Recognizing the impact of obstructive sleep apnea in patients with asthma

October 1, 2005
Guha Krishnaswamy, MD
Guha Krishnaswamy, MD

,
Mirle Girish, MD
Mirle Girish, MD

,
Bhuvana Guha, MD
Bhuvana Guha, MD

,
Robert Ballard, MD
Robert Ballard, MD

,
Harsha Vyas, MD
Harsha Vyas, MD

,
David S. Chi, PhD
David S. Chi, PhD

Volume 5, Issue 10

Abstract: The coexistence of asthma and obstructive sleep apnea (OSA) in a given patient presents a number of diagnostic and treatment challenges. Although the relationship between these 2 diseases is complex, it is clear that risk factors such as obesity, rhinosinusitis, and gastroesophageal reflux disease (GERD) can complicate both asthma and OSA. In the evaluation of a patient with poorly controlled asthma, it is important to consider the possibility of OSA. The most obvious clues are daytime sleepiness and snoring, but the definitive diagnosis is made by polysomnography. Management of OSA may include weight loss and continuous positive airway pressure (CPAP). Surgical intervention, such as uvulopalatopharyngoplasty, may be an option for patients who cannot tolerate CPAP. Management may include specific therapies directed at GERD or upper airway disease as well as modification of the patient's asthma regimen. (J Respir Dis. 2005;26(10):423-435)

Obstructive sleep apnea (OSA) and asthma are both common medical problems.1,2 It is estimated that up to 40 million persons in the United States have OSA, while 17 million have asthma.1-4 Moreover, OSA and asthma may coexist,5 further complicating airway inflammatory pathology and the management of airway disease.

In this article, we will discuss the association between OSA and asthma and the role of certain comorbidities, such as obesity, gastroesophageal reflux disease (GERD), nasal obstruction, and rhinosinusitis, that may complicate either or both diseases.

SLEEP APNEA

Central sleep apnea is characterized by intermittent apnea or hypopnea that is secondary to cessation of respiratory effort. OSA is characterized by periodic or complete upper airway obstruction during sleep, resulting in intermittent cessation of breathing that may be complete (apnea) or partial (hypopnea) despite continued respiratory effort (Table 1).2-4 The severity of a patient's OSA is determined by the number of apneic and/or hypopneic events occurring per hour, and OSA can be classified as mild, moderate, or severe.

Both forms of sleep apnea may coexist in a given patient. It has been estimated that sleep-disordered breathing may occur in as many as 24% of middle-aged men and 9% of middle-aged women, based on an apnea-hypopnea index (AHI) of more than 5 per hour.3 Up to 4% of men and 2% of women may have the full-blown OSA syndrome, including daytime hypersomnolence and apnea. OSA is not rare in children; the incidence may be as high as 1% to 3%.6 Despite the severe morbidity and mortality associated with OSA, it remains undiagnosed in most adults with this syndrome.6

The major risk factors for OSA include obesity, male sex, and a positive family history for the disease. A body mass index (BMI) of more than 30 kg/m2 is a significant risk factor.

THE OSA-ASTHMA LINK

Some of the risk factors for OSA can also contribute to asthma (Table 2). In fact, several of these risk factors may coexist in a patient who has both OSA and asthma.

Snoring and apnea are common in patients with asthma and allergic rhinitis.7 In some instances, upper airway resistance syndrome and OSA may be mistaken for nocturnal asthma.8 Sleep deprivation, upper airway edema, and systemic inflammation associated with OSA can complicate the course of asthma.5

Sleep and nocturnal asthma

Many physiologic changes associated with sleep can promote nocturnal worsening of asthma. For example, sleep is routinely associated with an increase in parasympathetic tone relative to sympathetic activity, which could promote increased bronchomotor tone and bronchoconstriction.

