REvIEW ARTICLE

Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links?
Michel Alkhalil, M.D.; Edward Schulman, M.D.; Joanne Getsy, M.D. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Drexel University College of Medicine, Philadelphia, PA

Recent data suggest that obstructive sleep apnea syndrome (OSAS) is an independent risk factor for asthma exacerbations. Neuromechanical reflex bronchoconstriction, gastroesophageal reflux, inflammation (local and systemic), and the indirect effect on dyspnea of OSAS-induced cardiac dysfunction have been suggested as mechanisms that lead to worsening asthma control in patients with concomitant OSAS. Vascular endothelial growth factorinduced airway angiogenesis, leptin-related airway changes, and OSAS-induced weight gain also may play a common mechanistic role linking both disorders. Several studies have confirmed that asthmatic patients are more prone to develop OSAS symptoms than are members of the general population. The common asthmatic features

that promote OSAS symptoms are nasal obstruction, a decrease in pharyngeal cross sectional area, and an increase in upper airway collapsibility. Clarifying the nature of the relationship between OSAS and asthma is a critical area with important therapeutic implications. Keywords: Asthma, obstructive sleep apnea (OSA), continuous positive airway pressure (CPAP), neural receptors, gastroesophageal reflux (GER), inflammation, ventricular dysfunction, vascular endothelial growth factor, leptin, obesity, rhinitis Citation: Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78. choconstriction, gastroesophageal reflux, inflammation (local and systemic), and the indirect effect on dyspnea of OSASinduced cardiac dysfunction. We explore what is currently known about each of these mechanisms and suggest additional mechanisms such as airway angiogenesis, leptin-related airway changes, and OSAS-induced weight gain (Figure 1). NEURAL RECEPTORS AND MECHANICAL EFFECTS Patients with OSAS have an increased vagal tone during sleep as a consequence of partial or complete airway obstruction occurring during apneas. The mechanics of this potent vagal stimulation are similar to those of the Mller maneuver, which consists of an inspiratory effort against a closed glottis.2,3 Increased vagal tone occurring during apnea episodes could be a trigger for nocturnal asthma attacks in sleep apnea patients. In fact, several studies have shown that increased vagal tone stimulates the muscarinic receptors located in the central airways leading to bronchoconstriction 4 and causing nocturnal asthma.5,6 Furthermore, suppression of the increased vagal tone by inhaled anticholinergic drugs leads to improvement in forced expiratory flow,7 reduction in early morning falls in peak expiratory flow, and protection against nocturnal asthma symptoms.8 Another factor in the neural reflex mechanism involves the neural receptors at the glottic inlets and in the laryngeal region; these receptors have powerful reflex bronchoconstrictive activity. Nadal et al9 showed that mechanical irritation of the laryngeal mucosa increased total lung resistance distal to the larynx in anesthetized and decerebrate cats. The afferent limb of the reflex is localized to the superior laryngeal nerve and the efferent limb, to the vagus nerves. Stimulation of the larynx also increases activity in efferent parasympathetic nerve fibers going to the trachea and
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SAS is characterized by repeated episodes of upper airway occlusion that result in brief periods of breathing cessation (apnea) or a marked reduction in flow (hypopnea) during sleep. This pattern is accompanied by oxyhemoglobin desaturation, persistent inspiratory efforts against the occluded airway, and arousal from sleep. Continuous positive airway pressure (CPAP) is the first line of therapy for sleep apnea.1 It prevents upper airway occlusion during sleep by creating a pneumatic splint. The August 2007 National Asthma Education and Prevention Program Expert Panel Report 3 (EPR3) recommends that clinicians evaluate symptoms that suggest OSAS in unstable, poorly controlled asthmatic patients, particularly those who are overweight or obese. To date, evidence of a correlation between OSAS and asthma is weak, and few studies have examined this relationship. POSSIBLE MECHANISMS BY WHICH OSAS WORSENS ASTHMA Asthma is a common chronic disorder of the airways that involves complex interactions among airflow obstruction, hyperresponsiveness, and underlying inflammation. Mechanisms proposed to lead to the worsening of asthma control in patients with concomitant OSAS include neuromechanical reflex bronSubmitted for publication May, 2008 Submitted in final revised form July, 2008 Accepted for publication August, 2008 Address correspondence to: Michel Alkhalil, M.D., Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Drexel University College of Medicine, 245 North 15th Street, Mail Stop 107, Philadelphia, PA 19102; Tel: (215) 762-7011; Fax: (215) 762-8728; E-mail: michelalkhali@hotmail.com
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vagal reflexes induced by exposure of the esophagus to acid. In fact, acid instillation into the mid esophagus results in a significant increase in airway resistance in adults with asthma.35,36 In canines, airway resistance was similarly affected by acid instillation into the esophagus, a response ablated by vagotomy.37 Microaspiration of gastric acid content is another mechanism of GER-induced bronchoconstriction.38-40 Treatment of GER with a proton pump inhibitor was reported to reduce nocturnal symptoms, reduce asthma exacerbations, and improve quality of life related to asthma.41 Also, surgical treatment for GER has been reported to reduce the symptoms of asthma and the requirement for medication.41 OSAS-induced acid reflux may play a causative role in triggering asthma symptoms.
Figure 1Interrelationship between obstructive sleep apnea and asthma

