Obstructive diseases of upper and lower airways, in particular rhinitis, asthma and chronic obstructive pulmonary diseases (COPD), influence the health status and quality of life of a large percentage of world population (1-3). Sleep represents one third of the human life and it modifies many physiological functions including breathing. The effects of changes during sleep on respiration can lead the symptomatic worsening in patients with chronic obstructive diseases. In addition, rhinitis, asthma, and COPD can lead to sleep fragmentation with consequent daytime fatigue, irritability, decreased mood, general malaise and cognitive impairment (4). Moreover, obstructive diseases of upper and lower airways may be involved in the pathogenesis of sleep breathing disorders such as obstructive sleep apnea syndrome (OSAS). This is a common disorder usually characterized by pharyngeal constriction during sleep, which causes sleep disruption, snoring, choking, frequent awakenings, and excessive daytime sleepiness. OSAS occurs in about 5–10% of the general population (5), and its prevalence increases with age. It is a heterogeneous disease, which causes chronic intermittent hypoxia (CIH) that drives the systemic inflammation that is the pathogenesis of the disease itself. Ioachimescu and Teodorescu have coined the acronym obstructive lung disease and obstructive sleep apnea syndrome (OLDOSA) to indicate the bidirectional links between obstructive lung diseases (OLD) and OSAS. The association between OSAS and COPD or “overlap syndrome” is well characterized, but the association between OSAS and asthma and rhinitis needs to be further investigated to clarify the cause and development of these conditions and the individualized therapeutic interventions (6).
The aim of this narrative review is to summarize the available knowledge about the link between OSAS and rhinitis, asthma, COPD. In particular, the sleep complaints resulting from the incomplete control of obstructive airways diseases and their relationship with OSAS will be discussed.
Sleep complaints and sleep-breathing disorders in rhinitis
In the relationship between sleep impairment and rhinitis, one could cause the other or they could share a common cause. That cause could be an additional medical condition that makes it more difficult to treat a concomitant disease, or these diseases could be independent from any kind of relationship. The latest ARIA guidelines [allergic rhinitis (AR) and its impact on asthma] classification considers rhinitis as a risk factor for sleep impairment and impaired sleep is a criterion to define the severity of the rhinitis. Studies analyzing the impact of rhinitis on sleep found that both in children and in adults almost 40–80% of patients with rhinitis complain of sleep impairment (7,8). Furthermore, Léger and colleagues published the results of an epidemiological study designed to assess the effects of rhinitis on sleep and to explore the relationship between AR duration and severity and the related sleep impairment (9). They studied 591 patients with AR of at least 1-year duration and 501 healthy controls. All the patients provided validated questionnaires assessing quality of life and sleepiness score. The results show a significant impact of AR on all dimensions of sleep quality and, consequently, a lower quality of life. Patients with AR, compared to the control group, had clinically relevant sleep complaints and sleep disorders. More than 40% of patients had snoring, non-restorative sleep, lack of sleep, nocturnal awakenings and difficulty falling asleep, and these complaints were more severe and persistent with increasing rhinitis severity and ARIA classification. A study performed in general practices on a large number of patients with AR (10), found that rhinitis severity was more important than its duration in causing sleep disturbances. Furthermore, the extrapolation of the DREAMS study results shows that rhinitis severity is mainly related to sleep complaints while the duration of rhinitis is associated with sleep apnea (11). Arousal and intermittent hypoxia can lead to a disruption of restorative sleep architecture with pre-cortical dysfunction that can cause problems in using information and leads to poor planning and haphazard execution of plans, disorganization, poor decision-making, rigid thinking, difficulty in maintaining attention and motivation, emotional liability (mood swings), overactivity and impulsivity (especially in children) (12). By mean of a specific neuropsychological assessment, the effect of rhinitis on a wide variety of cognitive processes and functions (attention, visual search and scanning, sequencing and shifting, psychomotor speed, abstraction, flexibility, ability to execute and modify a plan of action, and ability to maintain two trains of thought simultaneously) has been evaluated (13-15). The available results suggest that patients experience subtle slowing in the speed of cognitive processing (Marshall) and decreased efficiency. Also, AR patients may need to use more effort to reach the same performance as healthy subjects, with earlier exhaustion of their ability.
