Pulmonary Overlap

S y n d ro m e s , wi t h a F o c u s
o n C O P D a n d IL D
Katherine A. Dudley, MDa, Robert L. Owens, MDb,*,
Atul Malhotra, MDc
KEYWORDS
 Overlap syndrome  Sleep  Chronic obstructive pulmonary disease  Idiopathic pulmonary fibrosis
 Obstructive sleep apnea

KEY POINTS
 Overlap syndrome refers to the coexistence of chronic lung disease and obstructive sleep apnea
(OSA) in the same patient. To date, overlap syndromes have been poorly studied for a variety of
reasons.
 One difficulty is that each of the underlying disorders in an overlap syndrome occurs along a spectrum of disease severity. Thus, patients with an overlap syndrome are heterogeneous, and the goals
of therapy may differ in different patients.
 However, the importance of overlap syndromes is highlighted by recent data demonstrating
increased morbidity and mortality in patients with the overlap of both chronic obstructive pulmonary
disease (COPD) and OSA compared with either underlying disorder alone.
 Unrecognized OSA may also contribute to symptoms of sleepiness/fatigue in patients with chronic
lung disease. Clinicians should be mindful of the possibility of overlap syndromes in these patients.

and outcomes. These challenges are explored in

more detail later and throughout this review.
Importantly, several recent studies suggest that
OVS does, as Flenley thought, have worse outcomes than either disease in isolation. These findings have highlighted the urgent need for further
study of both the OVS and all overlaps between
OSA and chronic lung disease.

CLINICAL AND RESEARCH CHALLENGES OF

THE OVS
OVSs are poorly understood for many reasons.
Using the OVS as a prototype:
1. The diagnosis of OVS is nebulous, as both OSA
and COPD are heterogeneous disorders.

a
Harvard Combined Program of Pulmonary and Critical Care and Division of Sleep and Circadian Disorders at
Brigham and Womens Hospital, 221 Longwood Avenue, Boston, MA 02115, USA; b Divisions of Pulmonary and
Critical Care and Sleep and Circadian Disorders, Brigham and Womens Hospital, 221 Longwood Avenue,
Boston, MA 02115, USA; c University of California, San Diego, San Diego, CA
* Corresponding author.
E-mail address: [email protected]

Sleep Med Clin 9 (2014) 365379

http://dx.doi.org/10.1016/j.jsmc.2014.05.008
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First described in the 1980s by pulmonologist David Flenley,1 overlap syndromes (OVSs) refer to the
coexistence of chronic lung disease and obstructive sleep apnea (OSA). Although it could refer to
any of the lung diseases and OSA, the OVS is usually reserved for the coexistence of OSA and
chronic obstructive pulmonary disease (COPD),
which Flenley thought to have unique adverse
health consequences distinct from either condition
alone. Given the high prevalence of each disorder
alone, OVS is also likely to be common and clinically relevant. However, although OVS has been
described in the literature for nearly 30 years, the
lack of standard diagnostic criteria for the syndrome has limited rigorous discussion of diagnosis, prevalence, pathophysiology, treatment,

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Dudley et al
COPD and OSA both have wide ranges of
severity, in terms of both objective measurements of disease (eg, forced expiratory volume
in 1 second [FEV1], and apnea-hypopnea index
[AHI]) and patient-reported symptoms (eg, dyspnea and daytime tiredness). OVS is defined by
the presence of both conditions regardless of
the relative burden of one or the other. Therefore, patients with OVS may represent a very
heterogeneous population, falling into one of
many potential categories: mild COPD with
mild OSA, mild COPD with severe OSA, severe
COPD with mild OSA, severe COPD with
severe OSA, and so forth. Prognosis and treatment, therefore, could be considerably different
depending on the relative impact of each condition. Although it is a minor point, there is not a
single International Classification of Diseases,
Ninth Revision code for OVS, which impedes
even epidemiologic research.
2. The diagnosis of OSA in the setting of hypoxemic lung disease is uncertain. The definition
of OSA includes hypopneas and reductions in
airflow with associated desaturation, which is
more likely to occur in those with chronic lung
disease. The AHI, used to grade OSA severity,
does not differentiate between apneas and hypopneas. Thus, a patient with severe COPD
might have the same AHI consistent with severe OSA (based on a large number of hypopneas) as another patient with a very
collapsible upper airway without lung disease
(who predominantly has apneas). In addition,
a 10-minute prolonged desaturation caused
by hypoventilation may be scored as a single
hypopnea because the event duration has minimal effect on the definitions used. More
rigorous definitions of OSA might be useful,
such as the apnea index or scoring based on
airflow alone and arousals independent of oxygen desaturation.
3. The interactions of COPD and OSA are not understood. Thus, it is unknown at a pathophysiologic level whether each disorder might
predispose to the other disease. As discussed
earlier, the baseline hypoxemia of COPD likely
predisposes to a diagnosis of OSA. But other
links are possible; for example, the changes in
lung volumes that occur with COPD might
impact upper airway collapsibility. How COPD
and OSA interact to cause the increased
morbidity and mortality attributable to OVS is
not known. Is it simply from more prolonged
hypoxemia or hypercapnia than either disorder
alone? Or are poor outcomes caused by the indirect effects of the disorders, such as cardiovascular disease?

