Clinical manifestations

Presentation and course

Difficulty in initiating and maintaining sleep is frequently reported in chronic obstructive pulmonary disease (COPD) patients, causing several adverse consequences, including fatigue and sleepiness during waking hours, increased use of sedative medications, and decrement in quality of life. Morning headaches are common due to nocturnal hypoventilation and CO₂ retention. As well as a high frequency of restless legs syndrome and periodic limb movement disorder in this patient group, which can contribute to sleep disturbances (20; 85; 09; 18).

Objective evidence of disturbed sleep (prolonged sleep latency, frequent awakenings from sleep, reduced sleep efficiency, diminished deep NREM and REM sleep) has been demonstrated by polygraphic studies. Studies during sleep show that oxyhemoglobin saturation is reduced from waking levels, with episodes of further desaturation occurring in REM sleep, and that sleep continuity is disrupted by arousals related to hypoventilation and hypoxemia (23; 101). Cough or dyspnea with wheezing are often associated with the awakenings. Sleep becomes more disrupted with exacerbations; conversely, new or intensified symptoms of sleep disturbance should suggest a deterioration of lung function.

Chronic obstructive pulmonary disease refers to an irreversible progressive disease due to damage in the alveolar duct wall and inflammation in the respiratory tract, leading to a degradation of basic daily activities as a result of respiration symptoms (eg, shortness of breath, cough, and sputum), general symptoms (eg, fatigue, sleep disorders, and memory loss), and psychological problems (68). Consequently, sleep disturbances seem to be mainly related to the extent of nocturnal hypoxemia, which, in turn, depends on awake arterial pO2 and pCO2. Thus, important desaturation dips and sleep disturbances are usually observed in patients with a severe form of chronic obstructive pulmonary disease characterized by marked diurnal hypoxemia and daytime diurnal pulmonary hypertension. In these cases, examination during wakefulness may show evidence of respiratory insufficiency, including increased respiratory effort and tachypnea, central cyanosis due to hypoxemia and erythrocythemia, and peripheral edema as a sign of right heart failure.

Conversely, a consensus is lacking on the presence of sleep disturbances in patients with mild obstructive pulmonary disease and isolated nocturnal oxyhemoglobin desaturation (84; 52). Hynninen and colleagues evaluated insomnia symptoms by means of the Bergen Insomnia Scale and performed polysomnography in 73 patients with moderate or severe chronic obstructive pulmonary disease (39). Insomnia was reported by 69.9% of patients, and obstructive sleep apnea syndrome and periodic limb movement index of 15 or greater were observed during polysomnography in 75.3% and 35.6% of patients, respectively. The authors found that severity of pulmonary disease, particularly severity of dyspnea, was positively associated with severity of subjective insomnia symptoms, but not with any of the objectively measured sleep variables. In multivariate analysis, the score of the Bergen Insomnia Scale was independently associated with periodic limb movements, nocturnal respiratory disturbances, pain, and psychological distress, suggesting that insomnia in chronic obstructive pulmonary disease might have multifactorial origins. Restless legs syndrome (RLS) was determined to coexist 26.3% to 36.8% in chronic obstructive pulmonary disease patients, thus, more frequent in this disease than in the normal population. One study evaluated the restless legs syndrome symptoms in patients experiencing chronic obstructive pulmonary disease exacerbation showing a prevalence of 54.5% (04; 55).

The association between obstructive sleep apnea syndrome and chronic obstructive pulmonary disease, known as "the overlap syndrome," is not rare and is more prevalent with age, in male gender, cigarette use, and increase of body mass index. In patients with chronic obstructive pulmonary disease, loud snoring and awakenings with choking, marked diurnal hypersomnolence, and degrees of hypoxemia and hypercapnia disproportionate for the entity of pulmonary function impairment suggest the concomitant presence of obstructive sleep apnea syndrome (70; 51). Patients with overlap syndrome typically report poor sleep quality, snoring and broken sleep, daytime fatigue, and excessive daytime somnolence. Moreover, obstructive sleep apnea syndrome can lead to a permanent dysregulation of the autonomic cardiovascular control resulting in sustained sympathetic hyperactivity associated with hypertension, tachycardia, hyperthermia, and nocturnal hyperhidrosis (89).

In patients with obstructive sleep apnea, the early detection and treatment of cardiovascular dysautonomia can avoid the occurrence of life-threatening chronic autonomic hyperactivity.

In asthma, sleep is disrupted by "attacks" of bronchospasm. Nocturnal awakenings due to attacks are experienced by most asthmatics but are more frequent and more severe during exacerbations. In a study comparing patients with nocturnal asthma and control subjects, the asthmatics had higher scores for subjective sleepiness and worse daytime cognitive performance (28). Moreover, nightmares are reported more frequently by asthmatic patients compared to normal subjects (44). A case-control study reported a higher restless legs syndrome frequency in the asthma group than in the control one (32.1% vs. 15.7%) (37). Nocturnal asthma is not related to sleep stage or time of night (62), and oxyhemoglobin desaturation during REM sleep is less severe than in chronic obstructive pulmonary disease.