As mentioned before, rhinitis can be involved in sleep complaints as well as in the pathogenesis of sleep breathing disorders such as OSAS. Two physical principles may explain the relationship between rhinitis and OSAS. The Venturi principle states that air must pass faster through a small tube than through a larger one, if the volume of air and time to pass through are equal; the Bernoulli principle correlates the width of the airway to the risk of its collapsibility and the thinner the airways are, the greater the risk of collapsing and vice versa. Furthermore, upper airways act like a Starling resistor. A narrowing at the beginning (i.e., a blocked nose) causes the collapse of the lower tract (i.e., the pharynx) because of the collapsing forces it creates (16). Because of these physiologic principles, patients with chronic night-time rhinitis symptoms are 2 times more likely to snore than control subjects and this is the reason why about 50% of rhinitis patients with nasal congestion are 1.5 times more likely to snore than patients without nasal congestion (17). Several studies have shown this phenomenon. For example, Shedden and colleagues found that more than 80% of congested allergy sufferers have nasal obstruction as the cause of their sleep impairment (18). The logistic regression model estimating the association of congestion with snoring performed by Young, showed that individuals with chronic severe nasal congestion during the night have a 3.6-fold greater risk of habitual snoring at baseline and a 4.9-fold greater risk of habitual snoring at 5-year follow-up (19). Although the correlation between snoring and apnea needs to be better understood, nasal congestion is also associated with sleep apnea. The greater the increase of nasal resistance, the greater the increase in obstructive apnea. Moreover, apneas are longer and more frequent in patients with nasal congestion than those without it (20). This phenomenon seems strictly related to the cross sectional area of upper airways (21). Both nasal congestion and inflammation can contribute to sleep impairment in rhinitis patients. Several mediators and pro-inflammatory cytokines released in allergic inflammation act both in inducing mucosal edema and congestion and in altering sleep structure (22). Furthermore, the flow through a narrow upper airway could also be the cause of inflammation persistence through the vibration and trauma induced by snoring, and it is suggested that inflammation could alter the function of the pharyngeal reflex (23). In view of this information, it is clear that appropriate AR treatment is essential not only to ameliorate the typical rhinitis symptoms, but also to improve the related sleep and sleep breathing disorders. Several trials have been performed with different nasal steroid molecules. Hughes and colleagues showed that budesonide is able to improve sleep total score and to induce a refreshing and restorative sleeping (24). To support the value of corticosteroids, the efficacy of intranasal fluticasone in patients with OSAS and rhinitis has been assessed. It reduced the apnea-hypopnea index (AHI), in nasal congestion and improved daytime alertness (25,26). Similar results have been obtained using budesonide (24), flunisolide (27) and mometasone (28). To summarize, both symptoms and pathogenic mechanisms of rhinitis can induce sleep complaints. The anatomical features of rhinitis are involved in SDB development. Rhinitis treatment improves sleep impairments and seems crucial in facilitating the tolerability of continuous positive airway pressure (CPAP) in patients with OSAS (29,30).
Sleep disorders in asthma
As with rhinitis, asthma can be a cause of sleep complaints and be part to OSAS pathogenesis. In particular, OSAS and asthma can share a common cause or predisposing factors, they can be independent from each other or they can result from an add-on medical problem that makes it more difficult to control the concomitant pathology.
