Obstructive Sleep Apnea Syndrome (OSAS) and Asthma: A Simple Association: A New Syndrome or a Cluster?

Obstructive Sleep Apnea Syndrome (OSAS) and Asthma are two diseases with a high epidemiological impact that may coexist in some patients with the name of Alternative Overlap Syndrome. Both diseases have underlying pathogenic mechanisms (chronic inflammation, genetic predisposition etc). Epidemiological data suggest that the coexistence of OSA and asthma, also known as “Alternative Overlap Syndrome” has an adverse impact on health outcomes. Asthma and OSA overlap with similar comorbidities and underlying pathophysiology, potentiating the two conditions. The most common comorbidities associated with both diseases are Gastro-Esophageal Reflux Disease (RGE), rhinosinusitis and obesity. Neuromechanical reflex bronchoconstriction, local and systemic inflammation, the indirect effect on dyspnea of OSAS-induced cardiac dysfunction, angiogenesis and leptin-related airway changes may all play a common mechanistic role linking both disorders.

Nocturnal breathing disorders are related to Asthma, Obstructive Sleep Apnea (OSA) or both. An association between Asthma and OSA was first time described in 1979 in a patient with both diseases and resulting in severe hypoxemia [1]. Currently, the association of two disease is call “alternative Overlap” [2].

Asthma is an inflammatory disease of the lower respiratory tract, manifesting as intermittent bronchoconstriction of the airways. Obstructive Sleep Apnea (OSA), on the other hand, is a state-dependent condition that is characterized by intermittent obstruction of the upper airway during sleep leading to hypoxemia and sleep fragmentation. The pathophysiology of these two conditions seems to overlap significantly, as airway obstruction, inflammation, obesity, and several other factors are implicated in the development of both diseases. Moreover, OSA is generally linked to worse asthma outcomes. The effects of the direct pathophysiological consequence of OSA (e.g., chronic intermittent hypoxemia, circadian alteration of autonomic functions, and increased intrathoracic pressure swings related to the occluded upper airway) on the clinical severity of asthma are poorly understood. Moreover, the National Asthma Education and Prevention Program Expert Panel Report recommends evaluating for OSA as potential contributor to poor asthma control [3]. Thus, clarifying the nature of the relationship between OSAS and asthma is a critical area with important therapeutic implications.

OSAS is the most frequent respiratory disorder in sleep, although it remains underdiagnosed. OSAS with excessive daytime sleepiness reaches a frequency of 3-18% in men and 1-17% in women [4]. OSAS is characterized by repeated collapses of the upper airways which result in a marked reduction (hypopnea) or complete interruption (apnea) of the airflow. Associated with these events, phasic oxyhemoglobin desaturations, responsible for intermittent hypoxemia, and a consequent sympathetic hyperactivation with sleep fragmentation occur, which constitute the main mechanisms that make the disease a risk factor for cardiovascular diseases, diabetes, stroke, premature death, reduction of cognitive functions, of mood and quality of life [5,6].

In obese individuals, the prevalence of OSA varies between 55 and 90%. Visceral obesity, in fact, constitutes the major risk factor for OSAS, as it correlates with the deposition of peri-pharyngeal fat and determines a reduction in the longitudinal traction force of the trachea, favoring the collapse of the upper airways [7]. Over the years, in addition to anatomical factors, such as obesity, retrognathia, laxity of the soft palate or macroglossia, many other factors have been involved in the pathogenesis of the disease. Genetic predisposition, smoking, alcohol consumption and male sex are only risk factors for OSAS, while the pathophysiology remains much more complex, as will be discussed late.

The diagnosis of OSAS is based on the presence of symptoms and signs and associated medical conditions, but cannot disregard the objective confirmation of the presence of sleep apnea, with an instrumental examination which must be simpler than the stronger the suspicion of OSA (severe clinical picture, rich in specific symptoms and signs) [8]. The gold standard exam is represented by standard Polysomnography (PSG), routinely indicated for the diagnosis of respiratory disorders in sleep, which is quite expensive in terms of material and personnel and takes time. An excellent and less expensive alternative is therefore complete nocturnal cardiorespiratory (PM) monitoring, which can be used for the diagnosis of OSAS in patients at high risk for moderate/severe OSA, while it is not indicated in patients with lung disease, neuromuscular disease, heart failure or in those patients who probably have a mixed disorder. Validated questionnaires are the Berlin Questionnaire (BQ), the STOP-BANG Questionnaire (SBQ) and the sleep apnea scale of the sleep disorders questionnaire (SA-SDQ) [9,10].