LOCAL AIRWAY INFLAMMATION Obstructive sleep apnea syndrome has been shown to be associated with inflammation of both the upper and lower respiratory tracts. Inflammatory and oxidative stress markers including pentane, exhaled nitric oxide,42 IL-6, and 8-isoprostane43 have been noted in expired air of OSAS patients and may provide evidence of the presence of airway inflammation in OSAS. One proposed mechanism for airway inflammation in OSAS 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.44 Increases in polymorphonuclear leukocytes and inflammatory mediators such as bradykinin and vasoactive intestinal peptide (VIP) have been found in the local nasal mucosa of OSAS patients.45 Chronic inflammation of the soft palate with increased interstitial edema has also been noted.46 The uvula demonstrates mucous gland hypertrophy and infiltration of the lamina propria with T cells.47,48 Inflammatory changes of the upper airway musculature are also described.49 In a fashion similar to that noted in asthma of the upper and lower airways as a continuum, the presence of bronchial inflammation with elevated levels of neutrophils in induced sputum of OSAS patients has been demonstrated.50,51 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,52 which enhances susceptibility to bronchospasm,53 a major element in the pathogenesis of asthma. Therefore, local airway inflammation seen in OSAS may trigger asthma. SYSTEMIC INFLAMMATION In individuals with OSAS, even in the absence of an overt inflammatory insult, chronic, low-grade systemic inflammation is characterized by increased serum concentrations of cytokines, and chemokines.54-59 Also, OSAS in adults is associated with elevated levels of C-reactive protein CRP, a marker of inflammation and of cardiovascular risk.57 Previous studies have shown that the severity of OSAS is proportional to the CRP level,57 and that 1 month of effective treatment for OSAS with continuous positive airway pressure treatment led to a considerable decease in CRP level.60 The origin of this systemic inflammation appears to be, at least in
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bronchi. As a result, repeated stimulation of these neural receptors during heavy snoring and obstructive apneas could stimulate neural reflex-induced bronchoconstriction. It can follow that the more negative intrathoracic pressure developed during obstructive apneas intensifies pulmonary capillary blood volume. Such an increase was observed during sleep in asthmatic subjects with nocturnal symptoms10 and could contribute to the deleterious effect of decreased lung volume in the development of nocturnal bronchoconstriction in sleep apnea patients.11 An additional postulated trigger for reflex bronchoconstriction is stimulation of the carotid body by the hypoxia that results from obstructive apneas.12,13 Denjean et al revealed that mild hypoxia enhanced the bronchial responsiveness to methacholine in sheep and that this effect was abolished in all animals after carotid chemodenervation.14 Other investigators have shown that the hypoxia potentiated the bronchoconstricting reflex as well as the response to histamine in anesthetized dogs15 and the bronchial response to an aerosolized dose of histamine in awake sheep.16 Furthermore, a hypoxia-induced increase in bronchial responsiveness to methacholine was reported in asthmatic subjects.17 Evidence indicates that hypoxia may modulate the airway response to constricting stimuli through a vagal pathway.18-20 This vagal reflex is likely initiated by stimulation of the peripheral carotid body chemoreceptors.14 GASTROESOPHAGEAL ACID REFLUX (GER) The prevalence of GER is increased in patients with OSAS.21-23 Green et al24 and Valipour et al25 reported that GER was a complication in 62% and 58% of patients with OSAS, respectively. It has been suggested that obesity contributes to the same risk factors for OSAS and GER; however, OSAS patients exhibit significantly more GER than do members of the average population even when one controls for alcohol intake and body mass index.26 This situation is thought to be due to the increased transdiaphragmatic pressure and decreased intrathoracic pressure occurring during the apneic episodes, favoring GER.26-28 Other possible mechanisms include stomach dilatation, decreased gastric motility, and transient lower esophageal sphincter relaxation caused by autonomic nervous abnormality induced by the apneic episodes.29 GER occurring during sleep is a well-known trigger for nocturnal asthma30-34 and can provoke asthma symptoms through
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Obstructive Sleep Apnea Syndrome and Asthma