Sleep has also been associated with reductions in lung volume in patients with asthma, who typically have hyperinflation during wakefulness.9 This reduction in lung volume clearly contributes to the increased lower airway resistance that has been measured during sleep. Fortunately, there is evidence that ventilatory responsiveness to induced bronchoconstriction is adequately maintained during sleep, even if there is excessive sleepiness after prolonged periods of sleep deprivation.10

Finally, there has been substantial interest in the potential association between OSA and asthma. Proposed mechanisms of contribution include a neurogenically mediated increase in bronchomotor tone resulting from snoring-associated vibration of the upper airway,11 OSA-associated increase in systemic inflammation, and OSA-associated increase in pulmonary blood volume.12

Obesity

As noted above, obesity is a risk factor for OSA. Moreover, an increased incidence of obesity has been observed in patients with asthma.13-15

Reflux

GERD is common in patients who have OSA, obesity, or asthma. It may occur in persons who have sleep-disordered breathing resulting from apnea or in association with obesity.16 GERD can also ex-acerbate asthma and airway inflammation.17 It can cause a va- riety of aerodigestive complications, including cough and laryngitis.18,19 Reflux of gastric acid has been shown to worsen bronchial hyperresponsiveness.16,18,19

Upper airway disease

Allergic and structural airway disease, such as allergic rhinitis, tonsillar enlargement, and micrognathia, may be contributory factors in some patients with OSA and/or asthma. Nasal obstruction can occur in patients with allergic asthma, vasomotor rhinitis, nonallergic rhinitis eosinophilic syndrome, nasal polyposis, or structural disease (deviated nasal septum, concha bullosa). Nasal obstruction of any cause can augment airway collapse and worsen OSA.20-22

The CORE syndrome

The coexistence of rhinitis, nasal polyposis, obesity, and GERD may contribute to the increasing frequency of the diagnosis of concurrent asthma and OSA. The acronym "CORE" describes the interactive disease states of OSA and asthma: Cough/asthma, Obesity/ OSA, Rhinosinusitis, and Esophageal reflux.2

OSA and other CORE components need to be considered in the evaluation of patients who have asthma that is refractory to therapy. The patient described below demonstrates a classic case of the CORE syndrome.

A 67-year-old man was evaluated for severe chronic asthma, rhinosinusitis, and hypertension. He complained of persistent wheezing, dyspnea, coughing, fatigue, daytime somnolence, headaches, and poorly controlled GERD. He had a 30-pack-year history of smoking but had quit smoking 4 years ago. His current medications included salmeterol, ipratropium, inhaled triamcinolone, montelukast, and oral prednisone (10 mg/d). He used nebulized ß-agonists almost every day.

Examination revealed an obese man who weighed 275 lb and had a BMI of 39.5 kg/m2. He had a short, thick neck; bilateral expiratory wheezing; and peripheral edema. Pulmonary function tests revealed a forced expiratory volume in 1 second (FEV1) of 2.09 L (69% of predicted) and a ratio of FEV1 to forced vital capacity of 71%. Allergy skin test results were negative, and his total IgE level was normal.

Polysomnography (PSG) recorded 69 obstructive and 8 hypopneic events, and the patient's lowest oxygen saturation was 83% (Figure 1). Continuous positive airway pressure (CPAP) therapy reversed the abnormalities and improved the patient's nocturnal asthma and daytime wheezing.

Barium examination of the patient's upper GI tract indicated GERD and tertiary contractions (Figure 2). He was advised to lose weight, avoid sedatives and alcohol, and follow antireflux measures. His GERD and asthma were managed aggressively, and his symptoms improved.

Other factors

Several endocrinopathies may play a role in the OSA-asthma relationship. Specifically, hypothyroidism needs to be evaluated and treated in OSA patients. C-reactive protein and inflammatory factors, such as cytokines and systemic inflammatory responses, elicited during apnea are also important to airway inflammation and remodeling (see "The role of inflammation in the relationship between asthma and obstructive sleep apnea").1,2,14,23-26

DIAGNOSIS AND MANAGEMENT

Components of the diagnosis and management of OSA, asthma, and potential comorbidities are shown in Table 3.

Obesity

As noted above, obesity is a predisposing factor for OSA, and the incidence of asthma is increased in obese persons.13-15 The measurement of body fat and calculation of BMI assist in classification and diagnosis. The management of obesity involves counseling on diet and weight loss and, in some patients, pharmacologic therapy. Weight loss can reduce the severity of OSA.