The scoring criteria of both instrumental exams (PSG and PM) should be based on those defined by the American Academy of Sleep Medicine (AASM) of 2007 [8]. Obstructive apnea is defined as the absence of airflow for more than 10 s in the presence of continued respiratory effort while central sleep apnea occurs because brain doesn't send proper signals to the muscles that control breathing so it was defined as the absence of airflow for more than 10 s due to loss of respiratory effort. The sleep recommendation of the Italian Association of Hospital Pulmonologists (AIPO) recommends performing the sleep test examination in the presence of habitual and persistent snoring, reported breathing pauses, chooking, daytime sleepiness or signs such as Body Mass Index (BMI) > 29 kg / m2, neck circumference > 43 cm in males or > 41 cm in females, or craniofacial dysmorphisms. The presence of apneas on PM or PSG is determined using the Apnea Hypopnea Index (AHI), which is defined as the number of respiratory events (apneas and hypopneas) per hour of Total Sleep Time (TST). The diagnosis is given for an AHI ≥ 15 events for hours, even in the absence of symptoms, or for AHI between 5 and 15, only in the presence of the associated symptoms described above. OSAS is classified as mild, if AHI ≥ 5, but < 15, moderate, if AHI ≥ 15, but <30, and severe with an AHI ≥ 30 [8,11].

The treatment of choice is the application of Continuous Positive Airway Pressure (CPAP), which has been seen to reduce the risk of long-term mortality. In reality, in recent years, attention has increasingly shifted to a personalized therapeutic approach for these patients, in some of whom there is an indication of other approaches, compared to CPAP, which may be more effective, for example, Mandibular Advancement Devices (MAD), maxillofacial or ENT surgery, bariatric surgery in morbid obesity, hypoglossal nerve stimulation, or pharmacological approach with targeted therapies [12].

Bronchial asthma is a heterogeneous disease, characterized by chronic inflammation of the airways, which affects approximately 1-18% of the population of different countries. It is characterized by the presence of a variable limitation to the expiratory flow, bronchial hyper reactivity and respiratory symptoms such as wheezing, dyspnea, sensation of chest tightness and/or cough, which vary over time and in intensity depending on the severity of the disease [13]. For the diagnosis of asthma is necessary a spirometry that show an airway reversible obstruction. The diagnosis of airways obstruction, in general, is made using the pre-bronchodilator ratio of FEV1 to FVC showing a value less than the lower limit of normal. Reversibility (a greater than 12% and 200 ml increase in FEV1) following inhalation of a bronchodilator is recommended to confirm the clinical diagnosis.

Alternatively, asthma can be diagnosticated if a reduction of FEV1 is observed after exposure to a trigger factor, or is observed at least 20% reduction in FEV1, compared to baseline, after inhaling increasing doses, but < 400 mcg, of methacholine.

About 3-10% of asthmatics suffer from severe asthma, despite optimal therapy and undergo frequent exacerbations and hospital admissions. Often these patients require high doses of inhaled or oral steroids or therapeutic stepping up to triple or biologics. A significant percentage of asthma patients, up to 70%, experience symptoms during sleep. Both nocturnal asthma symptoms and uncontrolled asthma have a profound effect on sleep quality [14]. This finding is more marked in severe asthma, where severe asthma refers to a heterogeneous subgroup of asthma that is difficult to treat, i.e., asthma that remains uncontrolled despite complete adherence to the maximum optimal therapy of steps 4 or 5 according to the document of the Global Initiative for Asthma, GINA and treatment of contributing factors, or which worsens when maximal therapy dosage is reduced.

The main goal of asthma therapy is to achieve symptom control, or to minimize them, and prevent asthma exacerbations (defined as an acute clinical and functional worsening, which requires additional therapy). Asthma control is assessed through the use of validated questionnaires such as the Asthma Control Questionnaire (ACQ) and the Asthma Control Test (ACT) [13,15].