Asthma by itself may represent the cause of sleep complaints. GINA guidelines (Global Initiative for Asthma) consider sleep awakening due to asthma a sign of disease severity and a marker of uncontrolled disease (2). Sleep induces significant modification of breathing patterns (such as change in peak expiratory flow) (31) that are often overexpressed in asthmatics. In addition, sleep quality and daytime cognitive performance are impaired in patients with nocturnal asthma who are taking their usual maintenance medication compared to healthy controls. They had poorer scores in specific tests that assess concentration and attention, visual scanning, hand-eye coordination, and mental set flexibility (32). The correlation between OSAS and asthma was first investigated by Hudgel and Shrucard in the late 1970s (33). In asthmatic patients, OSAS contributes to poor asthma control (34) especially in patients who suffer most from nocturnal symptoms (35). It has been hypothesized that OSAS and asthma share most of their pathophysiological mechanisms; both often involve airways obstruction, gastroesophageal reflux, and obesity; moreover snoring could be a worsening factors for both the conditions. Teodorescu et al. (36) found a correlation between OSAS and uncontrolled asthma. Patients with obstructive apneas were 3.6 times more likely to have asthmatic symptoms despite receiving the correct treatment according to international guidelines. It is now accepted that the optimal management of either condition can ameliorate the perception and the treatment of the other (37). In fact, even in the late 1980s, Guilleminault and colleagues (38) noticed that asthmatic patients suffering from obstructive apneas who had CPAP therapy had less severe nocturnal asthmatic symptoms compared to patients who did not use CPAP. The beneficial effect of CPAP was concluded to be the reduction in vagal tone, which is increased in patients with OSAS during sleep, and consequently the reduction in episodes of nocturnal bronchoconstriction. Furthermore, according to the latest evidences, these improvements may be due to the recruitment of under-ventilated alveoli, the stabilization of the upper airway, and the improvement of inspiratory muscle activity (39,40). Furthermore, potential physiopathological correlations among asthma, rhinitis, and OSAS have been described (41). The increased upper airway collapsibility and the nasal obstruction that frequently accompany asthma may represent facilitating factors of OSAS onset in asthmatic patients. On the other hand some factors typical of OSAS, including neuroreceptorial mechanisms, gastroesophageal reflux disease (GERD), local and systemic inflammation, cardiac dysfunction, airways angiogenesis, leptin changes, and weight gain, can exacerbate nocturnal symptoms and negatively influence asthma control (42). The results of a real life survey (43) showed that the level of asthma control was inversely correlated with the presence of sleep disturbances. Well-controlled patients reported less frequent and less severe sleep disturbances compared to uncontrolled ones but, more interestingly, a significant percentage of subjects (11–20%) having achieved total control of asthma still reported sleep disturbances that contributed to increases in the impact of the disease and to impair quality of life. Nevertheless, although the correlation between asthma and obstructive sleep apneas is common, it is still underestimated and OSAS should be considered in patients with asthmatic symptoms, especially nocturnal, despite treatments based on international guidelines (44). US National Asthma Education and Prevention Program recommended to screen for OSAS all patients with asthma not fully controlled (45).