In adult patients with cystic fibrosis, polysomnographic studies demonstrated reduced sleep efficiency, more frequent awakenings, and lower mean arterial oxyhemoglobin saturation. This group of patients also showed daytime hypersomnia as measured by multiple sleep latency test (25). In children with cystic fibrosis, a significant decrease in sleep efficiency, prolonged REM sleep latency, and reduction in the percentage of REM sleep were observed when compared to controls (65). Sleep disturbances have also been demonstrated in patients with restricted lung function due to interstitial lung disease and fibrosis, kyphoscoliosis, and a variety of neuromuscular conditions including chronic poliomyelitis and the muscular dystrophies (17). Two studies in the mid-1980s have shown nocturnal hypoxemia, sleep fragmentation, an increase in stage 1 sleep, and a reduction in REM sleep in the presence of severe lung fibrosis (14; 73). Patients with pulmonary fibrosis secondary to systemic sclerosis showed very disrupted sleep with an increased amount of periodic limb movement disorder and increased frequency of restless legs syndrome (76). Excessive daytime sleepiness (77.7%), snoring (88.8%), witnessed apneas (44.4%), and daytime fatigue (61.1%) were observed in patients affected with idiopathic pulmonary fibrosis. Other data suggest that obstructive sleep apnea in idiopathic pulmonary fibrosis is more frequent than previously suspected (61; 49). Coexisting obstructive sleep apnea was mainly observed only in obese idiopathic pulmonary fibrosis patients with a significant impairment in pulmonary function testing (based on FVC and FEV1) (61).

Coronaviruses (CoVs) are a group of single-stranded RNA viruses that are able to infect humans. Six human coronaviruses have been identified, and in 2019, SARS-CoV-2 emerged in Wuhan, China, and rapidly spread worldwide causing a pandemic (104). The clinical spectrum resulting from infection with the responsible virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is broad, ranging from an asymptomatic response or development of a mild upper respiratory tract infection to critical illness. Initial reports of hospitalized patients in Wuhan described a high proportion of individuals with atypical pneumonia requiring critical care admission with features of acute respiratory distress syndrome (ARDS) (66; 99; 103; 104). The primary pulmonary pathology seemed to show not only diffuse alveolar damage but also evidence of direct viral cytopathy, implying a direct causative role of virus-induced damage in the development of ARDS rather than it resulting from a generalized inflammatory response (99). One study included 1733 discharged patients with COVID-19 reporting sleep difficulties as one of the most common symptoms (26%). Long-lasting symptoms in patients recovering from an acute phase are called “post-acute COVID-19 syndrome,” “post-acute sequelae of SARS-CoV-2 infection,” or “long COVID/long haul COVID” (64). Patients with post-acute COVID-19 syndrome present a heterogeneous combination of symptoms, including sleep disturbance, fatigue, exercise intolerance, persistent low-grade fever, lymphadenopathy, hair loss, muscle weakness, arthralgias, dyspnea, cough, palpitations, chest pain, anxiety, depression, and posttraumatic stress disorder (24). At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression (40). A French study of 556 participants from the general population revealed that 19.1% met the diagnostic criteria for clinical insomnia (45). A meta-analysis of 98 studies reported that the pooled prevalence of insomnia symptoms during the early and late stages of COVID-19 in China was 37.0% (95% CI 34.1%–39.9%) and 41.8% (95% CI 33.6%–50.0%), respectively (53). Overall, data from numerous studies in several countries suggest that among the general population, female gender, urban living, high-risk environment with regard to COVID-19, lower socioeconomic and educational status, preexisting psychiatric conditions with poorer coping mechanisms, absence of social support structures, and high level of exposure to COVID-19–related news are risk factors for COVID-19–related insomnia (08).

Some studies reported increased obstructive sleep apnea disorder after COVID‐19 infection. One study found a prevalence of obstructive sleep apnea of 73% in patients with COVID-19–related acute respiratory distress syndrome, 4 to 6 weeks after discharge (35). Another study of 68 patients with severe COVID‐19 requiring intensive care unit admission found that sleep apnea was involved in 91% of this population 3 months after symptom onset and was mainly of the obstructive type (95). A large‐scaled multi‐institutional retrospective study, based on ICD‐10 code, showed a high incidence of new diagnoses of obstructive sleep apnea after COVID‐19 infection (54). Compared to patients without COVID-19 infection, the COVID‐19 group was associated with an increased risk of obstructive sleep apnea at both 3 months of follow‐up (HR: 1.51, 95% CI: 1.48–1.54) and 1 year of follow‐up (HR: 1.57, 95% CI: 1.55–1.60).

Studies have reported data on the impact of the COVID-19 pandemic on the prevalence of restless legs syndrome. One cross-sectional survey evaluated the prevalence, current and pre-COVID, in 136 participants with long COVID-19 (89.7% females, age 46.9 ± 12.9 years) and 136 controls (65.4% females, age 49.2 ± 15.5) who never had overt symptoms of COVID-19. Restless legs syndrome prevalence in females with long COVID-19 was 5.7% pre-COVID-19 and 14.8% post-COVID-19 (p < 0.01) versus 6.7% in control females (100). An epidemiologic study in a large Korean adult population performed during the COVID-19 pandemic found that the prevalence of restless legs syndrome (16.2%) and chronic persistent restless legs syndrome (4.3%) was higher than that in the 2007 survey before COVID-19 (prevalence of 3.9% and 1.7%, respectively) (43). Furthermore, a longitudinal observational study (The National RLS Opioid Registry) reported increased restless legs syndrome severity during the early period of the COVID-19 pandemic (102).

