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Lesson 4, Volume 15—Nocturnal Asthma

By Nizar Jarjour, MD, FCCP

Effective December 31, 2004, PCCU Volume 15 is available for review purposes only. CME credit for this volume is no longer being offered.

Objectives

  1. To review the various mechanisms that have been proposed for nocturnal asthma.
  2. To discuss the role of various asthma medications in the treatment of nocturnal asthma.
  3. To explain the application of chronopharmacologic principles in treating asthma.
  4. To propose a step-by-step approach to management of nocturnal asthma.

Key words

b-agonists; airway inflammation; asthma; circadian rhythm; cytokines

Abbreviations

CPAP = continuous positive airway pressure; GER = gastroesophageal reflux; IFN-a = interferon-a; LAR = late asthmatic response; LTE4 = leukotriene E4; PEFR = peak expiratory flow rate; VCAM-1 = vascular adhesion molecule

Nocturnal asthma, more accurately named sleep-related asthma, has been recognized for centuries. It is a troublesome manifestation of asthma that is associated with sleep regardless of its time during the day. A number of studies have demonstrated a much greater prevalence of nocturnal asthma than previously anticipated.1-3 In a large postal survey of asthmatic patients under the care of primary-care physicians in the United Kingdom, 39% complained of nocturnal awakening every night and 64% of these patients had nocturnal wheezing at least three nights per week.1 These problems occurred while the patients were receiving antiasthma therapy. Even among the 3,015 patients who rated their disease as mild, nearly a quarter had nocturnal asthma every night despite using bronchodilator and corticosteroid inhalers.1 In a large pharmaceutical study in which more than 3,000 patients were evaluated during a washout phase, 90% of wheezing episodes occurred during the nighttime, with a peak incidence around 4 AM.2 Finally, Storms and colleagues,3 in a survey of their asthma patients under the care of asthma and allergy specialists, found a 67% incidence of nocturnal asthma. Taken together, these studies indicate that nocturnal asthma is a very frequent problem that is probably underappreciated by physicians and underreported by their patients.

Significance

Nocturnal asthma symptoms contribute to sleep deprivation and frequent arousals. Subsequently, patients often complain of daytime sleepiness, fatigue, and irritability. These problems can influence the patient’s school performance and work productivity. In addition, there is probably a link between the occurrence and severity of nocturnal wheezing and asthma mortality. Although asthma deaths are infrequent, they have increased over the past two decades for reasons that are not entirely clear. A survey of asthma mortality in London hospitals identified 19 deaths that occurred after patients were hospitalized for asthma exacerbations.4 Thirteen of these deaths occurred between midnight and 8 AM; the remainder of the deaths occurred throughout the day hours. In a subsequent study, the same group evaluated patients hospitalized for asthma exacerbations.5 In nearly 1,200 patients, there were 10 episodes of respiratory arrests. Interestingly, nine out of 10 patients who suffered an episode of respiratory arrest demonstrated > 50% diurnal variation in peak expiratory flow rate (PEFR). In contrast, only one third of the remaining patients showed similar magnitude of diurnal variation in peak flows. Therefore, it appears that worsening of asthma at night is an indicator of disease severity and potentially a contributor to increased asthma mortality.

Pathogenesis

Asthma is a disease characterized by airway obstruction, bronchial hyperresponsiveness, and airway inflammation. All of these features have been shown to have a circadian pattern with worsening in the early morning hours in the diurnally active patients.