4. Thus, the goals of therapy in OVS are poorly

defined. For a patient with severe OSA with
many apneas, the goal of therapy may be to
support patency of the upper airway and eliminate apneic events. For a patient with evidence
of hypoventilation, the goal may be to improve
nocturnal gas exchange and hypercarbia.
Maybe the best approach would be intensive
modification of cardiovascular risk factors (eg,
blood pressure, cholesterol modification).
These uncertainties contribute to the confusion
as to the ideal therapy to use.
5. The optimal treatment of OVS is unknown. Few
large clinical trials have been undertaken, and
no large studies have compared long-term
outcomes between randomized therapies.
Although continuous positive airway pressure
(CPAP) is the most commonly applied therapy,
some groups have used bilevel positive airway
pressure, which provides a higher pressure during inspiration than during expiration. Bilevel
may have benefits over CPAP for some patients,
particularly among patients with severe COPD
whereby it may aid with nocturnal ventilation
and resting of respiratory muscles. Finally, the
role of oxygen therapy, another treatment used
clinically, has not been fully explored in this population. The role of medical therapy aimed at
limiting cardiovascular events has also not
been explored.
6. An additional under-recognized consideration is
that sleep is poor in chronic lung diseases, independent of upper airway collapse. Many studies
have highlighted the high prevalence of sleep
complaints among patients with chronic lung diseases. There are many reasons behind this
finding, ranging from cough interfering with sleep,
increased anxiety and insomnia, side effects of
medications (eg, chronic glucocorticoids, beta
agonists), and frequent arousals. Although treatment of OVS with CPAP may improve upper
airway patency, CPAP will not address many of
the nonrespiratory problems that plague sleep
in this population. Thus, CPAP adherence may
be challenged in ways that are unique compared
with those without chronic lung disease.
These points are illustrated as the authors
discuss what is known about OVSs, focusing on
OSA and idiopathic pulmonary fibrosis (IPF),
perhaps the most common of the interstitial lung
diseases (ILDs).

COPD AND OSA

Throughout this section, OVS refers exclusively to
those with COPD and OSA.

Pulmonary Overlap Syndromes

COPD
COPD is a progressive lung disease characterized
by irreversible airway obstruction (FEV1/forced vital capacity [FVC]<70%). This disease can involve
the small airways, pulmonary parenchyma, or
both. COPD results from an inflammatory
response that can result in chronic sputum production (chronic bronchitis) as well as the destruction of alveolar walls distal to the terminal
bronchioles, leading to enlargement of the airspaces (emphysema). Although tobacco use is
strongly associated with the development of
COPD, it is not the only risk factor. In developing
countries, exposure to indoor air pollution plays a
critical role, in particular as a result of fuels burned
for cooking and heating. Occupational causes are
also well described, such as irritants and fumes.
Estimates are now that most COPD worldwide is
nonsmoking related, emphasizing caution about
labeling the disease as self-inflicted. COPD may
present as dyspnea, wheezing, cough, sputum
production, poor exercise tolerance, hypoxic
and/or hypercarbic respiratory failure, and right
heart failure (cor pulmonale). There are Global
Initiative for Chronic Obstructive Lung Disease
(GOLD)defined stages of disease severity based
on pulmonary function testing (the FEV1) and
symptoms. In the United States, more than 5%
of the population (at least 13.7 million people) is
burdened by COPD,2,3 which is a leading cause
of morbidity. Worldwide, about 10% of the population is affected.4 Although medications may
improve symptomatic control of the disease and
slow progression, the health-related consequences of COPD remain high.3 As of 2011,
COPD was the third leading cause of death in
the United States.5 Annual expenditures for the
disease are approaching $40 billion when direct
and indirect costs are considered.6
Although COPD is often considered a respiratory
condition, the impact on other organ systems and
overall health is increasingly well recognized. The
most recent GOLD definition of the disease highlights COPD as a systemic process with significant extrapulmonary effects that may contribute
to the severity in individual patients.7 Indeed,
depression, skeletal-muscle myopathy, anemia,
and osteoporosis are all common in COPD. Similarly, as is discussed later, sleep disturbance and
its consequences could be thought of as one of
these extrapulmonary manifestations. COPD is
also associated with adverse cardiac outcomes,
which may be of particularly importance when
thinking about the overlap with OSA, which also
has cardiovascular consequences.812 Even after
consideration of shared risk factors, such as

cigarette smoking, COPD is associated with higher

rates of coronary artery disease, congestive heart
failure, and arrhythmias.13,14 Additional mechanisms by which COPD may play a role in cardiovascular disease include increased oxidative stress,
inflammation, and increased platelet activation.
Of particular interest in the current discussion,
COPD is a heterogeneous disorder, with variable
amounts of airway and parenchymal disease.
Most patients have a predominance of one phenotype, though there is usually some overlap. In the
past, patients with chronic bronchitis were
described as blue bloaters, referring to hypoxemia, polycythemia, and cor pulmonale that often
accompanies patients with this form of COPD.
Pink puffers were those with an emphysematous
phenotype of COPD, often with muscle wasting
and hyperinflation but without oxygen desaturation. The GOLD criteria are designed to be inclusive to maximize disease recognition and prompt
treatment and, therefore, do not highlight these
distinctions. However, there may be critical differences in the pathophysiology among different
phenotypes that are important when considering
OVS.