part, the oxidative stress induced by oxygen desaturation during sleep apneas.61 With respect to airway smooth muscle, OSASrelated increases in serum TNF-54-56 are particularly interesting. TNF receptors are expressed on airway smooth muscle, and exogenous TNF- has been shown to increase in vitro contractility of mouse airways in response to a variety of contractile agonists.62 On the other hand, OSAS-induced oxidative stress and elevation of IL-8 might contribute to bronchial inflammation.50 Finally, this cytokine mix may enhance multiple additional proinflammatory effects including endothelial activation for leukocyte recruitment and enhanced activation of resident airway cells such as epithelial cells, fibroblasts, and mast cells. CARDIAC DYSFUNCTION OSAS has been shown to lead to many cardiovascular consequences, which may complicate a coexisting airway obstruction in asthmatic patients. OSAS increases the risk of ischemic heart disease and congestive heart failure (CHF).63 Moreover, dogs in which obstructive sleep apnea is induced develop left ventricular dysfunction.64 This situation is thought to be caused by several mechanisms. Large epidemiologic65 animal66 and human intervention studies67 indicate that OSAS contributes to the development of systemic hypertension, a precursor of CHF. Recurrent hypoxemia, hypercapnia,68 and baroreflex inhibition resulting from repetitive surges in nocturnal blood pressure69 may contribute to elevated sympathetic nerve activity, which is known to be cardiotoxic in patients with CHF.70 Hypoxemia may also independently lead to oxidative vascular wall injury.71,72 It has been observed clinically and experimentally that CHF causes airway obstruction,73 and accumulating clinical evidence indicates that one crucial component of bronchial narrowing in CHF is hyperresponsiveness to cholinergic stimuli with subsequent constriction of airway smooth muscles.74-78 Various mechanisms have been proposed to be involved in the airway hyperresponsiveness associated with CHF, including down-regulation of pulmonary -receptors with concomitant decreases in adenylyl cyclase activity, which results in significant attenuation of cAMP-mediated airway relaxation.79 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.80 OSAS, through aggravating cardiac dysfunction, could further stimulate airway hyperresponsiveness (AHR) in asthmatic patients. vASCULAR ENDOTHELIAL GROWTH FACTOR (vEGF) AND AIRWAY ANGIOGENESIS VEGF is a hypoxia-sensitive glycoprotein that stimulates vessel growth.81,82 VEGF is essential for neoangiogenesis during embryonic development, wound healing, and tumor growth.83,84 An increasing body of evidence indicates that VEGF may also play an important role in the pathogenesis of bronchial asthma85,86 and may contribute to bronchial inflammation and hyperresponsiveness.87 One recent study supported a critical role for VEGF in vascular remodeling in asthma.88 In addition, a correlation has been found between increased VEGF levels in asthmatic patients and the degree of airway obstruction.85
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Recent studies indicate that OSAS patients have elevated concentrations of VEGF that correlate with the severity of the syndrome as reflected by the level of the apneahypopnea index (AHI)89,90 and the degree of nocturnal oxygen desaturation.91 In OSAS, the most likely trigger of VEGF release is hypoxia through hypoxia-inducible factor (HIF)-mediated gene expression as a result of repetitive nighttime hypoxia.91 The VEGF increase in OSAS might also be secondary to alterations in other mediator systems. Free oxygen radicals and endothelin, which have been reported to be elevated in patients with OSAS, may enhance gene expression of VEGF.61,92-94 Also, the inhibitory effect of nitric oxide on VEGF gene induction may be weakened through the down regulation of nitric oxide synthesis that has been found in OSAS.95,96 Though the relationship is likely, no conclusive data yet exist implicating the elevated VEGF levels in OSAS patients with the bronchial inflammation and hyperresponsiveness fundamental to asthmatic airway inflammation. LEPTIN HYPOTHESIS Leptin is a protein produced by adipose tissue97 that circulates systemically and acts on the hypothalamus to induce satiety and increase metabolism.98 Nevertheless, serum leptin concentrations are markedly increased in obese patients,99 suggesting leptin resistance in obesity,97 similar perhaps to the insulin resistance observed in patients with type II diabetes. In addition to its effects on the regulation of body weight, leptin is also proinflammatory,100-102 stimulating the release of proinflammatory cytokines such as IL-6 and TNF- by adipocytes. Hematopoietic cells express leptin receptors, and monocytes and macrophages respond to leptin with increased LPS-stimulated production of cytokines. CD41 T cells exposed to leptin also demonstrate increased proliferative responses to T-cell mitogens. A novel hypothesis is emerging for the role of leptin 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 that of nonasthmatic children.103 In a murine model, administration of leptin to mice increased both airway hyperresponsiveness to inhaled methacholine and serum IgE levels, suggesting the role of leptin in increased activation of mast cells.104 Obese male patients with OSAS exhibit leptin levels approximately 50% higher than those of similarly obese men without OSAS.105 Clinically, several case-control studies have demonstrated increased levels of serum leptin in OSAS patients compared with those of nonapneic patients with similar levels of obesity.89-91 In addition, a significant inverse correlation (r = 0.73, p < 0.001) independent of BMI was found between plasma-soluble leptin receptor levels and the apnea-hypopnea index.106 The increased levels may result from the hypoxic stimuli characteristic of OSAS, which increases leptin secretion,107 although the exact mechanism is not yet understood. Because OSAS patients have higher leptin levels than do obese nonapneic patients, it is postulated that OSAS might lead to leptin resistance. Coupled with the increased levels of serum leptin observed in OSAS, the proinflammatory effects of leptin suggest that this hormone might be relevant to asthma exacerbation in OSAS. The relationship between elevated leptin levels in OSAS patients and airway