Prognosis and complications

Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of chronic obstructive pulmonary disease, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing increased the risk of these complications. Pulmonary hypertension in chronic obstructive pulmonary disease is relatively common in moderate-severe disease. The discovery of severe pulmonary hypertension in patients with chronic obstructive pulmonary disease requires the search for comorbidities, such as obstructive sleep apnea syndrome, obesity-hypoventilation syndrome, and chronic thromboembolic disease (93). In the majority of cases, chronic obstructive pulmonary disease-related pulmonary hypertension will progress slowly, but a minority of cases will develop cor pulmonale characterized by overt right heart failure and peripheral edema. The occurrence of “cor pulmonale” carries a significantly worse prognosis for the patient.

Long-term continuous oxygen therapy has been demonstrated to improve survival, sleep, and quality of life in severe forms of chronic obstructive pulmonary disease with daytime resting PaO2 equal to or less than 55 mm Hg or SpO2 less than 90% (69).

Significant nocturnal hypoxemia has been reported in up to 70% of patients with chronic obstructive pulmonary disease, with daytime saturations between 90% and 95%, however, isolated hypoxemia during sleep is a common occurrence in patients with advanced chronic obstructive pulmonary disease and may occur despite adequate awake oxygenation (52). Chronic obstructive pulmonary disease patients with nocturnal hypoxemia have a lower survival rate than those without nocturnal hypoxia. Nocturnal hypoxemia represents a potential contributory factor to this worsening due to a rostral shift of peripheral edema leading to compromise of the upper airway and associated alveolar hypoventilation (79). The development of increased pulmonary vascular resistance that is associated with poorer survival has been correlated with pronounced nocturnal oxygen desaturations during REM sleep. Supplemental oxygen prevents transient arterial hypoxemia in a majority of subjects with chronic obstructive pulmonary disease and nocturnal oxyhemoglobin desaturation and, therefore, might prevent the progression of pulmonary hypertension in patients who experience only nocturnal oxygen desaturations. Other studies showed a moderate increase in the survival rate in patients who received oxygen therapy (10). Supplemental oxygen would prevent transient arterial hypoxemia in a majority of subjects with chronic obstructive pulmonary disease and nocturnal oxyhemoglobin desaturation while preventing the progression of pulmonary hypertension in patients who experience only nocturnal oxygen desaturations. However, the discrepancy in survival rates might be explained by the fact that oxygen therapy in patients with chronic obstructive pulmonary disease produces a decrease in mean pulmonary arterial pressure, even though it may not improve pulmonary hemodynamics significantly (29).

Conversely, a larger 2-year, randomized study on chronic obstructive pulmonary disease patients with nocturnal oxygen desaturation without obstructive sleep apnea and mean daytime PaO2 between 56 mm Hg and 69 mm Hg did not find any survival benefit or effects on pulmonary hemodynamics in patients receiving oxygen supplementation. Moreover, it was observed that isolated nocturnal desaturation is not associated with impairment of quality of life, sleep quality, and daytime function in patients with chronic obstructive pulmonary disease (52).

Chronic obstructive pulmonary disease patients with insomnia, compared to those without insomnia, are more likely to suffer from daytime sleepiness, which potentially leads to decreased productivity at work, absenteeism, and traffic accidents. Moreover, patients complained of neuropsychological deficits including slower processing speed and increased visual memory errors and omissions (27).

The coexistence of chronic obstructive pulmonary disease and obstructive sleep apnea has implications with respect to outcomes. In patients with obstructive sleep apnea syndrome, the presence of chronic obstructive pulmonary disease is associated with lower and longer nocturnal oxyhemoglobin desaturations (07). Moreover, the coexistence of chronic obstructive pulmonary disease significantly increased the risk of mortality in patients with sleep apnea (50). A prospective study demonstrated higher mortality when untreated comorbid obstructive sleep apnea was present than with chronic obstructive pulmonary disease alone. The causes of death were primarily cardiovascular (28.1%), followed by cancer (26%), and pulmonary (25.8%). In patients with obstructive sleep apnea and concurrent chronic obstructive pulmonary disease, continuous positive airway pressure (CPAP) therapy improves survival; however, in CPAP-treated patients with chronic obstructive pulmonary disease and obstructive sleep apnea, the risk of mortality and severe exacerbations was similar to that observed in patients with chronic obstructive pulmonary disease only (56). Nevertheless, a significant proportion of such patients do not tolerate CPAP. A study analyzed early predictors of CPAP failure in patients with obstructive sleep apnea and concurrent chronic obstructive pulmonary disease, revealing that daytime hypercapnia and nocturnal hypoxia are independent predictors of early CPAP failure (47).

Patients with mild chronic obstructive pulmonary disease and obstructive sleep apnea syndrome have greater sleep perturbation and desaturations than those with only one disorder (84).

A study of 4668 participants with positive COVID-19 RNA PCR diagnostic results identified obstructive sleep apnea as a risk factor for COVID-19 mortality (15). Another study of 445 individuals with COVID-19, 38 of whom with obstructive sleep apnea, reported that the risk for contracting COVID-19 was the same for patients with obstructive sleep apnea and those without it but, among COVID-19-positive patients, obstructive sleep apnea was associated with higher risk for hospitalization (92). These results showed that obstructive sleep apnea is an independent risk factor for severe COVID-19 and highlighted the need for close monitoring of patients with sleep apnea who become infected. In patients with chronic obstructive pulmonary disease and community-acquired pneumonia, the presence of SARS-CoV-2 as an etiologic agent is associated with more cardiovascular events, longer hospital stays, and a 7-fold increase in mortality (86).