Sleep and COPD

More than three-quarters of patients with COPD
report bothersome nocturnal symptoms, such as
dyspnea.15,16 Patients who report cough and
wheeze during the day are more likely to have
sleep disturbances than those who do not.17
Patients report trouble falling asleep, frequent
awakening, difficultly returning to sleep, and nonrestorative sleep. In a survey of patients with
COPD, more than 60% had experienced at least
one sleep symptom in the preceding 28 days.15
Rates of clinical insomnia are high among patients
with COPD, present in more than one-fourth.18
As compared with controls, COPD confers an
increased risk of insomnia nearly twice that of
non-COPD patients.19 These sleep disturbances
are chronic, persisting over many years.20
Sleep complaints increase with more severe disease. Although mild obstructive lung disease is
associated with preserved sleep quality,21 a
more severe obstructive disease is associated
with increased sleep complaints.22 Severe disease
negatively impacts several objective sleep parameters, such as total sleep time, sleep efficiency,
rapid eye movement (REM) sleep,23 as well as
sleep-onset latency, arousals, and sleep-stage
transitions.2427
The mechanisms behind the sleep disturbances
are likely multifactorial. Symptoms such as cough
and wheezing may play a role as noted earlier.28,29

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Dudley et al
Recent work has also highlighted nonrespiratory
factors that also perturb sleep among patients
with COPD.30 For example, restless leg syndrome
has been found in up to one-third of patients with
COPD, and periodic limb movements are associated with worse insomnia.31 As a result of all of
these factors, the use of medications to aid sleep
is common, especially sedative hypnotics, which
are used by 25% of patients with COPD.17
Although data are sparse, these medications could
theoretically worsen hypoxemia/hypercapnia, though this may not be true for all patients.3235

Changes in Respiration During Sleep with

COPD and Nocturnal Oxygen Desaturation
Nocturnal oxygen desaturation (NOD) in chronic
lung disease is the result of the normal changes
that occur in ventilation with sleep. Put another
way, sleep is a stress test for those patients with
chronic lung disease that leads to nocturnal hypoxemia and hypercapnia. Understanding the
normal changes in respiration that occur with
sleep is key to understanding NOD.

Normal Changes in Respiration During Sleep

Sleep is divided into different stages based on electroencephalography waveforms, muscle tone, eye
movement, and breathing pattern, with the main
distinction being between non-REM sleep and
REM sleep. The main respiratory changes that
occur during sleep are a decrease in ventilation
(largely a decrease in tidal volume without a
compensatory increase in respiratory rate) and
decreased accessory muscle activity. The changes

in respiration are most pronounced in REM sleep,

which is notable for skeletal muscle atonia (with
the exception of certain muscles, including the diaphragm); in addition to decreased ventilation, the
breathing pattern becomes very irregular (especially during bursts of REMs). The decrease in respiratory drive reflects both a decrease in metabolic
rate, which results in less carbon dioxide (CO2) production and, thus, requirement for elimination, and
an increase in the CO2 set point.36 The reduction in
minute ventilation is further pronounced during
REM, when ventilation may be 40% less compared
with wakefulness.37,38 In addition to the decrease in
the respiratory set point, there is decreased
responsiveness to hypercapnia and hypoxia
compared with wakefulness.3941 Finally, upper
airway resistance increases during sleep, even in
those without OSA.42 An overview of the changes
is outlined in Fig. 1.

Sleep and Breathing with COPD

All of the aforementioned changes are physiologic
changes that occur from wakefulness to sleep.
However, in the presence of lung disease, the consequences may be dramatic and lead to oxygen
desaturation. First, these patients may already
have borderline hypoxemia, which puts them on
the steep part of the oxygen hemoglobin binding
curve; that is, small changes in PaO2 lead to a
decrease in oxygen saturation. Second, patients
with COPD have increased minute ventilation for
a variety of reasons and frequently rely on accessory muscles to aid ventilation. As a result, ventilation can decrease dramatically during sleep and

Fig. 1. The normal physiologic changes that occur with sleep. With sleep onset, respiratory drive is decreased, and
there is respiratory muscle hypotonia and a decrease in lung volumes. Even without OSA, the result is hypoventilation compared with wakefulness. Particularly with OSA and COPD, there are further pathophysiologic changes
that lead to greater hypoventilation and hypoxemia.

Pulmonary Overlap Syndromes

particularly in REM sleep when muscle activity decreases. Furthermore, patients with COPD may
have chest hyperinflation, which stretches the diaphragm and impairs contractile function.43
NOD is perhaps the most common sleep abnormality attributed to COPD, occurring in anywhere
from one-quarter to three-quarters of patients
with an awake oxygen saturation greater than
90% to 95%.4446 During sleep, desaturations
are frequent among patients with an FEV1/FVC
less than 65%21; increasing severity of obstructive
disease is associated with more severe desaturations during sleep. Among those with severe
obstructive lung disease (FEV1<30%), a 20%
decrease of oxygen saturation can be seen during
non-REM sleep and an impressive decline of 40%
during REM.37 There is substantial variation in reported NOD rates, in part caused by the heterogeneous nature of COPD as well as the definition of
NOD, which may be based either on nadir levels
or the duration of low oxygen tension.

