%) 17 (58) 19 (9) 11 (36) , 0.001
PaCO2, mm Hg 49 6 3 38 6 4 42 6 6 , 0.001
Definition of abbreviations: OHS 5 obesity-hypoventilation syndrome; Ppa 5
Definition of abbreviations: BMI 5 body mass index; FEV1 5 forced expiratory pulmonary artery mean pressure; PVR 5 pulmonary vascular resistance; PH 5
volume in one second; OHS 5 obesity-hypoventilation syndrome; SAHS 5 sleep pulmonary hypertension (defined by a Ppa . 20 mm Hg); SAHS 5 sleep apnea-
apnea-hypopnea-syndrome; TLC 5 total lung capacity; VC 5 vital capacity. hypopnea syndrome.
Data are expressed as means 6 SD. Adapted by permission from References 3 Data are expressed as means 6 SD. Adapted by permission from References 3
and 30. and 30.
240
the repetition of apneas and hypopneas (the time spent in ap-
nea represented 22 6 15% of the total sleep time in the over-
lap 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 in-
fluence the long-term results of this treatment. To our knowl-
edge, 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 hypox-
emia 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 noctur-
nal 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 demon-
strated (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, when-
ever possible, by polysomnography.
Finally, in the most severe overlap patients, a marked day-
time hypoxemia may persist in spite of the efficient treatment of
nocturnal apneas-hypopneas. These patients require conven-
tional long-term oxygen therapy (LTOT) (> 16–18 h/d) in ad-
dition 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 prev-
alence 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 de-
veloping hypercapnic respiratory insufficiency and pulmonary
hypertension when compared with patients with SAHS alone.
In patients with overlap, hypoxemia, hypercapnia, and pulmo-
nary 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
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 5 2008
who are markedly hypoxemic during daytime (PaO2 , 55–
60 mm Hg) should receive conventional LTOT in addition to
nocturnal ventilation.
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.
References
1. Fleetham JA. Is chronic obstructive pulmonary disease related to sleep
apnea-hyponea syndrome? Am J Respir Crit Care Med 2003;167:3–4.
2. Guilleminault C, Cummiskey J, Motta J. Chronic obstructive airflow
disease and sleep studies. Am Rev Respir Dis 1980;122:397–406.
3. Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler
R. Association of chronic obstructive pulmonary disease and sleep
apnea syndrome. Am Rev Respir Dis 1995;151:82–86.
4. Sanders MH, Newman AB, Haggerty CL, Redline S, Lebowitz M, Samet
J, O’Connor GT, Punjabi NM, Shahar E for the Sleep Heart Health
Study. Sleep and sleep-disordered breathing in adults with predom-
inantly mild obstructive airway disease. Am J Respir Crit Care Med
2003;167:7–14.
5. Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med
1985;6:51–61.
6. Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS. Global
strategy for the diagnosis, management, and prevention of chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:
1256–1276.
7. American Academy of Sleep Medicine. Sleep related breathing disor-
ders in adults: recommendations for syndrome definition and mea-
surement techniques in clinical research. Sleep 1999;22:667–689.
8. Bradley TD, Rutherford A, Grossmann RF, Lue F, Zamel N, Moldofsky
H, Phillipson EA. Role of daytime hypoxemia in the pathogenesis of
right heart failure in the obstructive sleep apnea syndrome. Am Rev
Respir Dis 1985;131:835–839.
9. Bradley TD, Butherford A, Lue F, Moldofsky H, Grossmann RF, Zamel
N, Phillipson EA. Role of diffuse airway obstruction in the hyper-
capnia of obstructive apnea. Am Rev Respir Dis 1986;134:920–924.
10. Petty TL, Pierson DJ, Dick NP, Hudson LD, Walker SH. Follow-up
evaluation of a prevalence for chronic bronchitis and chronic airway
obstruction. Am Rev Respir Dis 1976;114:881–890.
11. Lebowitz MD. The trends in airway obstructive disease morbidity in the
Tucson epidemiologic study. Am Rev Respir Dis 1989;140:S35–S41.