Sleep disorders, including obstructive sleep apnea, can be associated with immunological and inflammatory factors involved in morbimortality, and their role on infection by SARS-CoV-2 should be investigated. Death in asthma occurs most frequently during the sleep period (26). Vigorous treatment of nocturnal asthma may reduce mortality in this disease. Further, sleep disturbances (sleep fragmentation and inability to consolidate sleep) in patients with nocturnal asthma result in excessive daytime sleepiness, which may contribute to poor daytime functioning and cognitive impairment in comparison to age- and education-matched non-asthmatics (28).

In patients suffering from idiopathic pulmonary fibrosis, REM-associated sleep-related breathing disorders might play an important role in survival. The sleep-related desaturation in these patients might contribute to pulmonary vascular disease development, with pulmonary hypertension as one of the possible consequences. Therefore, it might be a risk factor for increased mortality (16).

Randomized controlled trials comparing a form of pressure preset or volume preset noninvasive ventilation to no noninvasive ventilation used for airway clearance or during sleep or exercise in people with acute or chronic respiratory failure in cystic fibrosis were reviewed. Trials reported on two of the review's primary outcomes (quality of life and symptoms of sleep-disordered breathing). Reviews of secondary outcome measures showed that they measured lung function, gas exchange, adherence to treatment and preference, and nocturnal transcutaneous carbon dioxide. Due to the small number of participants and statistical issues, there were discrepancies in the results. No clear differences were found between noninvasive ventilation compared with oxygen or room air except for exercise performance, which significantly improved with noninvasive ventilation compared to room air over 6 weeks. The trial found no clear differences between noninvasive ventilation compared to no noninvasive ventilation for any of our outcomes. One trial evaluating noninvasive ventilation for overnight support reported that one participant could not tolerate an increase in inspiratory positive airway pressure (63).

Clinical vignette

A 44-year-old male was referred to the sleep center because of a several-year history of daytime sleepiness, morning headache, snoring, and witnessed respiratory pauses. The patient had a history of asthma since childhood, a 15-pack-a-year smoking history, and progressive, worsening respiratory symptoms over the past 3 years to 4 years. He had numerous emergency room visits in the past several years prompting intermittent steroid use and chronic use of numerous respiratory medications including an inhaled steroid, beta agonist, ipratropium bromide, and an oral leukotriene antagonist. Formal pulmonary function testing demonstrated a forced vital capacity of 2.9 L (59% predicted) and a forced expiratory volume in 1 second of 1.58 L (40% predicted).

Room air blood gas showed a pH of 7.36, pCO2 of 49, and pO2 of 74. A formal sleep study demonstrated moderate sleep fragmentation, reduced slow wave, stage 2, and REM sleep, and significant REM-associated hypoventilation with few scorable respiratory events. His lowest oxygen saturation was 73% in REM sleep. An attempt at bi-level nocturnal ventilation was unable to completely eliminate REM-associated hypoventilation and was not tolerated by the patient. The patient was managed with aggressive respiratory care including intensified education on proper medication use along with nocturnal oxygen therapy.

Biological basis

Etiology and pathogenesis

The pathogenesis of sleep disorders in pulmonary disorders is a complex and multifactorial process where several pathophysiological changes including inflammation, sleep hypoxemia, and hypercapnia, medications, some comorbid disorders such as nocturnal gastroesophageal reflux (GERD), and environmental factors (such as nicotine) might play a role (10).

Ventilatory changes normally occur in humans during sleep. The normal sleep pattern of periodic cycles every 90 to 120 minutes starts with NREM sleep phases and culminates in an episode of REM sleep. In normal subjects, breathing control is different during wake, NREM, and REM sleep. Under normal conditions, there is, during wake, a balance of automatic (or metabolic) and voluntary (or behavioral) inputs that allow respiration. During sleep, only automatic inputs are active in determining ventilation.

At sleep onset and light sleep (stage I and II of NREM sleep), breathing often becomes periodic, and sporadic central apneas are frequently observed. Breathing oscillations occur periodically, every 20 to 30 seconds, associated with synchronous oscillations of cortical EEG activity, systemic arterial pressure, heart rate, and O2 saturation.

During deep NREM sleep, breathing becomes more regular, and systemic arterial pressure drops 20% to 30% below basal wakefulness values. REM sleep is subdivided into tonic and phasic periods. The entire REM sleep period is uniquely characterized by the absence of electromyographic-detectable skeletal muscle tone, but the phasic period is further identified by bursts of unsynchronized rapid eye movements. In association with phasic phenomena during REM sleep, arterial pressure and heart rate become irregular, and central apneas or hypopneas lasting 20 to 30 seconds may occur. Muscle inhibition in REM sleep is prominent in the intercostal and accessory breathing muscles, shifting the work of ventilation principally to the diaphragm. Minute ventilation decreases during sleep, particularly during REM sleep as the responses to hypercapnia and hypoxia are blunted, the rib cage contribution to ventilation is reduced, and the upper airway resistance is increased. Gas exchange is altered, with a minor but significant reduction in PaO2 and an increase in PaCO2.

Patients with chronic obstructive pulmonary disease present the common denominator of abnormal lung function and vulnerability to sleep-induced gas exchange alterations. Hypoventilation with reduced tidal volume and ventilation-perfusion mismatch cause hypoxemia and hypercapnia (23; 06; 58), which in turn produce increased respiratory effort and arousal.