Airway Obstruction

Several studies have shown that airway obstruction peaks around 4 AM. The nadir in peak flow rate or FEV1 occurs at that time, and peak pulmonary function typically occurs around 4 PM. This circadian pattern has also been demonstrated in normal subjects; however, the difference between daytime and nighttime peak flow rate is typically < 10%. In contract, patients with asthma, especially those with nocturnal asthma symptoms, have a day-night difference that often exceeds 15%, and can reach as high as 50%, with significant impact on asthma symptoms, arousals, and the need for nighttime rescue therapy.5,6

Airway Responsiveness

Nonspecific bronchial responsiveness also increases at night. Several studies have shown that methacholine responsiveness is greater (lower provocative dose causing a 20% fall in FEV1) in early morning compared with daytime values. This increase in reactivity can be so severe that even inhalation of the saline diluent can lead to > 20% drop in pulmonary function when the challenge is done at night.7 In addition to the enhanced nonspecific airway responsiveness, several studies have shown increased responsiveness to allergen at night. This is associated with a greater incidence, duration, and severity of the late asthmatic response following antigen challenge when the challenge is done during the night hours compared with a daytime challenge.8,9 Some studies have also shown that a single antigen exposure can lead to recurrent nocturnal asthma symptoms for several days afterward, indicating increased magnitude of circadian fluctuation in lung functions.10

Airway Inflammation

Airway inflammation has received increased emphasis in the past few years as an underlying mechanism for asthma and a correlate of its severity. Various tools have been used to assess airway inflammation including noninvasive methods (exhaled air, induced sputum), invasive direct methods (BAL, endobronchial biopsy, bronchial brushing, and transbronchial biopsy) and indirect methods (peripheral blood and urine sampling). In general, these studies reveal increased inflammatory markers in subjects with nocturnal asthma. Some of these studies have also shown enhanced inflammation at night in association with the fall in pulmonary function, suggesting that worsening airway inflammation is, at least in part, responsible for nighttime asthma symptoms. Martin and colleagues11 demonstrated that subjects with nocturnal asthma (defined as an average fall in PEFR of > 20% on three repeated nights) have increased proportions of granulocytes in BAL fluid at 4 AM compared with 4 PM, and that the increase in these cells correlated with the overnight fall in FEV1. In a study by Jarjour and colleagues,12 nocturnal asthma, defined as overnight decline in FEV1 of > 20%, was associated with increased airway cell generation of superoxide. Interestingly, this overnight enhancement in oxidative metabolism was seen only in subjects with overnight decline in lung function. Furthermore, the overnight fall in FEV1 correlated with the increased oxygen radical production.

In a subsequent study, Jarjour et al13 showed that BAL fluid obtained from nocturnal asthma subjects at 4 AM had higher levels of interleukin-1 (IL-1b) than at 4 PM, a change that was not seen in subjects without nocturnal asthma. While the source of IL-1b was not defined in that study, a study by Borish and colleagues14 demonstrated alveolar macrophages to be the likely source and confirmed that treatment with oral prednisone, given in the afternoon, significantly reduced the expression of IL-1a by alveolar macrophages at 4 AM in subjects with nocturnal asthma.

Kraft and colleagues15 evaluated the expression of epithelial cell markers and its circadian rhythm in subjects with asthma. They found that the expression of CD51 (a surface receptor for vitronectin and fibronectin) was enhanced at 4 AM in subjects with nocturnal asthma compared with control subjects and those with asthma but no nocturnal worsening. Furthermore, the expression of CD51 in the distal airway correlated with the degree of airway obstruction, suggesting that the increased expression of CD51 at night in asthma could be related to increased airway inflammation and contribute to airway obstruction at night.

In subsequent studies, the same group of investigators obtained endobronchial and transbronchial biopsies from asthma subjects with and without nocturnal asthma.16,17 They found that nocturnal asthma subjects have significant increase in the numbers of eosinophils and CD4+ lymphocytes at 4 AM. This change was not seen in the subjects with nonnocturnal asthma. The number of CD4+ cells in the alveolar tissue inversely correlated with FEV1 percent predicted at 4 AM and positively correlated with the numbers of alveolar tissue eosinophils. These findings suggest that the increase in CD4+ lymphocytes in alveolar tissue at night may contribute to recruitment and activation of eosinophils and, therefore, lead to nocturnal worsening of lung function. The influx of eosinophils from the vascular compartment into the airway tissue and airspace is facilitated by expression of specific adhesion molecules such as vascular adhesion molecule (VCAM-1). ten Hacken and colleagues18 evaluated the expression of VCAM-1 in bronchial biopsy specimens obtained at 4 PM and 4 AM from healthy subjects, asthmatics without nocturnal asthma, and asthmatics with nocturnal asthma (PEFR variation > 15%). Endobronchial biopsies from asthmatic subjects showed greater expression of VCAM-1 compared with normal subjects. In asthma, VCAM-1 expression correlated with the number of EG2+ cells (eosinophils). This was seen at both 4 AM and 4 PM. There were no day/night differences in expression of VCAM-1 in any of the three groups.