Weight reduction has been widely recommended for patients with OSA, and at least 2 prospective controlled trials have indicated that losing weight by following a low-calorie diet can achieve significant improvement in sleep-disordered breathing.27,28 Therefore, this would probably be helpful for obese patients who have OSA with concurrent asthma.

OSA

Because poorly controlled OSA may exacerbate asthma, the possibility of OSA must be considered in a patient with poorly controlled asthma. Signs of poorly controlled asthma include moderate to severe airway obstruction, persistent daytime and exercise-induced symptoms, and excessive use of ß2-agonists. In evaluating a patient who has poorly controlled asthma, look for clues such as excessive daytime sleepiness, morning fatigue, excessive snoring, nocturnal reflux, and peripheral edema

The history and physical examination are essential components of the evaluation of OSA. Loud guttural snoring that is worse in the supine position and that is punctuated by choking sounds, followed by cessation of breathing, is virtually pathognomonic of OSA. The snoring and apneic episodes may be worse after using alcohol or sleeping pills, because these substances decrease pharyngeal muscle tone.29,30 A collateral history should be obtained from the patient's bed partner.

Daytime fatigue and sleepiness are the most significant complaints of patients with OSA. Frequently, the patient falls asleep during sedentary activities, such as watching television. A higher incidence of automobile accidents has been described in patients with OSA. Other symptoms include nonrestorative sleep (or fatigue), early-morning headaches, neurocognitive dysfunction, nocturia, nocturnal gastroesophageal acid reflux and heartburn, and nocturnal diaphoresis. Diminished libido or impotence is not uncommon, even in younger persons.

The physical examination focuses on craniofacial and soft tissue conditions that are associated with increased upper airway resistance, such as retrognathia, deviated nasal septum, low-lying soft palate, enlarged uvula and base of the tongue, nasal polyps, and hypertrophy of the turbinate.31,32 An increased BMI, hypertension, and a greater neck circumference (16 inches in women and 17 inches in men) are associated with an increased risk of OSA. Increased upper body obesity, which is reflected by the neck circumference, is a particularly good predictor.

Some of the most severe cases of OSA have been seen in thin, young patients who have small jaws (micrognathia) with or without overbite or underbite. Another clue, which has not received general attention, is the tendency of a patient who has a small pharyngeal space to snort when laughing; this may represent the waking equivalent of apnea.

Despite the importance of the history and physical examination, their combined predictive value is only about 50%.6 The most valuable test for confirming OSA has been the overnight sleep study, or PSG.33 Standard PSG is a laboratory-based, technician-attended multimodality recording of sleep architecture by electroencephalography, electro-oculography, and electromyography; respiratory activity by nasal and oral airflow or pressure, thoraco-abdominal inductance plethysmography, and oximetry; electrocardiography; and limb movements by lower extremity electromyography. Rarely, esophageal pressure monitoring may be required if respiratory effort-related arousals or central sleep apnea is suspected.

The principal factor to note is the AHI. OSA is defined either by an AHI of 5 or more plus evidence of nonrestorative sleep, daytime sleepiness, or other daytime symptoms, or by an AHI of 15 or higher. An American Academy of Sleep Medicine expert panel recommended that mild OSA be defined by an AHI of 5 to 14, moderate by an AHI of 15 to 30, and severe by an AHI of more than 30.34

Screening studies using only a few channels (breathing effort, airflow, and oxygen saturation) are often performed at home without monitoring by technicians and may be helpful for follow-up. However, these studies are not a substitute for an in-laboratory, all-night diagnostic sleep study, and they often add to cost, since they frequently lead to further evaluation in a more formal setting.

The American Sleep Disorders Association standards of practice recommends that portable studies be reserved for patients with severe symptoms when standard PSG is not readily available and for those who are unable to be studied in the laboratory. Pulse oximetry is not considered a sufficient alternative to PSG; its value may lie at the extremes of the OSA spectrum.35 If clinical suspicion is high, pulse oximetry may help determine the timing of PSG when entry to a sleep center is delayed. If clinical suspicion is low, normal results effectively exclude OSA.