Hypoxemia with oxyhemoglobin desaturation is the hallmark of sleep disorders due to chronic lung disease. Patients with chronic obstructive pulmonary disease show a minute ventilation fall of nearly 20% during NREM sleep and 40% lower oxygenation during REM sleep compared to the awake state (06; 67). Worsening of hypoxemia in these patients is mainly due to reduced hypoventilation and ventilation-perfusion mismatch that is the consequence of a decrease in functional residual capacity.

The possible mechanisms for reduced functional residual capacity include respiratory muscle hypotonia, cephalad displacement of the diaphragm, and an decrease in lung compliance (58; 101).

The effect of hypoxemia is increased by hypercapnia. The maximum change in nocturnal oxygen saturation has been negatively correlated with the awake ventilatory response to hypercapnia and awake oxygen saturation. The combined effects stimulate breathing and cause arousal. Arousal is an important defense against compromised lung function. Thus, hypoxemia and hypercapnia, increased impedance to breathing, and airway irritation are each capable of producing arousal when the stimulus exceeds a threshold. The inhibitory effect of REM sleep on muscle excitation accounts for the severe desaturation that is associated with this sleep stage. Patients with compromised diaphragmatic function, including chronic obstructive pulmonary disease with severe air trapping, obesity with severely restricted lung function, and neuromuscular diseases with diaphragmatic involvement, are especially at risk for this effect of REM sleep.

During sleep, nocturnal desaturation also causes pulmonary vasoconstriction, resulting in elevated pulmonary arterial pressure, and increases the oxygen demands of the myocardium (87; 94). Several studies in patients with chronic obstructive pulmonary disease have demonstrated significant elevations of pulmonary arterial pressure during episodes of nocturnal desaturation, usually occurring during REM sleep. Hypoxemia stimulates endothelin-1 secretion, which can then act locally to elicit sustained pulmonary artery vasoconstriction, bronchoconstriction, and activation of alveolar macrophages (94).

In chronic obstructive pulmonary disease increased sympathetic activity resulted in consequent alteration of sympathovagal balance. Chronic hypoxia, hypercapnia, impaired baroreflex responses, hyperinflation, elevated pulmonary artery pressures, and dyspnea can all contribute to autonomic dysfunction. Indeed, plasma norepinephrine levels are elevated in hypoxemic patients with chronic obstructive pulmonary disease and decrease with long-term oxygen therapy (09). Consequently, nocturnal arrhythmias are also common in chronic obstructive pulmonary disease patients, with one study finding premature supraventricular and ventricular contractions to be twice as common in chronic obstructive pulmonary disease patients with the peak incidence occurring between 3:00 AM and 5:00 AM (31).

Apart from hypoxia and increased sympathetic activity, other mechanisms can contribute to hyperarousal and insomnia including bronchospasm and cough due to airway inflammation and excess secretions, nicotine use and withdrawal, comorbid disorders such as anxiety and depression, as well as comorbid sleep disorders including sleep-disordered breathing and restless legs syndrome. Contrariwise, medications such as inhaled steroids and inhaled B-agonists do not seem to worsen insomnia (12).

The coexistence of chronic obstructive pulmonary disease and obstructive sleep apnea might be favored by several conditions. In chronic obstructive pulmonary disease, central obesity and fat deposition in the neck due to chronic oral steroids may facilitate obstructive sleep apnea; chronic obstructive pulmonary disease is also associated with generalized muscle weakness, which might lead to higher upper airway collapsibility. On the other hand, obstructive sleep apnea can lead to bronchial airway inflammation and worsen gastrointestinal reflux. Gastroesophageal reflux disease is strictly related to obstructive sleep apnea and worsens the asthmatic component of chronic obstructive pulmonary disease. Acid reflux into airways can cause increased airway reactivity by either local inflammation or by enhancing vagal tone. It is plausible that nocturnal gastroesophageal reflux disease may play a role in the development of obstructive lung disease and obstructive sleep apnea symptoms. Indeed, one study showed worse respiratory and sleep apnea symptoms in those with gastroesophageal reflux disease (12). Finally, smoking, the major risk factor for chronic obstructive pulmonary disease, may also contribute to an increased prevalence and severity of obstructive sleep apnea. Both obstructive sleep apnea and chronic obstructive pulmonary disease are associated with inflammatory cell activation and hypoxia, leading to endothelial dysfunction and consequently several adverse outcomes (59).

The pathogenic relationship between obstructive sleep apnea and interstitial lung disease is not understood. Obstructive sleep apnea could appear during the natural course of interstitial lung disease as a consequence of lung function restriction. Otherwise, obstructive sleep apnea could promote gastroesophageal reflux disease or increase oxidative lung stress through chronic nocturnal intermittent hypoxia and these two mechanisms could increase the risk for interstitial lung disease (16).

Nocturnal exacerbation of asthma is common and is related to several mechanisms (36). Circadian regulation of respiratory function contributes to increased lower airway resistance during the night period, even when sleep is prevented (05). However, sleep-related increases in parasympathetic airway innervation might also play a role in nocturnal asthma (38) by increasing submucosal gland secretion, bronchial blood flow, and airway resistance. Further, decreased lung volume and reduced sighs during sleep may contribute to unloading airway smooth muscle, leading to an increase in actin-myosin binding, which, in turn, may contribute to enhanced bronchoconstrictive force generation (32). The latter is also increased in asthmatic patients due to inflammation-induced peribronchial thickening. Finally, variation in therapeutic effect due to dose schedules may also contribute to nocturnal bronchospasm.