COPD and OSA: the OVS

OSA is a common disorder, characterized by partial or complete collapse of the upper airway during sleep, resulting in intermittent hypoxia and
arousals. The repetitive nature of these breathing
events results in fragmented and nonrestorative
sleep. Among middle-aged men (5070 years
old), the prevalence of moderate to severe OSA
is predicted to be as high as 17% and slightly
lower but still concerning at 9% among middleaged women.47 OSA is associated with an
increased risk of serious neurocognitive and cardiovascular consequences, including hypertension, congestive heart failure, and stroke.4851
CPAP is the gold standard treatment of OSA and
consists of a mask worn during sleep connected
to a machine that delivers pressurized air, thereby
splinting open the airway during sleep. Although
CPAP is efficacious in treating OSA in almost all
cases, its effectiveness is limited by patient adherence. Although adherence rates may be improved
through intensive support and behavioral therapy,
the real-world nonadherence rates may approach
50%. In the context of OVS, these facts illustrate
the potentially large number of patients with OSA
at risk for OVS, that both OSA and COPD have
substantial cardiovascular morbidity and mortality,
and that positive airway pressure is unlikely to be
accepted by many patients.

Diagnosing OSA Among Those Patients with

COPD
OSA is diagnosed through polysomnography, with
apneas and hypopneas recorded during sleep. The

tendency toward oxygen desaturation described

earlier in those patients with chronic lung disease
impacts the diagnosis of OSA. Although the designation of apneas is straightforward and independent of oxygen desaturation, hypopneas are
based on flow limitation of at least 30% and require
either an accompanying 3% or greater oxygen desaturation or an arousal. Based on the sigmoidal
shape of the oxygen-hemoglobin desaturation
curve, any small change in PaO2 that occurs during
sleep will be reflected as a larger (and therefore
scorable as a hypopnea) change in oxygen saturation. Put another way, 2 patients with the same upper airway tendency to collapse, but one healthy
and the other with chronic lung disease, might
have very different apnea-hypopnea indices. A
similar observation that makes the same point is
that the AHI improves with descent from altitude,
largely because of a decrease in the number of hypopneas.52 Nevertheless, there are no current
alternative scoring criteria or guidelines for OSA
diagnosis in the setting of chronic lung disease.
Among patients with COPD, there are clues to
suggest OSA beyond the classic symptoms of
snoring, witnessed apneas, and daytime sleepiness. For example, headaches with the initiation
of nocturnal supplemental oxygen suggest coexistent OSA (caused by increased hypercapnia).
Hypercapnia, despite relatively preserved pulmonary function tests, may also signal the presence
of sleep-disordered breathing and prompt evaluation. Indeed, based on findings from one cohort,
FEV1 was severely decreased among patients
with COPD only with hypercapnia but only moderately reduced in patients who had both COPD and
OSA. Despite this difference in pulmonary function
tests, daytime PaCO2 was higher among those with
OVS compared with COPD only.53,54 Additionally,
obesity is more common among hypercarbic patients with COPD who have OSA as compared
with COPD only.54 For comparison, the characteristics of COPD alone, OSA alone, and OVS from
one cohort are outlined in Table 1.
The American Thoracic Society/European Respiratory Societys guidelines also highlight the
role of referring for overnight testing among those
with mild COPD and evidence of pulmonary hypertension. Although only 16% of patients with OSA
have been observed to have pulmonary hypertension, this number jumps to 86% for those with
OVS.55 This is an intriguing finding, given that
traditional markers of OSA severity and nocturnal
hypoxia in COPD are not predictive of pulmonary
hypertension. However, time spent with oxygen
saturation less than 90% is high among patients
with OVS, even without a severe obstructive
pattern on spirometry.

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Dudley et al

Table 1
Characteristics and physiologic measures of patients with COPD only, OSA only, and OVS

Age (y)
Weight (kg)
BMI (kg/m2)
FVC (% predicted)
FEV1 (% predicted)
FEV1/FVC (%)
PaO2 (mm Hg)
PaCO2 (mm Hg)
AHI (events/h)
Time SpO2 <90% (%)

COPD Group (n 5 32)

Overlap Group (n 5 29)

Pure OSA Group (n 5 152)

60.1  10.4
87.6  17.5
31  7
60  19
47  16
59  9
69  10
40  5
65
16  28

57.2  9.5
102.2  20.6
36  6
72  17
63  16
67  5
70  11
45  5
40  20
48  28

48.9  12.9
106.8  28.8
39  10
89  21
89  20
87  9
79  12
39  4
42  23
30  28

Overlap refers to both COPD and OSA.

Abbreviations: BMI, body mass index; SpO2, oxygen saturation.
Values are mean  SD.
Adapted from Resta O, Foschino Barbaro MP, Brindicci C, et al. Hypercapnia in overlap syndrome: possible determinant
factors. Sleep Breath 2002;6(1):14; with permission.