Noninvasive studies that evaluated exhaled nitric oxide revealed conflicting results. The study by Georges and colleagues19 showed a decrease in nitric oxide level from 4 PM to 10 PM and 4 AM. The levels at 4 AM and 10 PM were similar.19 This overnight fall in nitric oxide seen in subjects with nocturnal asthma was not observed in a group of subjects with nonnocturnal asthma. In contrast, ten Hacken and colleagues20 found that the levels of exhaled nitric oxide are elevated at both day and night in subjects with nocturnal asthma and that these levels did not reveal any circadian variation in asthma subjects with or without nocturnal asthma. Furthermore, there was no correlation between nitric oxide level and circadian rhythm in airway obstruction.

A study by Bellia and colleagues21 evaluated the association between nighttime asthma attacks and release of leukotrienes as expressed by urinary leukotriene E4 (LTE4) levels. Normal individuals and asthmatics without nocturnal attacks showed similar levels of LTE4. In contrast, subjects with nocturnal worsening of asthma (morning dip in PEFR > 20%) showed higher levels at night (9 PM to 9 AM) than in daytime samples (9 AM to 3 PM and 3 PM to 9 PM). Furthermore there was a significant correlation between the morning dip in PEFR and levels of LTE4 in the nocturnal samples, suggesting a role for leukotrienes in nocturnal asthma.

ten Hacken and coworkers22 also reported that serum interleukin 4 and 5 (IL-4 and IL-5) and interferon-g (IFN-g) levels were higher in asthma compared to healthy control subjects at both 4 PM and 4 AM. However, only IFN-g significantly correlated with a lower provocative dose of methacholine causing a 20% fall in FEV1 and an overnight fall in PEFR. This relationship was not noted with IL-4 and IL-5. These findings suggest a role for IFN-g in nocturnal asthma. Finally, Calhoun and colleagues23 demonstrated that the circulating eosinophils have increased survival and a higher proportion of hypodense cells at 4 AM than at 4 PM, suggesting that activation of circulating eosinophils could be a contributing factor to nocturnal worsening of asthma. Taken together, these data suggest that worsening of airway inflammation plays an important role in nighttime worsening of asthma.

Potential Contributing Factors

While the exact mechanism for nocturnal asthma remains unclear, many factors have been proposed as potential causes for or contributors to this process. These include enhanced vagal tone, supine position, rhinitis/sinusitis, pulmonary blood pooling, airway cooling, allergens, sleep, sleep apnea, gastroesophageal reflux (GER), circulatory catecholamine and cortisol, or alteration in b-adrenergic (or glucocorticoid) receptors. A detailed discussion of each of these factors is beyond the scope of this review; therefore, a brief review of selected factors is included.

Allergens. When exposed to a relevant allergen, most allergic asthma patients develop an immediate airway obstruction. This usually resolves within 1 h after exposure. Approximately 50% of these patients go on to show a late asthmatic response (LAR) with airway obstruction manifesting 3 to 8 h after antigen exposure. LAR is associated with increased airway responsiveness and inflammation. Some studies have shown that circadian variation in PEFR is increased with exposure to higher levels of house dust antigen or the presence of pets at home.24 Even patients with no allergy to pets can show this increase in circadian variation, presumably due to stirring up of house dust mites.24 However, in most asthmatics, exposure to allergen does not provide an adequate explanation for nocturnal asthma.