Epidemiology

The most prevalent chronic respiratory disorders are chronic obstructive pulmonary disease, asthma, and obstructive sleep apnea. In all chronic obstructive pulmonary diseases, epidemiological studies show a high frequency of sleep disturbances. Chronic obstructive pulmonary disease prevalence is related to the prevalence of tobacco smoking (19). Current estimates for the prevalence of chronic obstructive pulmonary disease and obstructive sleep apnea syndrome is at least 10% (72). The prevalence of obstructive sleep apnea is equally high with over 25% of adult males having an apnea-hypopnea index (AHI) greater than 5 and up to 15% and having AHI greater than 5 with associated excessive daytime sleepiness (EDS) (72). Furthermore, the prevalence of obstructive sleep apnea has been increasing over recent decades, most likely as a consequence of the rising prevalence of obesity. Still debated is the prevalence of obstructive sleep apnea in chronic obstructive pulmonary disease, which according to Bednarek, is not superior to that of the general population (10% to 30%) (07). The “overlap syndrome” (concurrence of obstructive sleep apnea and chronic obstructive pulmonary disease) occurs in approximately 1% of adults in the general population (77). Sanders and colleagues described polysomnographic characteristics in a cohort of subjects with mild obstructive airways disease founding that obstructive sleep apnea-hypopnea syndrome was not more prevalent in participants with obstructive airways disease (22%) than in those without obstructive lung disease (29%) (84). Also, Soler and colleagues found a high prevalence of obstructive sleep apnea in patients with severe chronic obstructive pulmonary disease, particularly when overweight (90).

Cormick and colleagues compared the quality of sleep of 50 patients with chronic obstructive lung disease with those of a similarly aged population without lung disease (23). This study found that patients reported more difficulty in initiating (36% vs. 15%) and maintaining sleep (76% vs. 53%) and more daytime sleepiness (72% vs. 30%) compared to controls. Further, more than twice as many patients (28%) as controls (10%) reported regular use of hypnotics. In a subsequent study describing the prevalence of sleep disturbances in a large general population (2187 adults), complaints of sleep disturbance were found to be significantly more common among the 310 subjects with chronic obstructive pulmonary disease (44). The prevalence of disorders of initiating and maintaining sleep was shown to be nearly 36% in adults classified as not having chronic obstructive pulmonary disease, whereas it was as high as 53% in patients with chronic bronchitis and 55% in patients with primary emphysema; diurnal hypersomnolence was present in 26% of patients with chronic bronchitis and 29% of patients with emphysema. Valipour and colleagues compared 52 patients with mild-to-moderate stable chronic obstructive lung disease with an equal number of controls and found that patients more frequently reported symptoms like difficulty in initiating and maintaining sleep (98). In a study evaluating sleep habits in a community-based sample of 3282 participants, increased odds of insomnia (1.9; P< 0.001) were found in participants with self-reported chronic obstructive pulmonary disease compared to those without (11). A pan-European survey aimed at exploring the prevalence and impact of nighttime symptoms through the Jenkins Sleep Scale in patients with chronic obstructive pulmonary disease found that 78% complained of nighttime symptoms (01). Finally, a study through an interviewer-conducted survey administered to 183 consecutive patients with chronic obstructive pulmonary disease found insomnia disorder (chronic sleep disturbance associated with impaired daytime functioning) in 27.3% of participants (10). The prevalence of restless legs syndrome is higher in chronic obstructive pulmonary disease (OR = 2.8) (09). Some studies reported an increased frequency of restless legs syndrome in patients with chronic obstructive pulmonary disease, with a prevalence of 26.3% to 36.8% and rising to 54.5% in those experiencing chronic obstructive pulmonary disease exacerbation (04; 55).

Nocturnal exacerbation of asthma is common and impairs sleep quality, causing daytime sleepiness, which adversely affects patients’ quality of life. A survey of 7729 asthmatic patients found nocturnal awakening due to asthmatic symptoms to occur nightly in 39% and at least one night per week in 74% of patients (97). Subsequently, Janson and colleagues found that difficulties inducing sleep and morning awakenings were twice as common, and complaints of daytime sleepiness were 50% more frequent in asthmatic patients compared to subjects without asthma (41). Further, they demonstrated a significant correlation between sleep disturbances and the number of asthma-related symptoms. Using a standardized sleep questionnaire, Mastronarde and colleagues demonstrated that symptomatic mild-to-moderate asthmatic patients have significant impairment in global sleep quality, which results in excessive daytime sleepiness (57).

In idiopathic pulmonary fibrosis, the association with obstructive sleep apnea ranges from 6% to 91%. The prevalence of obstructive sleep apnea ranged from 5.9% in an analysis of 9286 patients with idiopathic pulmonary fibrosis identified from two U.S. databases to 91% among 31 patients from a Greek outpatient interstitial lung disease unit (78). Lancaster found obstructive sleep apnea in 88% of an idiopathic pulmonary fibrosis sample; 68% with moderate-severe obstructive sleep apnea (apnea-hypopnea index > 15 events per hour) (49).

Prevention

Stopping daytime habits that might contribute to insomnia (eg, smoking, alcohol, and caffeine intake) should be strongly encouraged to improve sleep hygiene.

Smoking cessation is mandatory in the management of all patients with chronic obstructive pulmonary disease, and pulmonary rehabilitation is strongly recommended. Other therapies useful to optimize lung function in chronic lung disorders while reducing both exacerbations and the symptoms of the associated sleep disorders include preventive vaccination for influenza and pneumococcal pneumonia. Educating patients on the avoidance of respiratory depressants such as alcohol, opiates, or sedative hypnotics close to bedtime is also helpful. The avoidance of allergens and correct therapeutic management of the respiratory condition can maintain a higher level of lung function and, thus, reduce the severity of nocturnal respiratory events.