In literature there is a well know association between asthma and OSA. Nevertheless, in literature is not clarified the phenotype of patient with asthma with the major predisposing factors for OSA. One aspect is the coexisting factor of common comorbidities so when a patient with asthma is also obese or also have an untreated or uncontrolled gastroesophageal reflux or rhinitis is possible that these comorbidities are the link for development also obstructive sleep apnea. Patient could have an uncontrolled asthma for the coexistence of more disease. The definitions of control in literature were derived from the treatment goals of the Global Initiative for Asthma/National Institutes of Health guidelines [3]: “totally controlled” or “well controlled” or uncontrolled. Control definitions are composite measures that included: measure of peak flow rates, rescue medication use, symptoms, night-time awakenings, exacerbations, emergency visits, and adverse events. Totally controlled asthma is a patient with no exacerbations, emergency room criteria, or medication related adverse event. Even if is well clear and studied what is the definition of uncontrolled asthma, in the guidelines of asthma isn’t stressed the possible role of the uncontrolled disease or not well treated comorbidity as for example OSA.

Severe asthma, as mentioned above, is a type of asthma that does not respond well to standard asthma treatments. The symptoms by definition, are more intense than regular asthmatic symptoms and can last for prolonged periods. Sufferers of severe asthma often find their symptoms persistent and difficult to control for this reason sometimes in literature severe asthma or uncontrolled asthma has used as synonymous. Guidelines defined severe asthma as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy [16].

Accumulating data in younger patients suggests a role of OSA in asthma control. Treatment of OSA with Continuous Positive Airway Pressure (CPAP) improves asthma symptoms, peak flow rates, and quality of life. The sleep disorder is also an important risk factor for frequent exacerbations in difficult-to-control asthma patients [17].

Older patients with asthma as compared to younger asthmatics have worse asthma control and that poor control in older subjects may depend on comorbid OSA, CPAP use attenuated the likelihood of worse asthma control more robustly in older than in younger subjects. So underlying OSA may contribute to worse asthma control, particularly in the older patients, independent of other known comorbidities [18].

The few studies that collected asthma severity metrics reported associations of such measures with OSA risk. In the Wisconsin Sleep Cohort, asthma duration increased the incident OSA risk in a dose dependent manner: each 5-year increment in duration was associated with a 7% and 18% higher risk for incident OSA [19].

A trend of increasing OSA prevalence in a dose-dependent manner with asthma severity were noted [20] and regardless of asthma severity, the vast majority of respiratory events were obstructive hypopneas with arousals. For this reason some authors in the last few years hypothesized that OSA and asthma could be a new syndrome with also specifical pathophysiological and polysomnographic features [21,22].

Clinicians should screen their patients with asthma for OSA, particularly those who have asthma for longer durations, have uncontrolled disease, or are on higher doses of ICS or their asthma is defined as severe asthma [22].

Asthma and OSA are two high prevalence diseases with about 334 million asthmatics and over 100 million OSA patients in the world. Asthma and OSA may coexist and adversely affect quality of life. In adult patients with OSA the prevalence of Asthma is 35% [23]. On the other hand, the risk for OSA is much higher in patients with asthma than in the general population (39.5% vs. 27.2%) [24]. Moreover, OSA is more prevalent in severe asthma than moderate or good controlled asthma with a prevalence from 88 to 95% [25,26].

About 75% patients with severe asthma have at least one awakening experience per week, 39% one per night. 50% of deaths from asthma occur at night. Epidemiological data suggest the coexistence of OSA and Asthma caused an adverse impact on health outcomes and identified a specific cluster of OSA, prevalent in female patients [27,28].

Different factors associated with sleep itself have a significant additional effect on the worsening of asthma at night.

In severe and in poorly controlled asthma there are changes in sleep architecture with increased latency in the onset of sleep, difficulty in maintaining sleep, reduction of total sleep time, reduction in the duration of deep sleep (N3: stage of sleep with stable and regular breath) and daytime sleepiness which seem to correlate with poor disease control [29]. In particular, studies on patients with fragmented sleep, demonstrate a correlation with bronchoconstriction and sleep deprivation/fragmentation [29,30]. During the night, asthmatic patients have an increase in the parasympathetic bronchial constrictor tone associated with the reduction of NAN C bronchodilation. A study in patients with mild asthma showed that the activity of bronchodilation of the NAN-C at four in the morning is significantly lower than that observed in the same patients at four in the afternoon [31].