Sleep. Although nocturnal asthma is closely associated with sleep, the exact contribution of sleep to airway obstruction is unknown. In most patients, "nocturnal" asthma peaks 4 to 6 h after sleep onset. It is difficult to study the effect of sleep, independent of other factors such as the supine position, circadian rhythms, and GER. However, no consistent relationship has been shown with sleep stages. One study, by Ballard and colleagues,25 revealed that when patients are kept supine but awake overnight, a gradual increase in airway resistance is observed. However, when these subjects were allowed to sleep, the increase in airway resistance was significantly enhanced, suggesting that sleep itself was a contributor to nocturnal asthma.

Sleep Apnea. Asthma and sleep apnea are both common problems. Therefore, it is not surprising that the occurrence of sleep apnea in asthmatics is a real possibility. Asthma patients with sleep apnea tend to have more severe asthma manifestations, especially during sleep. In one study, treatment with nasal continuous positive airway pressure (CPAP) significantly improved both sleep apnea and asthma control.26 Interestingly, both AM and PM PEFR improved with CPAP therapy.26 While it was effective in those with sleep apnea, CPAP did not lead to improved airway function in nocturnal asthma patients without sleep apnea.27

Gastroesophageal Reflux. The prevalence of GER is increased in asthma.28 The supine position and the reduction of lower esophageal sphincter tone by anti-asthma medication probably contribute to this incidence. Interestingly, many of these patients do not have typical symptoms of GER (eg, heartburn). The role of GER in promoting nocturnal asthma remains controversial. Furthermore, it is unclear if actual aspiration of gastric acid is required or if stimulation of the esophagus causes a vagal reflex that mediates worsening of airway function. A study by Tan et al29 determined the airway response to intraesophageal acid infusion in patients with nocturnal asthma. They found little change in airway patency during spontaneous or simulated acid reflux. Asthma symptoms, especially cough, are commonly reported in association with GER. In a recent study, treatment with omeprazole 40 mg/d for 8 weeks was associated with improved nighttime asthma symptoms in patients with GER.30 Minimal changes in FEV1 were seen. Responders had a more severe GER than nonresponders. Other medical antireflux therapies (eg, H2-blockers) can reduce nighttime symptoms, and medication use, but have minimal effect on lung function.31 Most reports on the effect of antireflux surgery on nocturnal asthma are based on uncontrolled studies.32 Available data from controlled trials suggest that antireflux surgery may improve asthma symptoms with little effect on pulmonary function.

Epinephrine and b2-Adrenergic Receptors. Circulating catecholamine levels have a well-characterized circadian rhythm with peak levels at 4 PM and a nadir at 4 AM coinciding with peak and nadir pulmonary function. Based on this observation, Barnes et al33 suggested that decreased epinephrine at night promotes nocturnal asthma by allowing for enhanced smooth muscle contraction. However, in the study by Bates and associates,34 plasma epinephrine levels were lower at 10 PM in patients with nocturnal asthma compared with asthmatics who had no nocturnal decline in lung function. This study suggested that the effects of epinephrine might not be limited to smooth muscle but may extend to regulation of mediator release and airway inflammation. Interestingly, nocturnal asthma subjects were also found to have significantly decreased b2-receptor density on circulating leukocytes compared with normal subjects or with asthmatics without nocturnal asthma.35 More recently, a genetic polymorphism of the b2 receptor was found to be more common in nocturnal asthma.36 This polymorphism involves a substitution of glycine for arginine at position 16 (Gly 16). It appears that this alteration is associated with accelerated down-regulation of the b2 receptor. It is conceivable that reduced circulating levels of circulating catecholamines and down-regulation of b2 receptors contribute significantly to the occurrence of nocturnal asthma.