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hyperresponsiveness and inflammation could be an important causal link between the morbidities of OSAS and asthma. WEIGHT GAIN The repetitive episodes of hypoxia and sleep fragmentation that occur in OSAS have been shown to induce glucose intolerance and an increase in insulin resistance.108-112 In some studies, the severity of OSAS correlates with the degree of insulin resistance.113,114 The increase in insulin resistance in OSAS may be related to stimulation of the sympathetic nervous system, stimulation of the hypothalamic-pituitary-adrenal axis and release of adipocyte-derived inflammatory cytokines IL-6, TNF-, and leptin. Patients with insulin resistance may continue to gain weight, because circulating insulin further stimulates appetite and promotes the storage of fat. It has been noted that patients with OSAS have a decrease in growth hormone secretion.115-117 Because growth hormone has a lipolytic action, the suppression of secretion of growth hormone in untreated OSAS results in impaired lipolysis and therefore promotes the storage of fat and weight gain. Finally, daytime sleepiness and fatigue are well known sequelae of untreated OSAS and result from both the hypoxia and the fragmented sleep occurring when the termination of apneas and hypopneas cause brief arousals.118 The effects of daytime sleepiness may undermine efforts of weight self-management. Sleepiness negatively affects cognition,119 general activity,120 and mood.119 These consequences negatively influence healthpromoting activities, motivation to prepare healthy meals, and exercise, all fundamental factors in maintaining and loosing weight. Sleepiness may contribute to overeating, further exacerbating a sedentary life style. These habits, over time, result in a vicious cycle of obesity, which worsens sleep apnea, which leads to increased severity of both conditions. Mounting evidence implicates obesity as a major risk factor for asthma. In human subjects and in mice, obesity appears to predispose individuals to airway hyperresponsiveness. Asthma is more prevalent in obese individuals, and obesity appears to contribute to severe asthma, because obese or overweight patients account for 75% of emergency department visits for asthma.121 Longitudinal studies indicate that obesity antedates asthma and that the relative risk of incident asthma increases with increasing obesity.122,123 Morbidly obese asthmatic subjects studied after weight loss demonstrate decreased severity and symptoms of asthma.124 Obesity appears to be a risk factor for AHR as well as for asthma. For example, Litonjua et al125 reported an association between increased BMI and onset of AHR in a longitudinal study of aging in male subjects in the United States. Two other large cross-sectional studies confirm these observations.126,127 Although the association between BMI and AHR has not been universally observed in epidemiologic studies, it is noteworthy that obese mice also demonstrate innate AHR.128 It appears that OSAS, through stimulation of weight gain, may play a significant role in worsening asthma outcome. WHY ASTHMATIC PATIENTS ARE MORE PREDISPOSED TO DEvELOP OSAS Recent studies showed that symptoms of OSAS, such as snoring and witnessed apneas, are common in the asthmatic population.129,130 Others have found a similar relationship beJournal of Clinical Sleep Medicine, Vol.5, No. 1, 2009 74