Diagnostic workup

Sleep disorders attributed to chronic lung disease must be differentiated from other causes of insomnia and excessive daytime sleepiness. In adults with chronic obstructive pulmonary disease, obstructive sleep apnea should be excluded. Male gender, obesity, anatomic upper airway abnormality, prominent snoring, and other symptoms of upper airway obstruction in sleep should direct attention to this disorder. Central sleep apnea syndrome should be considered if congestive heart failure is present. Finally, the role of poor sleep hygiene is important to consider. Many patients with chronic illness spend an excessively long time in bed at irregular hours, which may contribute to sleep fragmentation and insomnia.

Spirometry and arterial blood gas analysis should be performed in all patients who report any combination of dyspnea, chronic cough, or chronic sputum production, especially if there is a history of exposure to triggers of chronic obstructive pulmonary disease (eg, tobacco smoke, occupational dust, indoor biomass smoke), a family history of chronic lung disease, or presence of associated comorbidities (heart failure, metabolic syndrome, and sleep apnea).

In the evaluation of patients with chronic obstructive pulmonary disease, chest radiography is typically performed to exclude alternative diagnoses. Chest computed tomography is necessary to exclude certain complications of chronic obstructive pulmonary disease (eg, thromboembolic disease) (34).

The ECG may provide suggestive or supportive evidence of pulmonary hypertension by demonstrating right ventricle hypertrophy and right atrial dilatation. Transthoracic echocardiography provides several variables that correlate with right heart hemodynamics and should always be performed in the case of suspected pulmonary hypertension. Polycythemia can be investigated with a hemoglobin concentration test (33).

Although the gold standard investigation for sleep-disordered breathing is overnight polysomnography (PSG), this study is not practical for the large number of patients suffering from chronic obstructive pulmonary disease, except when there are clinical suspicions of obstructive sleep apnea or complications of hypoxemia that are not explained by the awake arterial oxygen levels. Clinical assessment in all patients with chronic obstructive pulmonary disease should include questions about possible coexisting sleep apnea syndrome. All patients with chronic obstructive pulmonary disease with relatively low daytime saturation (< 93%) should be considered for overnight oximetry (48). Chronic obstructive pulmonary disease patients with symptoms suggestive of obstructive sleep apnea, such as snoring or witnessed apneas, or in patients with the presence of pulmonary hypertension should be evaluated with polysomnography. Home-sleep testing, although cheaper and relatively more convenient to diagnose sleep-disordered breathing, has not been validated in chronic obstructive pulmonary disease and is not recommended by the American Academy of Sleep Medicine. In-lab PSG is superior to in-home testing due to the ability to continuously monitor oxygen saturation and noninvasively monitor PCO2 (22).

Management

Management of sleep problems in chronic obstructive pulmonary disease should be primarily focused on optimizing the patient’s overall respiratory condition through correct treatment to ensure that poor symptom control is not the main cause of sleep disturbances (03).

Treatment of severe hypoxemia with long-term oxygen therapy is one of the few interventions shown to prolong survival in hypoxemic chronic obstructive pulmonary disease patients, also improving sleep and quality of life. Long-term continuous oxygen therapy should be introduced to improve survival, sleep, and quality of life only in severe forms of chronic obstructive pulmonary disease with daytime resting PaO2 equal or less than 55 mm Hg or SpO2 less than 90% (69). Prescription of oxygen flow is based primarily on the waking PaO2 values, and the therapeutic goal is to maintain PaO2 greater than 60 mm Hg and SpO2 greater than 90% during waking rest (03; 34).

An increase of 1 L/min is usually requested during sleep as a high percentage of patients do not reach optimal correction of nocturnal SpO2 greater than 90% (75). The goal of treatment is in fact to maintain SaO2 of more than 90% for 70% of the sleep time. However, this high oxygen flow rate may increase nocturnal hypoventilation and consequently diurnal hypercapnia through bicarbonate retention and blunted response to hypercapnia (83). In these patients, noninvasive ventilation during sleep could represent a therapeutic option (74).

Nocturnal oxygen therapy is not recommended in patients who present only isolated nocturnal hypoxemia and are not severely hypoxemic when awake at rest except in the presence of complications of hypoxemia (polycythemia, pulmonary hypertension, or peripheral edema suggesting congestive cardiac failure) (42).

Noninvasive ventilation is used effectively for exacerbations of chronic lung disease; conversely, a consistent and significant effect of this treatment in stable hypercapnic patients with chronic obstructive pulmonary disease on respiratory function, sleep efficiency, and survival has not been proved (80; 34). Also, there is limited evidence in the management of nocturnal sleep-disordered breathing in patients with the overlap syndrome (60).

A number of pharmaceutical agents have been shown to benefit nocturnal arterial oxygen saturation. Theophylline acts as a central respiratory stimulant and improves diaphragmatic contractility, thus, improving gas exchange during sleep in chronic obstructive pulmonary disease, and has the added benefit of reducing the level of sleep-disordered breathing in obstructive sleep apnea syndrome. Furthermore, bronchodilatation with long-acting anticholinergic agents and long-acting agonists may also improve sleep parameters and sleep quality in patients with chronic obstructive pulmonary disease (01; 42).