Cortisol. Like epinephrine, cortisol has a circadian pattern in normal and asthmatic subjects, with peak levels between 6 and 8 AM and a nadir around midnight.33 This circadian pattern was found to be similar in asthmatic subjects with and without nocturnal asthma.34 Infusing physiologic doses of hydrocortisone does not prevent the occurrence of nocturnal asthma completely, while pharmacologic doses (100 mg/h) infused during sleep significantly improve pulmonary function.

Summary

The mechanism of nocturnal exacerbation of asthma remains poorly understood. It probably results from multiple (perhaps synergistic) factors. Furthermore, nocturnal asthma may represent a syndrome in which different patients manifest nocturnal symptoms in response to different factors. While all of these are probably important, one or two factors are probably sufficient to induce this syndrome in a given patient. Finally, nocturnal asthma may not represent a distinct entity, but rather a feature of more severe asthma or the result of various provocative factors that are enhanced during sleep.

Treatment

Despite the high prevalence of nocturnal symptoms in asthma patients, they often do not complain about it to their physicians. Therefore, physicians are advised to ask patients specifically about nighttime symptoms or include a specific question about nocturnal problems in a questionnaire that the patients fill out at the time of their clinic visit. In those patients who have troublesome nocturnal asthma symptoms, steps to identify the triggers and modify the therapy should be initiated.

Identify and Modify (or Treat) Known Triggers

Frequent nocturnal wheezing should prompt a re-evaluation of the overall management of asthma. The potential triggers that can contribute to asthma exacerbation at night should be explored and, when found, treated or minimized. Several studies have shown that eliminating these triggers can lead to improved asthma control at night. For example, allergic rhinitis can contribute to nocturnal asthma, and effectively treating rhinitis helps to reduce nocturnal asthma. Exposure to allergens in the daytime, particularly house dust mites, can contribute to worsening of the overnight fall in lung function. Steps to reduce house dust mites (eg, keeping low humidity, avoiding carpeting, washing bed sheets weekly in hot water, keeping pets out of bedrooms) may also improve asthma control during sleep. The contribution of GER to nocturnal asthma can be difficult to determine. Some patients, in whom GER is known to play a role in worsening of asthma symptoms, have shown significant improvement after acid-suppressive therapy.30 In more severe cases, surgical antireflux therapy has been advocated, and should be considered when medical therapy has failed.31,32 Sleep apnea can also contribute to nocturnal worsening of asthma. Reversing obstructive sleep apnea with nasal CPAP can improve day- and nighttime control of asthma.26

Optimize Daytime Management of Asthma

Patients who have nocturnal symptoms more than twice a month should be on daily therapy, preferably an anti-inflammatory agent, in addition to short-acting b-agonists. When used regularly, inhaled steroids reduce the frequency and severity of nighttime symptoms and the fall in pulmonary function. Inhaled steroids also lead to reduced airway responsiveness, fewer exacerbations, decreased need for bronchodilators, and fewer hospitalizations. In children, inhaled corticosteroids can cause a minimal reduction in growth velocity. Although the adult height of these asthmatic children is not significantly affected, there continues to be a concern among pediatricians and parents about the possible side effects of inhaled steroids in children. Therefore, a trial of cromolyn or nedocromil should be considered. These drugs provide reasonable anti-inflammatory effects that are associated with better disease control. If the response to cromones is suboptimal, inhaled steroids should be considered. Another treatment option is slow-release theophylline. It is now recommended to target a serum theophylline level of 5 to 15 mg/mL to reduce theophylline side effects and improve the therapeutic margin. Finally, the addition of leukotriene-modifying drugs, including receptor blockers (eg, montelukast, zafirlukast) or 5-lipoxygenase inhibitor (zileuton) should be considered to help reduce nighttime symptoms and improve morning peak flow rate. Zileuton was also shown to reduce the overnight increase in leukotriene B4 in BAL fluid and urinary excretion of LTE4.37 However, concerns about side effects of these drugs (eg, Churg-Strauss syndrome and zileuton-related hepatotoxicity) have reduced some of the initial enthusiasm for their widespread use as alternatives to inhaled corticosteroids.