Management of OSA is multidisciplinary. Conservative treatment may be an option for patients with mild OSA and may involve education on weight loss, avoidance of alcohol and tranquilizers, and sleeping in the lateral position.2-4 Many types of oral appliances have been designed for patients who have upper airway obstruction. In some patients, such mandibular advancement therapy may be effective, but it is inferior to nasal CPAP in patients who have moderate or advanced OSA.

The use of CPAP in patients with moderate-severe OSA is accompanied by improvements in daytime somnolence, quality of life, mood, and alertness.2-4 Studies have also shown that treatment of OSA with CPAP leads to improvements in peak flow rates in patients with concomitant asthma.5

The actual effects of treating OSA on the outcome of asthma have been poorly studied. A study by Guilleminault and associates36 demonstrated no beneficial effect of nasal CPAP on daytime asthma. In a small study by Martin and Pak,37 2 of 7 patients with poorly controlled asthma had improved oxygen saturations and FEV1 after nasal CPAP therapy.

One problem with the use of CPAP is compliance, partly because of the associated nasal obstruction in patients who are already suffering from rhinitis and asthma. In some patients, "self-adjusting machines" may be used. In patients who are intolerant of CPAP, surgical therapies may include uvulopalatopharyngoplasty, laser-assisted uvulopalatoplasty, tongue ablation, mandibular reconstruction, and tracheostomy. These surgical procedures have a high complication rate, and their effectiveness is unclear.

Upper airway obstruction

Appropriate evaluation of nasal obstruction includes allergy testing, CT of the paranasal sinuses, and fiberoptic rhinoscopy. Aggressive treatment may include intranasal corticosteroids, leukotriene modifiers, antihistamine-decongestants, and allergy immunotherapy.

GERD

Patients with GERD may complain of burning chest pain, regurgitation, water brash, and odynophagia. In some patients, GERD may be asymptomatic.

The evaluation may include barium study, upper endoscopy or, in difficult cases (especially in patients with nonerosive reflux), a 24-hour esophageal pH study. In select patients, therapy with a proton pump inhibitor may reduce the symptoms of GERD, thus supporting the diagnosis.

Elevation of the head of the bed; avoidance of nicotine, caffeine, and other substances that may exacerbate reflux; weight loss; surgery (fundoplication); and the use of antireflux drugs, such as proton pump inhibitors, can improve control of GERD, and of asthma as well.

Airway inflammation

Pulmonary function tests, such as spirometry, are essential to the diagnosis and classification of asthma. If the patient has persistent symptoms, such as cough, shortness of breath, and mucus production, but has essentially normal spirometric results, methacholine challenge testing may be considered to establish the diagnosis of asthma.

Because inflammation is a feature of both OSA and asthma, besides monitoring pulmonary function tests, measurement of exhaled nitric oxide and sputum levels of mediators and eosinophils may be beneficial when such techniques are available. Therapy with inhaled corticosteroids, long-acting ß2-agonists, or leukotriene modifiers may be required.1 A newer treatment option for patients with allergic asthma is omalizumab, a recombinant, humanized monoclonal antibody to IgE.1

Cardiovascular disease and other complications

Neuropsychiatric complications of OSA include daytime somnolence, cognitive dysfunction, and depression. Cardiovascular disease is common in patients with OSA and can result from poorly treated OSA.

OSA can be complicated by hypertension, stroke, congestive heart failure, coronary or cerebrovascular atherosclerosis, cardiac arrhythmia, myocardial infarction, unstable coronary syndrome or angina pectoris, and ischemic ventricular dysfunction.6,38-43 Left ventricular hypertrophy and diastolic dysfunction have also been described in OSA.44,45

In addition, cardiac dysfunction can present as asthma or worsen underlying asthma. These events may lead to worsening hypoxemia and may contribute to progressive cognitive decline, leading to poor compliance with medications. Frequently asking about medication use, monitoring compliance, and asking the patient to bring all of his or her medications to the office visit will help address the problem.