Treatment of insomnia requires, again, the optimal management of the respiratory condition and the improvement of sleep hygiene. Pharmacological therapy should avoid the use of traditional benzodiazepines, which have been associated with adverse pulmonary events. Non-benzodiazepine receptor agonists (zopiclone, eszopiclone, zolpidem, zaleplon) seem to have fewer adverse effects on pulmonary function. Finally, the selective melatonin receptor agonist ramelteon has been determined to be safe and efficacious in patients with mild to moderate chronic obstructive pulmonary disease and not detrimental in those with severe form (82). As a second line, treating anxiety and depression may help in improving insomnia.

In obstructive sleep apnea patients, continuous positive airway pressure (CPAP) has been shown to significantly decrease the apnea-hypopnea index and improve sleep-related symptoms, particularly in patients with severe disease (AHI greater than 30/h). Apart from eliminating apneas, CPAP off-loads respiratory muscles and reduces the work of breathing, which decreases hypoventilation and improves daytime oxygenation in patients with chronic obstructive pulmonary disease, contributing to the reduction of the number of severe exacerbations and hospital admissions. As a result, in the “overlap syndrome,” CPAP therapy is considered the gold standard therapy for the treatment of obstructive sleep apnea, and both oxygen and continuous positive airway pressure are complementary therapies (51). In-lab polysomnography may be better than auto-CPAP titration, and use needs to be carefully considered because lung disease, including obesity hypoventilation syndrome, lack of snoring, or central sleep apnea, can often represent contraindications to autoCPAP.

Despite these benefits, nightly CPAP use remains problematic for some patients due to mask discomfort or claustrophobia, pressure intolerance, lifestyle or social considerations, or a combination of these factors. For patients with obstructive sleep apnea with an intolerance to CPAP or those who have hypoventilation in the setting of obesity, the noninvasive ventilation modality of bi-level positive airway pressure (Bi-level PAP) may be considered. Bi-level PAP administers varying pressures between the inspiratory and expiratory cycles. During the inspiratory cycle, the greater level of pressure combats the inspiratory flow limitation in the upper airway, inducing a greater tidal volume and unloading of the respiratory muscles compared to CPAP, and it essentially treats nonobstructive sleep-related hypoventilation.

Finally, consider the possibility of using mandibular advancement devices for those patients with mild to moderate obstructive sleep apnea or patients with severe obstructive sleep apnea who decline or cannot use PAP therapy, and, in selected and appropriate patients, the nasal, palatal, or jaw surgeries (71).

In asthma, the focus of therapy is on the overall reduction in inflammation and bronchial hyperreactivity. Changes in medication schedules considering circadian variation in relevant biological rhythms are essential to optimize therapeutic drug effects. Treatment with theophylline in sustained-release form administered once daily in the early evening or with inhaled corticosteroids given prior to bedtime improves nocturnal lung function and sleep compared to conventional schedules. Similarly, the administration of sustained-release beta2-adrenergic agonists improves bronchoconstriction in the early morning (13; 36). Continuous positive airway pressure improves nocturnal symptoms as well as overall lung function only in some asthmatic patients with concomitant obstructive sleep apnea (88).

In restrictive pulmonary diseases related to neuromuscular disease, kyphoscoliosis, or sequelae of tuberculosis nasal intermittent positive pressure ventilation improves clinical symptoms and survival (80). Treatment with CPAP has been effective in reducing systemic levels of inflammatory biomarkers in patients with obstructive sleep apnea and improving the quality of life in those with concomitant idiopathic pulmonary fibrosis.

One study analyzed the use of CPAP in patients with idiopathic pulmonary fibrosis and obstructive sleep apnea and showed a significant improvement in quality of life, sleep, daily living activities, and survival in these patients (73). The study provided the first evidence that treatment of some comorbidities such as obstructive sleep apnea might influence mortality in idiopathic pulmonary fibrosis patients. However, more studies are required to determine if effective improvement of oxygen desaturation in idiopathic pulmonary fibrosis patients with obstructive sleep apnea would confer a survival benefit (91). Finally, one of the most interesting future research fields is the study of the potential effect of new antifibrotic therapies on underlying comorbidities such as the development of obstructive sleep apnea.

Outcomes

Insomnia and restless legs syndrome are associated with a further decrement in quality of life in chronic obstructive pulmonary disease. Presence of chronic obstructive pulmonary disease increases the risk of depression, anxiety, and panic disorder.

Chronic obstructive pulmonary disease patients with nocturnal hypoxemia have a lower survival rate than those without nocturnal hypoxemia, but treatment with oxygen therapy seems associated with an improvement in survival.

In chronic obstructive pulmonary disease, sleep-related hypoventilation and hypercapnia reduce myocardial and diaphragmatic contractility, increase pulmonary artery pressure, and predispose to arrhythmias. Sleep-related hypoventilation is associated with reduced life expectancy. Chronic obstructive pulmonary disease comorbid with obstructive sleep apnea is associated with more pronounced adverse clinical outcomes compared to chronic obstructive pulmonary disease or obstructive sleep apnea alone. The concurrence of these two conditions is associated with an increased risk of cardiac dysrhythmias, pulmonary hypertension, and right heart failure (12).

Special considerations

Pregnancy

Pregnancy imposes a load on the ventilatory system. In patients with already compromised pulmonary reserve, pregnancy can affect lung function adversely, but the effects during sleep have not been studied.

Anesthesia

Sedatives of all types should be used with caution in patients with chronic lung disease, particularly in the presence of respiratory insufficiency.