tween asthma and witnessed apneas and have noted increased daytime sleepiness in asthmatic patients,131 perhaps indicating the presence of a sleep disorder. A high prevalence of snoring in young women with atopy and a significant association of snoring with asthma have also been found.132 Yigla et al reported a high prevalence of OSAS (95.5%) among patients with unstable asthma receiving long-term or frequent bursts of oral corticosteroid therapy.133 In a representative sample of a general population in Sweden, after correction for age, gender, and smoking habits, snoring was reported by 10.7% of all subjects, in 21.3% of subjects with recurrent wheeze, and in 17.0% of those with physician-diagnosed asthma. Witnessed apneas were reported by 6.8% of all subjects, in 17.1% of those with recurrent wheeze, and in 14.3% with physician-diagnosed asthma.134 Because snoring and daytime sleepiness are common symptoms in OSAS, these data suggest a possible association between asthma and OSAS. The gold standard for the diagnosis of OSAS remains an attended polysomnogram (PSG).135 Population-based studies using laboratory PSG in asthmatic patients have not been reported to date, probably due to the significant cost of such an endeavor. However, with the use of home overnight multichannel monitoring, Redline et al136 performed portable monitoring on 399 children and adolescents and confirmed a significant association between upper and lower respiratory symptoms and asthma with sleep disordered breathing (AHI > 10) and demonstrated that these associations were independent of sex, obesity, family history, and race. A recent report from the National Sleep Foundation found that 26% of the general adult population would meet the criteria for high risk for OSAS by the Berlin Questionnaire,137 which has been validated as having a high positive predictive value for OSAS.138 In a study that used the Berlin Questionnaire, researchers noted a higher prevalence of OSAS symptoms in an asthmatic population compared with a primary care population (39.5% vs. 27.2%, p = 0.004). This study suggested the increased likelihood of OSAS in asthmatic patients compared with non-asthmatic patients.139 A possible etiology for the high prevalence of OSAS symptoms in asthmatic patients is the increased incidence of nasal obstruction in asthmatic patients. The nose is the preferred breathing route during sleep,140 and nasal obstruction contributes to sleep disordered breathing in predisposed individuals.141-143 Rhinitis and chronic sinusitis are common conditions that may cause nasal congestion and consequently contribute to upper airway obstruction in OSAS. Nasal and nasopharyngeal polyps may also be associated with upper airway obstruction.144 Clinical studies indicate that the majority of patients with asthma have rhinitis.145 One study showed that 100% of subjects with severe (steroidrequiring) asthma and 77% of subjects with mild to moderate asthma had abnormal results on computed tomographic scans of the sinuses.146 Linneberg et al, in an epidemiologic study, found a substantial association between allergic rhinitis and asthma.147 A study by Gaga et al148 assessed nasal biopsies in nonatopic subjects with asthma. Both study groups, with or without nasal symptoms, showed similarly high nasal eosinophil counts compared with those of healthy control subjects. The increased nasal obstruction in asthmatic patients induces an increase in nasal resistance that in turn increases the negative pressure in the upper airway during inspiration, a key factor for developing OSAS.

Obstructive Sleep Apnea Syndrome and Asthma

Another cause of the high incidence of OSAS in asthmatic patients may be the reduction of airway cross-sectional area and upper airway patency. One reason behind this reduction is the permanent airway mucosal inflammation observed in asthmatic patients. In fact, Collett et al found a significant reduction of upper airway dimension during inspiration and expiration during asthma flares.149 Increased fat deposits in the pharyngeal wall from weight gain is another reason asthmatic patients have reduced airway patency. Weight gain may continue with time, due to a limited ability to exercise, sleep deprivation with increased insulin resistance, depression,150 and the use of oral steroids.133 Finally, the disruption of sleep architecture following repeated nocturnal asthma attacks131,151 might set the scene for OSAS. Indeed, chronic sleep deprivation and especially sleep fragmentation increase upper airway collapsibility,152 another factor contributing to the development of OSAS (see Figure 1). CONCLUSION OSAS and asthma are detrimental to each other. Recent data suggest that OSAS is an independent risk factor for asthma exacerbations153 and that OSAS symptoms are more common in asthmatic patients than in the general population. We have shown that OSAS can worsen asthma and vice-versa, and we have outlined potential etiologies for this interaction. Several studies have shown an improvement in asthma symptoms after the initiation of CPAP;154-156 therefore future research may need to explore this pathway to further confirm the hypothetical link in causality and management between the two conditions. Practitioners should understand the relationship between asthma and OSAS and how important it is that OSAS be considered, identified, and treated in patients with asthma. ACkNOWLEDGMENTS Irvin Tantuco, MD, Elie Zainoun, and Pamela Fried assisted in this review. DISCLOSURE STATEMENT This was not an industry supported study. The authors have indicated no financial conflicts of interest. REFERENCES
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