Elderly patients with OSA who have wheezing or dyspnea may need to be evaluated for asthma as well as for systolic or diastolic cardiac dysfunction. Antihypertensive medication, dietary salt restriction, and the management of any underlying cardiac disease are important. When hypertension complicates OSA in a patient with asthma, the choice of antihypertensive agent must be made carefully. For example, ß-adrenergic antagonists may worsen bronchospasm, and angiotensin-converting enzyme inhibitors may cause cough.

References:

REFERENCES


1. Krishnaswamy G. Treatment strategies for bronchial asthma: an update.

Hosp Pract (Off Ed).

2001;36:25-26, 29-35.
2. Arter JL, Chi DS, Girish M, et al. Obstructive sleep apnea, inflammation, and cardiopulmonary disease.

Front Biosci.

2004;9:2892-2900.
3. Qureshi A, Ballard RD. Obstructive sleep apnea.

J Allergy Clin Immunol.

2003;112:643-651.
4. Flemons WW. Clinical practice. Obstructive sleep apnea.

N Engl J Med.

2002;347:498-504.
5. Bonekat HW, Hardin KA. Severe upper airway obstruction during sleep.

Clin Rev Allergy Immunol.

2003; 25: 191-210.
6. Attarian HP, Sabri AN. When to suspect obstructive sleep apnea syndrome. Symptoms may be subtle, but treatment is straightforward.

Postgrad Med.

2002; 111: 70-76.
7. Larsson LG, Lindberg A, Franklin KA, Lundback B. Symptoms related to obstructive sleep apnoea are common in subjects with asthma, chronic bronchitis and rhinitis in a general population.

Respir Med.

2001; 95: 423-429.
8. Guerrero M, Lepler L, Kristo D. The upper airway resistance syndrome masquerading as nocturnal asthma and successfully treated with an oral appliance.

Sleep Breath.

2001;5:93-96.
9. Ballard RD, Irvin CG, Martin RJ, et al. Influence of sleep on lung volume in asthmatic patients and normal subjects.

J Appl Physiol.

1990;68: 2034-2041.
10. Ballard RD, Tan WC, Kelly PL, et al. Effect of sleep and sleep deprivation on ventilatory response to bronchoconstriction.

J Appl Physiol.

1990;69:490-497.
11. Ballard RD. Sleep, respiratory physiology, and nocturnal asthma.

Chronobiol Int.

1999; 16: 565-580.
12. Desjardin JA, Sutarik JM, Suh BY, Ballard RD. Influence of sleep on pulmonary capillary volume in normal and asthmatic subjects.

Am J Respir Crit Care Med.

1995;152:193-198.
13. Schachter LM, Peat JK, Salome CM. Asthma and atopy in overweight children.

Thorax.

2003;58:1031-1035.
14. Ford ES. Asthma, body mass index, and C-reactive protein among US adults.

J Asthma.

2003;40:733-739.
15. Gilliland FD, Berhane K, Islam T, et al. Obesity and the risk of newly diagnosed asthma in school-age children.

Am J Epidemiol.

2003; 158: 406-415.
16. Teramoto S, Ohga E, Matsui H, et al. Obstructive sleep apnea syndrome may be a significant cause of gastroesophageal reflux dis-ease in older people.

J Am Geriatr Soc.

1999; 47: 1273-1274.
17. Gislason T, Janson C, Vermeire P, et al. Respiratory symptoms and nocturnal gastroesophageal reflux: a population-based study of young adults in three European countries.

Chest.

2002;121:158-163.
18. Harding SM. Recent clinical investigations examining the association of asthma and gastroesophageal reflux.

Am J Med.

2003;115 (suppl 3A): 39S-44S.
19. Harding SM. Acid reflux and asthma.

Curr Opin Pulm Med.

2003;9:42-45.
20. Virkkula P, Maasilta P, Hytonen M, et al. Nasal obstruction and sleep-disordered breathing: the effect of supine body position on nasal measurements in snorers.

Acta Otolaryngol.

2003; 123: 648-654.
21. Yang C, Woodson BT. Upper airway physiology and obstructive sleep-disordered breathing.

Otolaryngol Clin North Am.