In asthmatic patients both bronchial hyperactivity and airway inflammation appear to worsen at night. Maximum Peak Expiratory Flow (PEF) and airway conductance value occurs about mid-afternoon, while the minimum peak occurs around four in the morning with greater variability in the asthmatic patient than normal (52% vs. 8%) [32]. With regard to airway inflammation, on the other hand, the number of eosinophils and macrophages present in the alveolar tissue of patients with nocturnal symptoms of asthmas greater at four in the morning and moreover a significant role is played by leukotrienes with higher levels of urinary LTE 4 during the night.

In the asthmatic patient, the fact that symptoms worsen or are prevalent at night suggests that in sleep there may be an element that contributes to the presentation or aggravation of the disease. The asthmatic often, especially in severe or uncontrolled asthma, has a poor quality of sleep, characterized by nocturnal awakenings and consequent sleep fragmentation, which can affect the achievement of phase N3, and can contribute to ventilatory instability. There may also be moments of rapid and shallow breathing, which determine a fluctuation of CO2 and ventilatory instability, pathogenetic elements that recall the characteristics of those patients with OSAS in which there is a low arousal threshold [12Common Comorbidities Could in Part Explain the Link

Asthma and OSA overlap with similar comorbidities and underlying pathophysiology potentiating the two

conditions. Gastro-Esophageal Reflux Disease (RGE), rhinosinusitis, and obesity are the most important comorbidities associated with both diseases and some authors refer to the coexistence of these pathologies as a single syndrome named “CORE Syndrome” (Cough, Obesity/OSA, Rhinosinusitis and Esophageal reflux) [33].

Obesity, OSA and asthma

Obesity is epidemic in western continent. Even if the pathophysiological mechanism of OSA in now well understood and we know that only the 20% of patient with OSA are obese, obesity is the major risk factor for OSA. Obesity contributes to the pathogenesis of OSA by modifying the anatomy and collapsibility of the upper airways, influencing ventilation control (leptin role) and increasing respiratory workload. OSA itself can contribute to the development of obesity. Both OSA and obesity lead to the activation of inflammatory biological cascades, which are probable pathogenic mechanisms due to their cardiovascular and metabolic consequences.

An increasing body of literature suggests a possible association between Obesity and Asthma. Although the exact nature of this association remains unclear. Many investigators interpreted the data proposing obesity as an increase risk of incident asthma, since obesity precedes the onset of asthma in a significant proportion of patients, especially in children. Obesity and asthma could be considered a single entity, named obesity-related asthma. In this phenotype of patients asthma is less well controlled and often the poor control is disproportionate to their pulmonary function tests. Pro-inflammatory effects of adipose tissue increase the prevalence and the severity of asthma in obesity people. Visceral adiposity is correlated with circulating levels of proinflammatory cytokines, and adipose tissue propagates inflammation both locally and systemically, in part through recruitment of macrophages via chemokines such as monocyte chemoattractant protein-1 (MCP-1) and in part via elaboration of cytokines and chemokines such as (but not limited to) leptin, interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), and eotaxin. Modifications of atopy, lung development, Th1–Th2 balance, immune responsiveness, and airway smooth muscle have been hypothesized to be mechanisms by which obesity might increase asthma risk or modify asthma phenotype [30]. 

Obesity leads to alterations of lung volume due to thoracic compression, particularly Expiratory Reserve Volume (ERV), leading to a rapid, shallow breathing pattern that occurs close to closing volume. Obesity also causes reduced peripheral airway diameter, a phenomenon that, perturbs smooth muscle function, causing a change from rapidly cycling actin–myosin cross-bridges to slowly cycling latch bridge, potentially increasing both airway obstruction and Airway Hyperresponsiveness (AHR) [34].

However, neither inflammation nor reduced lung volume is sufficient to explain respiratory impairments in obese subjects with asthma. A recent study [35] and postulated accumulation of adipose tissue within the airway wall may occur in overweight patients and contribute to airway pathology. In individuals with elevated Body Max Index (BMI), the adipose tissue accumulates within the airway wall and correlates with greater wall thickness and airway inflammation. This represents a new mechanism for airway pathophysiology in obese asthmatic patients that may contribute to airflow limitation in a manner not previously proposed [35].