Prevalence and Epidemiology of OVS

Clinical Consequences of OSA and COPD

In general, small studies from the early 1990s suggested that severe COPD was a risk factor for
OSA.56 For example, one early study found greater
than 80% prevalence of OSA among patients with
COPD and excessive daytime sleepiness referred
for evaluation.12 In certain populations, too, such
as Veterans Administration patients, the coexistence of OSA and COPD was high (29%) among
patients who had polysomnogram and spirometry
data available.57
More recently, larger epidemiology studies
including a more broad range of subjects, such
as the Sleep Heart Health Study and Multinational
Monitoring of Trends and Determinants in Cardiovascular Disease, have not demonstrated an
increased risk of OSA among those with obstructive lung disease, at least among those with mild
obstructive lung disease.21,58 In these large cohorts, the prevalence of OSA was 11% to 14%,
which was similar in those with or without obstructive lung disease.21,58 Thus, it seems likely that
there is little connection among those with mild
COPD; whether more severe COPD can contribute
to OSA is not clear.
Although the answer is not yet known, proposed
mechanisms of OSA risk in severe COPD include
the following: fluid shifts in those with cor pulmonale from lower extremity edema to the neck,59 a
generalized myopathy from COPD alone that
affects the upper airway muscles,60 or a steroidinduced myopathy from systemic or inhaled corticosteroids. All of these changes would increase
upper airway collapsibility.

The large aforementioned cohort studies did highlight that among those with obstructive lung disease and OSA, the nocturnal desaturations and
sleep disturbances are greater (both oxygen saturation nadir and duration of hypoxemia) than would
be expected for either disease alone.21 Whether
causal or not, more recent reports have suggested
an increased mortality in OVS compared with
COPD and OSA alone and have increased awareness about OVSs. First, Marin and colleagues61
found decreased survival among patients with
OVS compared with either COPD or OSA alone
(Fig. 2). There were differences in death from any
cause and cardiovascular causes when patients
with OVS using CPAP were compared with those
not on CPAP. No differences were seen between
COPD only and patients with OVS using CPAP.61
That patients with OVS using CPAP have reduced
mortality compared with OVS without CPAP has
now also been reported in other cohorts6264
Jaoude and colleagues64 found that CPAP only
improved outcomes from OVS in those patients
who were also hypercapnic. Further exploring the
observed therapeutic benefit of CPAP, Stanchina
and colleagues63 found that greater time on
CPAP was associated with reduced mortality in
patients with OVS.
Although the improvement with CPAP seems
dramatic, these are not randomized data; these
were cohort studies in which subjects chose to
adhere to or abandon CPAP therapy. Patients
who did not adhere to CPAP may have been those
with more COPD/less OSA; had more respiratory

Pulmonary Overlap Syndromes

Fig. 2. Kaplan-Meier survival curves for patients with

COPD. Patients with OVS on CPAP, and patients with
OVS not on CPAP. Treatment with CPAP seems to prevent against the excess mortality in patients with OVS.
Importantly, these data are observational. (Adapted
from Marin JM, Soriano JB, Carrizo SJ, et al. Outcomes
in patients with chronic obstructive pulmonary disease
and obstructive sleep apnea: the overlap syndrome.
Am J Respir Crit Care Med 2010;182(3):328; with
permission.)

symptoms, such as dyspnea or sputum that limit

CPAP use; or were less likely to adhere to other
medication therapy, which is also important for
limiting poor outcomes (eg, statin therapy). Nevertheless, these findings highlight the need to focus
more resources on the care and understanding of
these patients.
It is assumed, but not known, that the worse
outcomes in OVS are caused by excess cardiovascular events. As discussed earlier, both
COPD and OSA increase cardiovascular risk.
Some data support this potential mechanism, suggesting that OSA can augment vascular changes
among patients with COPD, such as arterial stiffness.65 Sharma and colleagues66 found that patients with OSA have more extensive remodeling
of the right ventricle seen on cardiac magnetic
resonance compared with those with COPD alone;
the extent of right ventricle remodeling was correlated with the oxygen desaturation index.

Treatment of OVS
Treatment of OVS may be thought of as addressing the underlying COPD, OSA, or both. Although
the specific goals of treatment remain poorly
defined, most clinicians strive to eliminate sleepdisordered breathing and eliminate NOD. What to
target for ideal oxygen saturation, however, remains unclear, as does the impact of normalizing
hypercarbia. The most commonly applied therapy
is CPAP.
Before CPAP is applied, however, it is critical to
consider the use of therapies that target the

underlying COPD, such as bronchodilators and

antiinflammatories. Therapies aimed at COPD
alone can improve nocturnal oxygen saturation
as well as decrease symptoms. Ipratropium and
tiotropium, cholinergic bronchodilators, longacting beta-agonists, and oral steroids all have
data to support improvements in oxygen saturation during sleep.6770 Some of these agents,
such as ipratropium, have also been shown to
improve sleep quality and increase REM and total
sleep time, although, surprisingly, tiotropium did
not.67,68,70 Although the mechanism of these improvements has yet to be teased out, these
studies suggest that optimizing COPD treatment
can play a key role in the degree of nocturnal oxygen saturation. The impact on upper airway
patency is unknown; some have hypothesized
that (inhaled) steroids might predispose the upper
airway to myopathy and increased collapsibility.
However, at least in asthmatic patients receiving
high-dose inhaled corticosteroids, there was no increase in collapsibility.71
Nocturnal oxygen is a mainstay of therapy for
hypoxemia in COPD with demonstrated mortality
benefits.72,73 Among patients with OSA, nocturnal
oxygen therapy alone may improve hypoxemia;
however, arousals, sleep architecture, and daytime symptoms, such as sleepiness, are not
impacted,74 pointing to the potential impact of
sleep fragmentation caused by arousals triggered
by airway obstruction, which is not addressed by
oxygen therapy. Thus, supplemental oxygen alone
for OSA seems unlikely to be of benefit.