Moreover, obesity seems to play an important role in both conditions. Obesity is considered the most important risk factor for OSAS (46) because it increases upper airway collapsibility and alters sleep architecture through neurohormonal abnormalities, such as leptin-grelin hormonal changes. Leptin is a mediator of energy balance, which suppresses food intake and promotes weight loss. Obese patients have been found to be leptin-resistant, so plasma leptin levels are increased in these subjects. A novel hypothesis focuses on the potential pathogenic role of leptin in asthma exacerbations. Leptin receptors might be upregulated in the airways of patients suffering from obstructive lung diseases (47). Shore et al. found that the administration of leptin to mice induces bronchial hyperreactivity (BHR), mast cell activation, and increases IgE serum levels (48). Serum leptin levels have been found to be higher in non-obese asthmatic children compared to non-obese non-asthmatic controls (49), and in asthmatic adults compared to obese asthmatic controls (50). Leptin is also increased in OSAS: obese patients with OSAS have higher serum leptin levels than obese patients without OSAS and this might be due to the intermittent hypoxia although the exact mechanism is still unknown (51,52). This hormone could play an important role in asthma exacerbations in patients affected by the “alternative overlap syndrome”. Another relevant pathogenic factor common to both OSAS and asthma is GERD. GERD may exacerbate an underlying asthma directly via microaspirations of both acid and basic materials, gastric or duodenal, and indirectly via enhancing reflex bronchospasm. Thus, GERD interferes with achievement and maintenance of asthma control. The prevalence of GERD in OSAS patients is very high, as suggested by Valipour and Green in their studies, which estimated the presence of this comorbidity as 58% and 62% of patients with OSAS (53,54). The most important risk factor for GERD in OSAS patients has been identified as transient lower esophageal sphincter relaxations (TLESR) that occur during the arousal episodes that fragment sleep structure (55-58). Emilsson et al. conducted a longitudinal study on a general population assessing the prevalence of GERD in patients with sleep disordered breathing. They found that people with nocturnal reflux were 2 times more likely to have asthma and new onset of respiratory symptoms when compared to controls without nocturnal reflux (59). An indirect evidence of this comorbidity is the decreasing of nocturnal reflux symptoms, nocturnal asthma exacerbations, and amelioration of nighttime asthmatic symptoms during CPAP treatment (60,61). Both patients with OSAS and asthmatic patients have increased serum levels of vascular endothelial growth factor (VEGF), a hypoxia-stimulated protein that enhances neoangiogenesis, as compared to control subjects. Angiogenesis is a keystone in airway remodeling that occurs in asthma. Hoshino and colleagues found that airway remodeling and BHR were correlated with the expression of VEGF by airway cells (62,63). Moreover, studies conducted on OSAS patients highlighted that VEGF levels correlate with AHI and nocturnal hemoglobin desaturation (64,65) and that CPAP therapy has been shown to reduce nocturnal hypoxia and consequently also plasma VEGF and leptin levels (66). Nevertheless, at the present time little information about VEGF levels in asthmatic patients with OSAS is available.
Sleep complaints and sleep breathing disorders in COPD
It is well-known that sleep affects breathing by variations in airways resistance, muscular contractility, and central respiratory controls. This generally has no significant consequences for healthy subjects but might produce complications in patient with COPD who suffer from episodes of hypoxemia, especially nocturnal. In fact, in 1962 Trask and colleagues documented the worsening of hypoxemia during sleep in patients with COPD (67). Sleep effects on respiration include reduced responsiveness to cortical inputs, reduced chemoreceptors sensitivity (68,69), and respiratory muscles threshold response, in particular of accessory muscles including the intercostals which COPD patients are particularly dependent on (70,71), and increased airway resistance through nocturnal bronchoconstriction (72). Furthermore, during sleep, and in particular during REM sleep, there is a reduction of functional residual capacity (FRC), which is even more reduced in patients with COPD with subsequent mucus accumulation and worsening of ventilation/perfusion mismatch. Despite the severity of these premises, it was generally accepted that routine apposite sleep assessment was not indicated in patients with COPD with respiratory insufficiency (73). Due to the above-mentioned effect of sleep on airways patency and breathing pattern, COPD symptoms can be consistently present during the night (74). A quantitative internet-based interview of 803 COPD patients, including 289 patients with severe disease, showed that more than 30% of severe patients and more than 20% of overall population find night the most troublesome period for COPD symptoms (75). Other authors showed that overnight symptoms, assessed with the Jenkins sleep scale, are bothering respectively about 50%, 60%, 70% and 80% of mild, moderate, severe and very severe COPD patients (76). In a large observational study, the presence of nocturnal dyspnea was significantly predicted by lower FEV1, higher day-time dyspnea score (mMRC), more chronic bronchitis, more weezhing, and atrial fibrillation. Moreover night-time symptoms were strongly related with hospital admission, exacerbations, and decreased survival (77). An open question was used to assess the presence of an association of COPD with sleep breathing disorders such as OSAS. A large multivariate retrospective analysis conducted by Lacedonia and colleagues aimed at assessing the prevalence of OSAS and/or COPD in a sample of 720 patients, showed this association in almost 25% of patients (78). However, Bednarek and colleagues found OSAS approximately in 1% of patients (79). The results of several other studies are reported in Table 1.