12. Fabbri L, Pauwels RA, Hurd SS. Global strategy for the diagnosis, man-
agement, and prevention of chronic obstructive pulmonary disease:
GOLD executive summary updated 2003. COPD 2004;1:105–141.
13. Lopez AD, Shibuya K, Rao C, Hansell AL, Held LS, Schmid V, Buist S.
Chronic obstructive pulmonary disease: current burden and future
projections. Eur Respir J 2006;27:397–412.
14. Menezes AM, Perez-Padilla R, Jardim JR, Muino A, Lopez MV,
Valdivia G, Montes de Oca M, Talamo C, Hallal PC, Victora CG.
PLATINO Team. Chronic obstructive pulmonary disease in five
Latin American cities (the PLATINO study): a prevalence study.
Lancet 2005;366:1875–1881.
15. Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun
MJ, Connel C, Jemai A, Lee TA, Miravitlles M, et al. Epidemiology
and costs of chronic obstructive pulmnary disease. Eur Respir J 2006;
27:188–207.
16. Buist AS, Wollmer WM, Sullivan SD, Weiss KB, Lee TA, Menezes AM,
Crapo RO, Jensen RL, Burney PG. The burden of obstructive lung
disease initiative (BOLD): rationale and design. COPD 2005;2:277–
283.
17. Davis RM, Novotny TE. The epidemiology of cigarette smoking and its
impact on chronic obstructive pulmonary disease. Am Rev Respir Dis
1989;140:S82–S84.
18. 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.
19. Quan SF, Howard BV, Iber C, Kiley JP, Nieto FJ, O’Connor GT,
Rapoport DM, Redline S, Robbins J, Samet JM, et al. The Sleep
Heart Health Study: design, rationale, and methods. Sleep 1997;20:
1077–1085.
20. Enright PL, Johnson LR, Connett JE, Voelker H, Buist AS. Spirometry
and the lung health study. Am Rev Respir Dis 1991;143:1215–1223.
21. 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;323:1230–1235.
Weitzenblum, Chaouat, Kessler, et al.: Association of COPD and Sleep Apnea
22. Bixler E, Vgontzas A, Ten Have T, Tyson K, Kales A. Effects of age on
sleep apnea in men. Am J Respir Crit Care Med 1998;157:144–148.
23. Bixler E, Vgontzas A, Lin H, Ten Have T, Rein J, Vela-Buen A, Kales
A. Prevalence of sleep-disordered breathing in women. Am J Respir
Crit Care Med 2001;163:608–613.
24. Duran J, Esnaola S, Rubio R, Iztueta A. Obstructive sleep apnea-
hypopnea and related clinical features in a population-based sample
of subjects aged 30 to 70 yr. Am J Respir Crit Care Med 2001;163:685–
689.
25. Leitch AG, Clancy LI, Leggett RJE, Tweeddate P, Dawson P, Evans JJ.
Arterial blood gas tensions, hydrogen ion, and electroencephalogram
during sleep in patients with chronic ventilatory failure. Thorax 1976;31:
730–735.
26. Arand DL, Mc Ginty DJ, Littner MR. Respiratory patterns associated
with hemoglobin desaturation during sleep in chronic obstructive
pulmonary disease. Chest 1981;80:183–190.
27. Fleetham J, West P, Mezon B, Conway W, Roth T, Kryger MH. Sleep,
arousals and oxygen desaturation in chronic obstructive pulmonary dis-
ease: the effect of oxygen therapy. Am Rev Respir Dis 1982;126:429–433.
28. Calverley PMA, Brezinova V, Douglas NJ, Catterall JR, Flenley DC.
The effect of oxygenation on sleep quality in chronic bronchitis and
emphysema. Am Rev Respir Dis 1982;126:206–210.
29. Cormick W, Olson LG, Hensley MJ, Saunders NA. Nocturnal hypo-
xaemia and quality of sleep in patients with chronic obstructive lung
disease. Thorax 1986;41:846–854.
30. Kessler R, Chaouat A, Schinkewitch Ph, Faller M, Casel S, Krieger J,
Weitzenblum E. The obesity-hypoventilation syndrome revisited: a
prospective study of 34 consecutive cases. Chest 2001;120:369–376.