Chronotherapeutic Approach

Patients who continue to have nocturnal symptoms despite initiating inhaled anti-inflammatory therapy should be considered for additional modes of therapy aimed at improving nighttime lung function and symptoms. Chronotherapy targets the use of medications to the time when they are most needed. This is in contrast to the homeostatic approach that aims to keep drug levels steady throughout a 24-h period regardless of the time when they are most needed.

Inhaled Long-Acting b-Agonists. Several studies have evaluated the role of salmeterol in the treatment of nocturnal asthma.38-41 Due to its 12-h duration of bronchodilation, salmeterol given twice daily reduces the overnight fall in pulmonary function, reduces nocturnal asthma symptoms, and improves daytime cognitive function. While oral b-agonists have also been shown to improve nocturnal asthma,42,43 they generally have a higher rate of side effects than inhaled agents.

Theophylline. Theophylline was a popular medication for asthma, but its narrow therapeutic margin, potential for interaction with several medications, and the availability of safer alternatives have significantly reduced its use in asthma. Theophylline controls nighttime bronchoconstriction in a dose-dependent fashion. Once-daily theophylline preparation given at dinner time leads to peak serum concentration about 10 h later (about 4 AM).44 This usage takes advantage of chronotherapeutic principles, ie, provide a higher concentration when therapy is most needed. Theophylline was also found to have a modest anti-inflammatory effect, reducing numbers of mucosal EG2-positive (activated) eosinophils,45 reducing the severity of antigen-induced LAR,9 and decreasing BAL neutrophils and leukotriene B4 levels at night.46 Despite these advantages, inhaled long-acting b-agonists might be preferred due to lesser toxicity and equal (or superior) efficacy.

Corticosteroids. The timing of corticosteroid administration in asthma can influence efficacy and complications. Beam et al47 demonstrated that a 3 PM dose of prednisone resulted in a significant reduction in overnight fall in FEV1 and airway inflammation (as shown by inflammatory cells in BAL at 4 AM). These changes were not seen when the same dose of prednisone was given at 8 AM or 8 PM. This study suggested that giving corticosteroids at 3 PM facilitates the control of inflammatory events that contribute to nocturnal asthma and that dosing at 8 PM is probably too late, and 8 AM too early, to provide maximal effectiveness in that regard.

Anticholinergics. The contribution of vagal tone to nocturnal asthma has long been recognized. Therefore, anticholinergic drugs such as ipratroprium bromide can provide some relief from nocturnal asthma. However, owing to its relatively short duration of action, ipratroprium does not provide adequate protection when used at bedtime. Until a long-acting preparation becomes available, the role of this type of drug in nocturnal asthma is limited.

Conclusion

Nocturnal asthma is a common manifestation of asthma and it results in significant morbidity and potential mortality. After determining its presence and identifying potential provoking factors, the overall asthma treatment regiment should be re-evaluated. If optimizing daytime asthma management does not result in adequate control of nighttime asthma, treatment targeted at nighttime symptoms (chronotherapy) should be considered and often results in significant improvement in nighttime asthma.