CPAP and Lung Function in COPD

There are a few studies that have assessed treatment with CPAP in patients with OVS. Small
studies have demonstrated improvements in daytime oxygen saturation and degree of hypercarbia
with nocturnal CPAP use.75,76 Improvements in
FEV1, echocardiogram estimates of mean pulmonary artery pressure, PaO2, and PaCO2 have been
documented.75,77,78 Other studies have found a
decline in lung function among patients with OVS
who were adherent to CPAP therapy.79 Differences in study design, and subject characteristics
make it difficult to generalize or reconcile the findings from these studies. It has been hypothesized
that improvements in gas exchange may reflect
improvement in daytime lung function, although
the mechanism remains unclear and controversial.
The prevention of repetitive upper airway collapse
in an animal model seemed to improve lower
airway resistance.80 Off-loading of respiratory
muscles during sleep through CPAP may also
be important, contributing to decreased oxygen

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consumption, CO2 production, and reducing sleep
hypoventilation. After CPAP initiation, fewer
COPD-related hospital admissions are seen in
some populations.63,81
As discussed earlier, recent papers suggest that
the treatment of OVS with CPAP is associated with
reduced mortality. First, in the Brazilian cohort,
5-year survival with CPAP was 71%, as compared
with 26% among patients using oxygen alone.62
This cohort included more than 600 patients who
required long-term oxygen therapy for hypoxemic
COPD and had at least moderate OSA. Patients
with OSA were prescribed CPAP, and those who
were nonadherent to CPAP continued to use oxygen for COPD. Similarly, the findings from a Spanish cohort of patients with OVS also suggested a
benefit, lowering the mortality risk to that of
COPD alone.61 The striking improvement in both
cohorts supports a beneficial role of CPAP as
well as highlighting the very poor outcomes in
those with OVS. Again, patients in both studies
were not randomized but were self-selected
based on adherence to CPAP (or were not able
to afford CPAP therapy). That is, these are observational studies comparing patients with OVS who
are and are not adherent to CPAP. Although these
studies do not elicit the mechanism for the
reduced mortality, if caused by CPAP, this may
be through the reduction in cardiac risk factors.
Indeed, CRP levels, a nonspecific marker of
inflammation, were significantly reduced in patients with OVS using CPAP as compared with
pretreatment.82
Noninvasive ventilation (NIV), such as bilevel
positive airway pressure, is an attractive treatment
modality in this population. Even in the absence of
OSA, nocturnal NIV is often applied for patients
with more severe COPD to off-load respiratory
muscles, supplement ventilation, decrease hypercapnia, and reduce hypoxemia. Studies in this
area have generally been small, nonrandomized,
and in patients with stable disease. Taken
together, these studies did not demonstrate any
improvements in lung function, gas, exchange,
sleep efficiency, or mortality according to a 2003
meta-analysis.83 Since that time, however, 2 areas
of investigation deserve to be highlighted. Among
patients with OVS with stable hypercapnic COPD
(patients with OSA were excluded), one moderately large randomized trial demonstrated a mortality benefit with NIV use, though NIV was
accompanied by a decrease in quality of life.84 A
mortality benefit compared with historical controls
has also been seen using very high ventilation settings.85 These investigators argue that so-called
high-intensity noninvasive positive pressure ventilation (with very high driving pressures, for

example, inspiratory pressures of 28 cm of H2O

and respiratory rate of more than 20 breaths per
minute) among patients with COPD does not
seem to impact sleep quality and may have
some benefits, such as improvement in gas exchange and lung function.8688
Weight loss is beneficial among patients with
OSA and obesity.89 Among patients with COPD
alone, however, weight loss is often a concerning
finding, stemming from pulmonary cachexia,
infection, malignancy, or deconditioning. The role
of weight loss among patients with OVS has not
been examined; however, it is probably safe for
obese patients with OVS to target weight loss.90
Although purely speculative, given the high rates
of cardiovascular disease in OSA and COPD, it
may also make sense to consider cardioprotective
therapies (eg, aspirin, statin) as the primary prevention in patients with OVS.
Based on all of the aforementioned information,
the authors propose the diagnostic and treatment
algorithm in Fig. 3.