31. Alford NJ, Fletcher EC, Nickeson D. Acute oxygen in patients with
sleep apnea and COPD. Chest 1986;89:30–38.
32. Fletcher EC. Interaction of sleep apnea and chronic lung disease. In:
Peter JH, Podszus T, Von Wichert P, editors. Sleep related disorders
and internal diseases. Berlin, Heidelberg: Springer-Verlag; 1987. pp.
279–298.
33. Fletcher EC. Chronic lung disease in the sleep apnea syndrome. Lung
1990;168:751–761.
34. Fletcher EC, Schaal JM, Miller J, Fletcher JG. Long-term cardiopulmo-
nary sequelae in patients with sleep apnea and chronic lung disease.
Am Rev Respir Dis 1987;135:525–533.
35. Weitzenblum E, Krieger J, Apprill M, Vallée E, Ehrhart M, Ratomaharo
J, Oswald M, Kurtz D. Daytime pulmonary hypertension in patients
with obstructive sleep apnea syndrome. Am Rev Respir Dis 1988;138:
345–349.
241
36. Ashutosh K, Mead G, Dunsky M. Early effects of oxygen administration
and prognosis in chronic obstructive pulmonary disease and cor
pulmonale. Am Rev Respir Dis 1983;127:399–404.
37. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive
sleep apnoea by continuous positive airway pressure applied through
the nares. Lancet 1981;1:862–865.
38. Rapoport DM, Garay SM, Epstein H, Goldring HA. Hypercapnia in the
obstructive sleep apnoea syndrome: a re-evaluation of the Pickwick-
ian syndrome. Chest 1986;89:627–635.
39. Kessler R, Chaouat A, Weitzenblum E, Oswald M, Ehrhart M, Apprill
M, Krieger J. Pulmonary hypertension in the obstructive sleep apnoea
syndrome: prevalence, causes and therapeutic consequences. Eur
Respir J 1996;9:787–794.
40. Strumpf DA, Millman RP, Carlisle CC, Grattan LM, Ryan SM, Erickson
AD, Hill NS. Nocturnal positive-pressure ventilation via nasal mask
in patients with severe chronic obstructive pulmonary disease. Am Rev
Respir Dis 1991;144:1234–1239.
41. Meecham-Jones DJ, Paul EA, Jones PW. Nasal pressure support
ventilation plus oxygen compared with oxygen therapy alone in
hypercapnic COPD. Am J Respir Crit Care Med 1995;152:538–544.
42. Gay PC, Hubmayr RD, Stroetz RW. Efficacy of nocturnal nasal
ventilation in stable, severe chronic obstructive pulmonary disease
during a 3-month controlled trial. Mayo Clin Proc 1996;71:533–542.
43. Subramanian S, Strohl KP. A management guideline for obesity-
hypoventilation syndromes. Sleep Breath 1999;3:131–138.
44. Perez de Liano LA, Golpe R, Piquer MO, Racamonde AV, Caruncho
MV, Muinelos OC, Carro CA. Short-term and long-term effects of
nasal intermittent positive pressure ventilation in patients with
obesity-hypoventilation syndrome. Chest 2005;128:587–594.
45. Masa JF, Celli BR, Riesco JA, Hernandez M, Sanchez de Cos J, Disdier
C. The obesity hypoventilation syndrome can be treated with non-
invasive mechanical ventilation. Chest 2001;119:1102–1107.
46. Chouri-Pontarollo N, Borel JC, Tamisier R, Wuyam B, Levy P, Pépin
JL. Impaired objective daytime vigilance in obesity-hypoventilation
syndrome: impact of non-invasive ventilation. Chest 2007;131:148–
155.
47. American Thoracic Society. Standards for the diagnosis and care of
patients with chronic obstructive pulmonary disease. Am J Respir Crit
Care Med 1995;152(Suppl 5):S77–S120.
48. Weitzenblum E, Sautegeau A, Ehrhart M, Mammosser M, Pelletier A.
Long-term oxygen therapy can reverse the progression of pulmonary
hypertension in patients with chronic obstructive pulmonary disease.
Am Rev Respir Dis 1985;131:493–498.