Rhinitis, OSA and asthma

OSA has a prevalence of 65% in patients with chronic rhinosinusitis. Chronic rhinosinusitis, especially in allergic patients, if untreated, leads to asthma. Rhinitis, not only asthma, has a circadian rhythm with a maximum of nasal obstruction and inflammatory cytokines in the second part of the night. Nasal steroids can improve congestion and OSA symptoms in some patients. Inflammation, as shown by high levels of nitric oxide, as well as the reflex stimulation of the vagus of the nasal mucosa receptors could be part of the physiopathological mechanism of association between rhinitis and OSA. However, even if OSA’s pharynx is the main structure predispose to collapse, the starling model suggests that an increase of resistance of nose, due to rhinitis or snoring, increase upper airway collapsibility [36,37].

Gastroesophageal Reflux (GER), OSA and asthma

40-60% 71.4% of patients with OSA have GE [38]. Pharyngeal spasm and mucosal exudative neurogenic inflammation, occurring as a result of proximal migration of gastric acid and prolonged acid clearance during sleep, could render the upper airway dysfunctional and prone to collapse during sleep.

Apnea, in turn, can promote reflux. The change in endothoracic pressure associated with apnea causes an altered relaxation of the esophageal sphincter which favors acid reflux. In asthma patients, acid reflux causes inflammation and bronchial obstruction directly by microaspiration or indirectly by vagal activation (retrograde way) [39].

Furthermore, asthma itself can worsen gastroesophageal reflux decreasing the tone of the lower esophageal sphincter because hyperinflation alters the transdiaphragmatic pressure gradient. Also, drugs used in Asthma, as Beta 2 agonists and theophylline, can reduce the tone of the lower esophageal sphincter [40].

GER, Obesity, Rhinitis are the most common link between the two diseases but other factors could contribute to the overlap and determine mutual worsening: neuromechanical reflex bronchoconstriction, inflammation (local and systemic), the indirect effect on dyspnea of OSAS-induced cardiac dysfunction, angiogenesis, leptin-related airway changes. Each of these factors may play a common mechanistic role linking both disorders [41].

Increased vagal tone and neuromechanical reflex bronchoconstriction

Vagal tone stimulates the muscarinic receptors located in the central airways leading to bronchoconstriction and causing nocturnal asthma. In OSA different mechanisms increase vagal tone: first negative endothoracic pressure following apnea (Muller maneuver), second stimulation neuronal receptor on the larynx and pharynx by the snoring and third, the hypoxic stimulus on carotid bodies [42].

Role of leptin

A novel role of leptin is supposing by new study in the pathogenesis of asthma. Even after controlling for Body Mass Index (BMI), leptin was noted to be increased in the serum of male asthmatic children compared with non-asthmatic children [43].

In OSA, obese male patients exhibit leptin levels approximately 50% higher than those of similarly obese men without OSA. Clinically, several case-control studies have demonstrated increased levels of serum leptin in OSA patients compared with those of non-apneic patients with similar levels of obesity [44].

Cardiac dysfunction

OSA has been shown to lead to many cardiovascular consequences, which may complicate a coexisting airway obstruction in asthmatic patients. Recurrent hypoxemia, hypercapnia and baroreflex inhibition resulting from repetitive surges in nocturnal blood pressure may contribute to elevated sympathetic nerve activity, which is known to be cardiotoxic in patients with CHF.

Various mechanisms have been proposed to be involved in the airway hyperresponsiveness associated with CHF, including down-regulation of pulmonary β-receptors with concomitant decreases in adenylyl cyclase activity, which results in significant attenuation of CAMP-mediated airway relaxation.

Other mechanisms include pulmonary edema-induced airway constriction by vagal reflexes, nonspecific bronchial C-fiber activation, thickening of bronchial walls, changes in epithelial sodium and water transport, and increased endothelin levels. OSAS, through aggravating cardiac dysfunction, could further stimulate Airway Hyperresponsiveness (AHR) in asthmatic patient [45].

Vascular Endothelial Growth Factor (VEGF) and airway angiogenesis

One recent study supported a critical role for VEGF in vascular remodeling in asthma. In addition, a correlation has been found between increased VEGF levels in asthmatic patients and the degree of airway obstruction [46,47]. OSA patients have elevated concentrations of VEGF that correlate with the severity of the syndrome as reflected by the level of the Apnea–Hypopnea Index (AHI) and the degree of nocturnal oxygen desaturation. So, VEGF could play an important role in the pathogenesis of both diseases [48].