Several pathophysiological factors in COPD might predispose to OSAS. Redolfi and colleagues demonstrated that rostral fluid shift from legs into the neck in the supine position could predispose to obstructive sleep apneas (OSA), incrementing pharynx collapsibility (89). Both in COPD and asthma patients, the use of corticosteroids might predispose to OSA, particularly in COPD patients requiring long-term oral corticosteroids, inducing the accumulation of fat in parapharyngeal tissues and myopathy which might increase upper airway collapsibility (90). A keystone in the Overlap Syndrome is the presence of cardiovascular diseases; OSAS episodes of hypoxemia have been associated with increased risk of cardiovascular diseases and death due to systemic inflammation and augmented production of cytokines playing an important role in vascular and cardiac dysfunctions. Both OSAS and COPD have an underlying base of oxidative stress which, together with an increased sympathetic activation, leads to endothelial dysfunction via increased levels of NF-κB, C-reactive protein (CRP), IL-6, TNF-α and IL-8 and to the enlargement of atherosclerotic plaques. Furthermore, hypoxia induces the expression of two important transcription factors: NF-κB regulates the production of TNF-α and IL-8 which are promoters of atherosclerosis through the expression of several adhesion molecules (91); HIF-1 regulates the transcription of several genes involved in the formation of new vessels in poorly-oxygenated tissues (92). Both NF-κB and HIF-1 have been found to be elevated in patients with severe OSAS and COPD who suffer from CIH. Furthermore, circulating plasma levels of NF-κB are significantly correlated with OSAS severity (93). Similarly, CRP and IL-6 levels have been found to be increased both in OSAS and COPD patients (94-96) and contribute to atherosclerosis promoting the expression of vary adhesion molecules. According to the latest evidences, both increased levels of CRP and IL-6 are predictors of cardiovascular events (97,98). The clinical burden of these pathogenetic pathways has been assessed in the NHANES III study where a correlation between CRP levels and myocardial ischemia has been found (99). Despite this evidence, there is little proof that CPAP therapy can reduce plasma levels of these two mediators. In fact, a randomized controlled trial conducted by Kohler and colleagues didn’t find any differences in their plasmatic levels after a 4-week CPAP-therapy period (100). Viceversa, NF-κB, a mediator involved in cardiovascular inflammatory damage-related chronic exposure to intermittent hypoxia and reoxygenation (101), was significantly reduced by CPAP therapy (93).
Rhinitis, asthma and COPD are causes of sleep complaints that may be limited with optimization of their management. Furthermore, they represent a risk factor for both pathogenesis and worsening of sleep breathing disorders such as OSAS. Moreover, if OSAS treatment by CPAP permits a better control of obstructive airways diseases, the optimization of airways patency is necessary to facilitate nocturnal obstruction control. Nowadays we cannot manage sleep disordered breathing like a single pathology. It is necessary to study the patient’s overall condition. Therefore, in order to further improve SDB and OLD responses to their appropriate therapies, a holistic approach to the patient should be taken. In particular, it’s advisable for physicians to evaluate the presence of OSAS in patients with difficult to control asthma and vice versa to check for rhinitis, asthma and COPD in patients with OSAS presenting with daytime and seasonal symptoms, keeping in mind the importance of the relationships with disease severity and the undeniable value of making the diagnosis.
The authors thank Associazione Ricerca Malattie Immunologiche ed Allergiche (ARMIA), Associazione Pazienti Disturbi Respiratori nel Sonno (ASPADIRES) for the support in developing the study.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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