OSA AND ILD, WITH EMPHASIS ON IPF

ILD/IPF Background
ILD may refer to several heterogeneous conditions, such as IPF; sarcoidosis; autoimmunerelated pulmonary disorders, such as systemic
sclerosis and hypersensitivity pneumonitis; or secondary to an environmental or drug exposure,
such as amiodarone. The common features of
the ILDs are (1) that these are distinct from
obstructive lung diseases (such as COPD) and
demonstrate restrictive physiology and (2) that
the anatomic basis of the disease is usually the interstitium (the alveolar epithelium, pulmonary
capillary endothelium, basement membrane, perivascular, and perilymphatic tissues). The focus of
the authors discussion is primarily among patients
with IPF.
IPF is a restrictive lung disease of unknown
cause. It is characterized by chronic, progressive
lung fibrosis of unknown cause.91 It is an irreversible process, with an unpredictable course. Progression can vary markedly on an individual
basis, from slow chronic decline to a rapid acceleration of disease; acute exacerbations may also
punctuate the disease course. Prognosis is generally very poor, and there are no known effective
medical treatments. Despite ongoing research,
the cause of the disease remains poorly understood. Histologically, IPF correlates with the
pattern of usual interstitial pneumonitis; the terms
are sometimes used synonymously.
As compared with COPD, IPF is a rare condition,
affecting approximately 14 to 28 per 100,000

Pulmonary Overlap Syndromes

Fig. 3. Management algorithm for patients with COPD. Patients with COPD should be assessed for any red flags
that might suggest the presence of concurrent OSA. If present, COPD should be optimized before undergoing
polysomnography. Attention should be paid to the flow signal and apnea index when assessing the severity of
OSA. If hypercapnia is present, patients can begin on bilevel positive airway pressure (PAP). If flow limitation
is present without significant apneas, conservative therapy, such as a mandibular advancement device, weight
loss, and positional therapy, should be considered. If apneas predominate, CPAP should be started. Supplemental
oxygen should be added if hypoxemia persists. HTN, hypertension; PFT, pulmonary function tests.

people in the United States.92 It is more common

in older individuals and mens.93 The relatively
low prevalence of IPF means that, as compared
with COPD, the prevalence of coexisting OSA
and IPF (or any ILD) is presumably also rare. However, OSA and IPF might be worth studying if (1)
IPF predisposes to OSA, (2) symptoms traditionally ascribed to IPF (eg, fatigue) are actually
caused by OSA and can be successfully treated
with OSA treatment, and (3) treatment of OSA in
these patients improves outcomes.

Sleep in IPF
Poor sleep is common among patients with IPF.
Global measures of sleep quality and excessive
daytime sleepiness are significantly different as
compared with controls, with patients with IPF
complaining of poor sleep and excessive daytime
sleepiness.94 Insomnia is also a frequent occurrence, found in almost one-half of patients with
IPF, which may contribute to the high rates of daytime symptoms.95 When sleep is objectively assessed by polysomnography, as compared with
controls, patients with IPF have increased sleep
fragmentation and stage I sleep.9698 Total sleep

time, sleep efficiency, and REM sleep are all

reduced.9698
The mechanisms for these sleep abnormalities
remain incompletely understood, though are likely
to be multifactorial. Disruption from cough has
been frequently cited as one factor that contributes to sleep disturbance and the inability to
sleep.95,99101 The effect of medications, such as
corticosteroids, which are still used empirically
given the lack of other treatment options, may
further contribute to some of the sleep abnormalities reported by patients with IPF. Nearly
two-thirds of patients in one series were on prednisone,94 which may interfere with sleep when
used at high doses. Patients with IPF are often
additionally burdened by depression and other
mood disorders, which are often characterized
by sleep disturbances and changes in energy
level; the medications used to treat these disorders may also impact sleep and daytime function.

Respiration During Sleep in IPF

The pathologic changes in pulmonary fibrosis are
decreased lung compliance and increased ventilation/perfusion mismatch. These changes will increase minute ventilation and the work of

373

374

Dudley et al
breathing. As a result, patients with IPF exhibit
rapid, shallow breathing during wakefulness.98
During sleep, the tachypnea persists; as
compared with normal controls, there is no
decrease in respiratory rate, although tidal volume
decreases.98 Thus, similar to COPD as discussed
earlier, among patients with ILD, sleep may serve
as a stressor to the respiratory system. Oxygen
desaturation is frequently more profound than during wakefulness. The importance of evaluating
nighttime respiratory patterns has been recently
highlighted, as it may have prognostic value in assessing mortality in ILD.102 Specifically, among
patients with newly diagnosed IPF, the degree of
nocturnal desaturation was greater than seen during exercise and was predictive of survival,103105
possibly mediated through worsening pulmonary
artery hypertension.103

ILD and Sleep-Disordered Breathing

The prevalence of sleep-disordered breathing is
reported to be extraordinarily high among patients
with ILD. Symptoms such as fatigue, commonly
reported in patients with IPF, may be attributable
to this.98 In published series, the incidence of
OSA ranges from more than two-thirds to nearly
90%.106108 Fig. 4 outlines the symptoms that
are commonly reported in IPF and how they may
overlap with OSA. The nature of OSA in these populations remains incompletely characterized, such
as whether events are caused by airway collapse
and flow limitation or oxygen desaturations.
Among patients with IPF, AHI is not strongly correlated with the body mass index, again suggesting
that other mechanisms, aside from obesity, may
be contributing to the diagnosis of OSA in this
population.108 Indeed, as compared with controls,
patients with IPF spend more time with an oxygen
saturation less than 90%, even when the AHI is
similar. These observations raise the possibility

IPF
Pathophysiology
Fibrosis with decreased lung compliance,
decreased lung volumes.
Increased V/Q mismatch leads to hypoxemia
Increased hypopneas?