Inflammation

One proposed mechanism for airway inflammation in OSA is the mechanical stress exerted on the mucosa by the high negative pressures transmitted against a closed airway passage as a result of the strong inspiratory effort produced by snoring and obstructive apneas. This repeated mechanical trauma on the upper airway triggers local inflammation of the nasal and pharyngeal mucosa. It is well documented that inflammation of the airways can affect not only the airway caliber and flow rates but also the underlying bronchial hyperresponsiveness, which enhances susceptibility to bronchospasm, a major element in the pathogenesis of asthma. Inflammatory and oxidative stress markers including pentane, exhaled nitric oxide,42 IL-6, and 8-isoprostane have been noted in expired air of OSA patients [49].

In individuals with OSA there are an increased serum concentration of cytokines, and chemokines.

The systemic inflammation appears to be, at least in part, the oxidative stress induced by oxygen desaturation during sleep apnea. Previous studies shown C-Reactive Protein (CRP) level is proportional to the OSA severity, and 1 month of effective treatment of OSA with continuous positive airway pressure led to a considerable decrease in CRP level [50]. Recent studies showed that not only inflammation is one of mechanism of both diseases but also when the two disorders coexist there is a prevalence of neutrophilic inflammation. In SARPII study [51] asthmatic patients were divided in high risk OSA and low risk OSA: this study showed that in high risk OSA patients, there were higher percentage of PMNs, whereas percentage of sputum eosinophils were similar between the two groups. The study analyzes 94 patients with severe asthma, 161 non-severe and 146 controls subjected to sleep quality questionnaire, risk of OSA and induced sputum. Patients with asthma with more difficult control, more both day and night symptoms and even greater exacerbations also had greater risk of OSA. Sputum eosinophils and PMNs (expressed as percentage of sputum total white blood cell counts) in asthmatic subjects with high OSA risk showed a reduction of 2.5 times in eosinophils count and increase of 1.4 times in neutrophils [51].

Another study of Taillè, et al. [52] showed that OSA is associated with specific inflammatory changes of the airways with predominance of neutrophils of metalloproteinases 9 of interleukin 8 and of changes in the thickness of the basement membrane and remodeling of the airways in asthma. On 55 patients with asthma difficult to treat (mostly women, 1/3 obese also with use of oral steroid) 49% of patients had OSA, 31 of these patients underwent bronchus with biopsy and those with OSA had greater thinning of the basement membrane whose thickness was inversely proportional to the AHI. Only 29 patients were underwent to induced sputum analysis and the results showed a greater number of neutrophils, IL8 and MM9 in patients with both diseases in front of patient with asthma alone [52].

In OSA, neutrophilic low-pathway inflammation correlates with the severity of the disease, 60% of asthma patients not responsive to therapy have neutrophilic inflammation. Neutrophilic inflammation is more prevalent in severe asthma and fatal asthma. This finding suggests an hypothetical role of neutrophilic inflammation as a link of OSA and severe asthma.

Asthma itself can be considered a risk factor for OSA for different reasons. Some studies [53] show that the dose of steroid used for therapy in asthma patients correlates with the probability of developing OSA. The steroid could also determine a myopathy of the pharynx dilator muscles, even in a dose dependent manner [54].

Asthmatic attacks result in bronchoconstriction and therefore reduction in the area of ​​section of the airways but also through reflex constriction of the glottis and pharynx [55]. Fragmentation of sleep increases collapse of the upper airways. Reduction of lung volumes reduces tracheal traction force and stabilization of the upper airways (especially in REM). Systemic inflammation has negative effects on the mechanisms of protection of the airway.

In cross-sectional epidemiologic studies, the prevalence of sleepiness, snoring and apnea were significantly higher participants with asthma [41]. Teodorescu, et al. [24] evaluated association of presence and duration of asthma with 4-year incidences of both OSA and OSA concomitant with habitual daytime sleepiness in 1105 patients. They found twenty-two out of 81 (27%) participants with asthma experienced incident OSA over their first observed compared to 75 incident cases of OSA among 466 participants without asthma (16%). The authors demonstrated that asthma was associated with increased risk of new-onset OSA and that the asthma-OSA association was significantly dose-dependent on duration of asthma.