2003;36:409-421.
22. Salib RJ, Sadek SA, Dutt SN, Pearman K. Antrochoanal polyp presenting with obstructive sleep apnoea and cachexia.

Int J Pediatr Otorhinolaryngol.

2000;54:163-166.
23. Bohadana AB, Hannhart B, Teculescu DB. Nocturnal worsening of asthma and sleep-disordered breathing.

J Asthma.

2002;39:85-100.
24. Carpagnano GE, Kharitonov SA, Resta O, et al. Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients.

Chest.

2002;122:1162-1167.
25. Salerno FG, Carpagnano E, Guido P, et al. Airway inflammation in patients affected by obstructive sleep apnea syndrome.

Respir Med.

2004;98:25-28.
26. Ewing R, Schmid T, Killingsworth R, et al. Relationship between urban sprawl and physical activity, obesity, and morbidity.

Am J Health Promot.

2003;18:47-57.
27. Smith PL, Gold AR, Meyers DA, et al. Weight loss in mildly to moderately obese patients with obstructive sleep apnea.

Ann Intern Med.

1985; 103(6 pt 1):850-855.
28. Schwartz AR, Gold AR, Schubert N, et al. Effect of weight loss on upper airway collapsibility in obstructive sleep apnea.

Am Rev Respir Dis.

1991;144(3 pt 1): 494-498.
29. Shepard JW Jr. Cardiopulmonary consequences of obstructive sleep apnea.

Mayo Clin Proc.

1990; 65: 1250-1259.
30. Kales A, Caldwell AB, Cadieux RJ, et al. Severe obstructive sleep apnea--II: associated psychopathology and psychosocial consequences.

J Chronic Dis.

1985; 38: 427-434.
31. Carskadon MA, Dement WC, Mitler MM, et al. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness.

Sleep.

1986;9:519-524.
32. Davies RJ, Ali NJ, Stradling JR. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome.

Thorax.

1992; 47: 101-105.
33. Practice parameters for the indications for polysomnography and related procedures. Polysomnography Task Force, American Sleep Disorders Association Standards of Practice Committee.

Sleep.

1997;20:406-422.
34. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force.

Sleep.

1999;22:667-689.
35. Tobert DG, Gay PC. New directions for pulse oximetry in sleep disorders.

Mayo Clin Proc.

1995; 70: 591-592.
36. Guilleminault C, Quera-Salva MA, Powell N, et al. Nocturnal asthma: snoring, small pharynx and nasal CPAP.

Eur Respir J.

1988;1:902-907.
37. Martin RJ, Pak J. Nasal CPAP in nonapneic nocturnal asthma.

Chest.

1991;100:1024-1027.
38. Lattimore JD, Celermajer DS, Wilcox I. Obstructive sleep apnea and cardiovascular disease.

J Am Coll Cardiol.

2003;41:1429-1437.
39. Yaggi H, Mohsenin V. Sleep-disordered breathing and stroke.

Clin Chest Med.

2003; 24: 223-237.
40. Wolk R, Somers VK. Cardiovascular consequences of obstructive sleep apnea.

Clin Chest Med.

2003; 24: 195-205.
41. Fletcher EC. Obstructive sleep apnoea and cardiovascular morbidity.

Monaldi Arch Chest Dis.

1996; 51: 77-80.
42. Baguet JP, Pepin JL, Hammer L, et al. Cardiovascular consequences of obstructive sleep apnea syndrome.

Rev Med Interne.

2003; 24: 530-537.
43. Hermann DM, Bassetti CL. Sleep-disordered breathing and stroke.

Curr Opin Neurol.

2003; 16: 87-90.
44. Kraiczi H, Caidahl K, Samuelsson A, et al. Impairment of vascular endothelial function and left ventricular filling: association with the severity of apnea-induced hypoxemia during sleep.

Chest.

2001;119:1085-1091.
45. Cloward TV, Walker JM, Farney RJ, Anderson JL. Left ventricular hypertrophy is a common echocardiographic abnormality in severe obstructive sleep apnea and reverses with nasal continuous positive airway pressure.

Chest.

2003;124:594-601.