Increased
upper airway
collapsibility?

Symptoms
cough
fatigue
Sleep fragmentation
dyspnea
poor exercise tolerance

OSA

Fig. 4. Links between IPF and OSA. Many symptoms

and findings among by patients with IPF overlap
with those of OSA, including daytime fatigue, poor
sleep, and nocturnal hypoxia. Similarly, the pathophysiologic changes of IPF may contribute to OSA.

that the lower baseline oxygen saturation and

increased tendency toward desaturation are overestimating the collapsibility of the upper airway.
The 2009 study by Lancaster and colleagues108
is helpful in this regard. First, their subjects with
mild OSA had a mean AHI of 10.7 events per
hour, of which less than 1 event per hour was apnea. Additionally, approximately half of the hypopneas were scored based on a 3% oxygen
desaturation (rather than arousal). In those with
moderate to severe OSA, the average AHI was
39.4 events per hour. But again, the apnea index
was only 7.1 events per hour; nearly half of all hypopneas were scored based on oxygen
desaturation.
In support of a mechanistic link between IPF and
OSA, some investigators have invoked so-called
tracheal traction, the link between lung volumes
and the upper airway.109,110 Briefly, in patients
without lung disease, a decrease in lung volumes
leads to increased upper airway resistance,
increased collapsibility, and worse OSA
severity.111,112 However, whether this relationship
still holds when compliance of the lung is altered
is not clear; no formal measurement of airway
resistance or collapsibility has been made in patients with IPF to test this hypothesis. Again, in
the study by Lancaster and colleagues,108 total
lung capacity did not seem to predict OSA.

Treatment
There are no proven therapies that target the underlying disease process in IPF. Oxygen therapy
is widely used as supportive care. Studies suggest
that oxygen therapy can be associated with improvements in exercise performance.113,114 However, no studies have demonstrated a mortality
benefit115 or improvement in exertional dyspnea,116 as rapid shallow breathing persists
despite addressing hypoxemia.
Treatment with CPAP among patients with IPF
with at least moderate OSA results in gains in
sleep-related quality-of-life measures, though
adherence to CPAP may be challenging in light
of chronic cough and other barriers.117 There are
no studies that have explored the impact of
CPAP on outcomes in IPF, such as disease progression or mortality. Taken together, OSA may
be common in IPF; treatment with CPAP may
improve OSA symptoms.

Other OVS: Beyond COPD and IPF

From the earlier discussion, it is clear that there are
many research and clinical questions that remain
for OVS, even for the OVS, which is relatively common. Even less is known about the prevalence,

Pulmonary Overlap Syndromes

consequences, and best management of OSA
among other chronic lung diseases. However,
there are some pearls that the sleep physician
should know regarding other lung diseases.
Sarcoidosis is a chronic condition of unknown
cause characterized by the formation of granulomas in many organs, most commonly the lung.
Lung disease may range from mild to severe and fibrosing in nature. Steroids are often given in more
severe disease. Fatigue and excessive daytime
sleepiness are more common among patients
with sarcoid as compared with controls.118120
Consideration of OSA among these patients is,
therefore, important, particularly among those
with abnormal lung function.118 There remains a
population of patients, however, with hypersomnolence unrelated to OSA. Relevant for sleep medicine physicians, fatigue improves with stimulant
therapy (armodafinil).121 This improvement may
serve as a paradigm for patients with chronic lung
disease and fatigue to receive empiric therapy.
Although most of the data are in pediatric populations, OSA seems to be more common among
patients with sickle cell anemia as compared
with controls.122124 OSA among patients with
sickle cell disease is accompanied by more severe
nocturnal desaturations and hypercarbia.123
Although larger studies are needed to better
describe the relationship, OSA, through nocturnal
hypoxia, may serve as a trigger for vasoocclusive
sickle events.125 This relationship highlights the
potential importance of recognizing and treating
OSA among those with sickle cell disease.
Cystic fibrosis (CF) is a systemic disease characterized by abnormal chloride channel function.
Obstructive lung disease, bronchiectasis, and
repeated pulmonary infections caused by tenacious sputum are common among patients with
CF. Sleep apnea is common (in up to 70% of children with CF).126 OSA presents at an early age as
compared with controls, as young as preschool
age.126 NOD is also common among patients
with CF, particularly those with awake oxygen
saturation less than 94%.127

SUMMARY
The combination of chronic lung disease and OSA
in a single patient is still, as yet, poorly understood.
Many research and clinical questions remain,
including how best to quantify upper airway
collapsibility and sleep fragmentation in patients
already at risk for hypoxemia caused by chronic
lung disease. These questions must be answered
given the high prevalence of the OVS, COPD and
OSA, and observational cohort studies that show
very high mortality without OSA treatment.

Other chronic lung diseases, such as IPF, are

much less common; yet diagnosis and treatment
of OSA may be important. Within these patient
populations, there are few or no therapies available to target the underlying disease and its consequences. Recognition and treatment of OSA,
therefore, could offer key benefits, such as improvements in quality of life or fatigue level.

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