A systematic review of Sarah E Davies, et al. [56] have evaluated the epidemiological association of asthma and OSA and also have analyzed asthma severity and clinical outcomes of both diseases. The authors found 19%-60% prevalence of asthma in OSAS, 50-95% of which was severe/difficult to treat asthma. Two studies looked at the association between severe/difficult-to-treat asthma and prevalence of OSA. Julien et al. [26] reported a prevalence of OSA of 50% (13/26) in severe asthma and 23% 6/26 in moderate asthma compared to 12% (3/26) in controls. There was significantly more OSA in severe

versus moderate asthma (p = 0.044) and severe versus controls (p = 0.003), but not when comparing moderate to controls (p = 0.303). A study of 22 difficult-to-treat asthma patients by Yigla, et al. [25] showed a particularly high prevalence of OSA at 21/22 (95.5%). Clinical outcomes were worse in asthma patients with coexisting OSA. The concomitant diagnosis of OSA and asthma was associated with worsened asthma-related clinical outcomes. However, this finding was not universal between studies

It has also been reported CPAP treatment to be effective to improving the asthma control and the nocturnal attacks in asthmatic and apneic patients [57]. Some studies [58] suggest that nocturnal CPAP treatment used with a heated humidifier in patients with stable asthma and newly diagnosed OSA did not modify the respiratory functional parameters, such as PC20 or FEV1. Nevertheless, the CPAP treatment improved the quality of life. QOLAs. This improvement was greater in obese patients and in patients with a high AHI at baseline [58]. In a recent survey among 1586 patients with OSAS of which 12.4% were asthmatics, long-term treatment with CPAP (mean of 5.7-4.7 years) reduced symptoms of asthma and improving asthma control in 152 patients [59]. Several non-randomized/not controlled prospective studies have reported on effects of CPAP treatment for OSA of various durations on asthma outcomes. All show improved asthma symptoms, exacerbations and quality of life [60]. In a recent and multicenter study, Serrano-Pariente, et al. [61] examined the 6-month impact of CPAP in 99 patients with moderate and severe asthma. The study showed a significant but small improvement in asthma control scores. While the percentage of patients with uncontrolled asthma decreased from 43% to 17.2% (P = 0.006) in the study with emerging benefits at 3 months. In addition, CPAP reduces asthma attacks from 6 months (35.4% to 17.2%, P = 0.015). This study also suggests benefits to be greatest in patients with moderate-to-severe versus mild–intermittent asthma, those with severe OSA (RDI > 30/h) and those adherent to CPAP (≥4 h/night). Recently, Tsay-yu Wang, et al. [62] have hypothesized that OSA is an independent factor associated with the decline in pulmonary function in patients with asthma, and CPAP treatment prevents the decline by improving nocturnal hypoxia and frequency of acute exacerbation. The annual decline in FEV1 of asthmatic patients with severe OSA was significantly accelerated compared to those of patients with mild-to-moderate OSA. Thirty-eight percent (13/34) of asthmatic patients with severe OSA treated with CPAP had good compliance. In the annual decline in FEV1 before and after CPAP treatment, after adequate CPAP treatment for the next 2 years, the annual decline in FEV1 was 41.2 ± 36.1 mL, which was significantly lower than that before CPAP treatment (69.4 ± 66.4 mL, p = 0.028).

These overlaps are frequently unrecognized. Patients with asthma may not report sleep symptoms, or may attribute them to the primary lung disease. Standard screening questionnaires are also imperfect. Oxygen desaturation observed during the night should not only be attributed to lower airway disease. Providers must be vigilant and periodically consider the diagnosis of OSA, particularly in patients with lung disease of longer duration and increased severity, who are using higher doses of ICS, or who have shared risk factors such as obesity, nasal disease and gastro-oesophageal reflux. Second, physicians should recognize that treatment of patients with OSA and asthma has the potential to improve important patient-focused outcomes and may reduce healthcare utilization.

Individualized therapy addressing moderating factors as weight gain and GERD is warranted for optimal health outcomes. Recognition and treatment of OSA in asthmatics is an important element in improving asthma control. Further research is needed to examine the long-term impact of therapy for OSA on clinical outcomes in asthma. The common coexistence of the two diseases, the common comorbidities, the common physopathological mechanisms and the fact that treating one improves symptoms and outcome of the other one, it could make us think of the coexistence of asthma and OSA as a single disease, called “Alternative Overlap” or to consider the asthmatic patient with OSA a particular patient phenotype.

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