References

  1. Turner-Warwick M. Epidemiology of nocturnal asthma. Am J Med 1988; 85(1B):6–8
  2. Dethefsen U, Repges R. Ein neues Therapieprinzip bei nächtlichem Asthma. Med Klin 1985; 80:44–47
  3. Storms WW, Bodman SF, Nathan RA, et al. Nocturnal asthma symptoms may be more prevalent than we think. J Asthma 1994; 31:313–318
  4. Cochrane GM, Clark TJH. A survey of asthma mortality in patients between ages 35 and 64 in the greater London hospitals in 1971. Thorax 1975; 30:300–305
  5. Hetzel MR, Clark TJH, Branthwaile MA. Asthma: analysis of sudden deaths and ventilatory arrests in hospital. Br Med J 1977; 1:808–811
  6. Hetzel MR, Clark TJH. Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate. Thorax 1980; 35:732–738
  7. Martin RJ, Cicutto LC, Ballard RD. Factors related to the nocturnal worsening of asthma. Am Rev Respir Dis 1990; 141:33–38
  8. Mohiuddin AA, Martin RJ. Circadian basis of the late, asthmatic response. Am Rev Respir Dis 1990; 142:1153–1157
  9. Jarjour NN, Lacouture PG, Busse WW. Theophylline inhibits the late asthmatic response to nighttime antigen challenge in patients with mild atopic asthma. Ann Allergy Asthma Immunol 1998; 81:231–236
  10. Davies RJ, Green M, Schofield NM. Recurrent nocturnal asthma after exposure to grain dust. Am Rev Respir Dis 1976; 114:1011–1019
  11. Martin RJ, Cicutto LC, Smith HR, et al. Airways inflammation in nocturnal asthma. Am Rev Respir Dis 1991; 143:351–357
  12. Jarjour NN, Busse WW, Calhoun WJ. Enhanced production of oxygen radicals in nocturnal asthma. Am Rev Respir Dis 1992; 146:905–911
  13. Jarjour NN, Busse WW. Cytokines in bronchoalveolar lavage fluid of patients with nocturnal asthma. Am J Respir Crit Care Med 1995; 152(5 Pt 1):1474–1477
  14. Borish L, Mascali JJ, Dishuck J, et al. Detection of alveolar macrophage-derived IL-1 beta in asthma: inhibition with corticosteroids. J Immunol 1992; 149:3078–3082
  15. Kraft M, Striz I, Georges G, et al. Expression of epithelial markers in nocturnal asthma. J Allergy Clin Immunol 1998; 102:376–381
  16. Kraft M, Djukanovic R, Wilson S, et al. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996; 154:1505–1510
  17. Kraft M, Martin RJ, Wilson S, et al. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med 1999; 159:228–234
  18. ten Hacken NH, Postma DS, Bosma F, et al. Vascular adhesion molecules in nocturnal asthma: a possible role for VCAM-1 in ongoing airway wall inflammation. Clin Exp Allergy 1998; 28:1518–1525
  19. Georges G, Bartelson BB, Martin RJ, et al. Circadian variation in exhaled nitric oxide in nocturnal asthma. J Asthma 1999; 36:467–473
  20. ten Hacken NH, vanderVaart H, vanderMark TW, et al. Exhaled nitric oxide is higher both at day and night in subjects with nocturnal asthma. Am J Respir Crit Care Med 1998; 158:902–907
  21. Bellia V, Bonanno A, Cibella F, et al. Urinary leukotriene E4 in the assessment of nocturnal asthma. J Allergy Clin Immunol 1996; 97:735–741
  22. ten Hacken NH, Oosterhoff Y, Kauffman HF, et al. Elevated serum interferon-gamma in atopic asthma correlates with increased airways responsiveness and circadian peak expiratory flow variation. Eur Respir J 1998; 11:312–316
  23. Calhoun WJ, Bates ME, Schrader L, et al. Characteristics of peripheral blood eosinophils in patients with nocturnal asthma. Am Rev Respir Dis 1992; 145:577–581
  24. Meijer GG, Postma DS, vanderHeide S, et al. Exogenous stimuli and circadian peak expiratory flow variation in allergic asthmatic children. Am J Respir Crit Care Med 1996; 153:237–242
  25. Ballard RD, Saathoff MC, Patel DK, et al. Effect of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J Appl Physiol 1989; 67:243–249
  26. Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of snoring and obstructive sleep apnea. Am Rev Respir Dis 1988; 137:1502–1504
  27. Martin RJ, Pak J. Nasal CPAP in nonapneic nocturnal asthma. Chest 1991; 100:1024–1027
  28. Harding SM, Buzzo MR, Richter JE. The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med 2000; 162:34–39
  29. Tan WC, Martin RJ, Pandey R, et al. Effects of spontaneous and simulated gastroesophageal reflux on sleeping asthmatics. Am Rev Respir Dis 1990; 141:1394–1399
  30. Kiljander TO, Salomaa ER, Hietanen EK, et al. Gastroesophageal reflux in asthmatics: a double-blind, placebo-controlled crossover study in omeprazole. Chest 1999; 116:1257–1264
  31. Field SK, Sutherland LR. Does medical antireflux therapy improve asthma in asthmatics with gastroesophageal reflux? A critical review of the literature. Chest 1998; 114:275–283
  32. Field SK, Gelfand GA, McFadden SD. The effects of antireflux surgery on asthmatics with gastroesophageal reflux. Chest 1999; 116:766–774
  33. Barnes P, FitzGerald G, Brown M, et al. Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol. N Engl J Med 1980; 303:263–267
  34. Bates ME, Clayton M, Calhoun W, et al. Relationship of plasma epinephrine and circulating eosinophils to nocturnal asthma. Am J Respir Crit Care Med 1994; 149(3 Pt 1):667–672
  35. Szefler SJ, Ando R, Cicutto LC, et al. Plasma histamine, epinephrine, cortisol, and leukocyte beta-adrenergic receptors in nocturnal asthma. Clin Pharmacol Ther 1991; 49:59–68
  36. Turki J, Pak J, Green SA, et al. Genetic polymorphisms of the beta2-adrenergic receptor in nocturnal and nonnocturnal asthma: evidence that Gly16 correlates with the nocturnal phenotype. J Clin Invest 1995; 95:1635–1641
  37. Wenzel SE, Trudeau JB, Westcott JY, et al. Single oral dose of prednisone decreases leukotriene B4 production by alveolar macrophages from patients with nocturnal asthma but not control subjects: relationship to changes in cellular influx and FEV1. J Allergy Clin Immunol 1994; 94:870–881
  38. Pearlman DS, Chervinsky P, LaForge C, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 1992; 327:1420–1425
  39. Faurschou P, Engel A-M, Haanaes OC. Salmeterol in two different doses in the treatment of nocturnal asthma poorly controlled by other therapies. Allergy 1994; 49:827–832
  40. Kraft M, Wenzel SE, Bettinger CM, et al. The effect of salmeterol on nocturnal symptoms, airway function, and inflammation in asthma. Chest 1997; 111:1249–1254
  41. Fitzpatrick MF, Mackay T, Driver H, et al. Salmeterol in nocturnal asthma: a double-blind, placebo-controlled trial of long-acting inhaled a2 agonist. Br Med J 1990; 301:1365–1368
  42. Bogin RM, Ballard RD. Treatment of nocturnal asthma with pulsed-release albuterol. Chest 1992; 102:362–366
  43. Van Keimpema ARJ, Ariaansz M, Raaijmakers JAM, et al. Treatment of nocturnal asthma by addition of oral slow-release albuterol to standard treatment in the stable asthma patients. J Asthma 1996; 33:119–124
  44. Arkinstall WW, Atkins ME, Harrison D, et al. Once-daily sustained-release theophylline reduces diurnal variation in adult asthmatics. Am Rev Respir Dis 1987; 135:316–321
  45. Sullivan P, Bekir S, Jaffar Z, et al. Anti-inflammatory effects of low-dose oral theophylline in atopic asthma [published erratum appears in Lancet 1994; Jun 11; 343(8911):1512]. Lancet 1994; 343(8904):1006–1008
  46. Kraft M, Torvik JA, Trudeau JB, et al. Theophylline: potential antiinflammatory effects in nocturnal asthma. J Allergy Clin Immunol 1996; 97:1242–1426
  47. Beam WR, Weiner DE, Martin RJ. Timing of prednisone and alterations of airways inflammation in nocturnal asthma. Am Rev Respir Dis 1992; 146:1524–1530

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