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Nocturnal Asthma^*

^* From the Asthma, Allergy, and Airway Research Center, University of Pittsburgh, Pittsburgh, PA.

Correspondence to: William J. Calhoun, MD, FCCP, Division of Pulmonary, Allergy, and Critical Care Medicine, MUH 628 NW, 3459 Fifth Ave, Pittsburgh, PA 15213; e-mail: calhounwj{at}msx.upmc.edu

	Abstract

TOP Abstract Introduction Newer Observations in Nocturnal... Controversies in Nocturnal... Mechanisms of Nocturnal Asthma Treatment of Nocturnal Asthma Summary References

 
Lung function in a healthy individual varies in a circadian rhythm, with peak lung function occurring near 4:00 PM (1600 hours) and minimal lung function occurring near 4:00 AM (0400 hours). An episode of nocturnal asthma is characterized by an exaggeration in this normal variation in lung function from daytime to nighttime, with diurnal changes in pulmonary function generally of > 15%. The occurrence of nocturnal asthma is associated with increased morbidity and inadequate asthma control, and has an important negative impact on quality of life (QOL). Newer data have shed light on physiologic and immunologic mechanisms that underlie the nocturnal development of airway obstruction. It remains controversial whether nocturnal asthma is a distinct entity or is a manifestation of more severe asthma. The current data do not resolve these two alternatives, as well-controlled studies have reached opposite conclusions. However, the clinical associations of gastroesophageal reflux disease and obesity appear to be strong. The treatment of asthma with effective controller agents can reduce nighttime symptoms, improve psychometric outcomes, and improve QOL.

	Introduction

TOP Abstract Introduction Newer Observations in Nocturnal... Controversies in Nocturnal... Mechanisms of Nocturnal Asthma Treatment of Nocturnal Asthma Summary References

 
Nocturnal symptoms commonly affect patients with asthma. Not only do these symptoms affect sleep and functioning, but they also appear to be associated with increased asthma morbidity. The most recent US guidelines for asthma management¹ place particular emphasis on the presence of nocturnal symptoms as an indicator for more aggressive controller therapy. Thus, the presence of nocturnal asthma symptoms appears to have clinical importance.

The mechanisms by which nocturnal asthma develops remain unclear and may vary from patient to patient. Mechanisms suggested to be related to the development of nighttime symptoms are listed in Table 1 .

Finally, newer data suggest that many available asthma treatments can improve nocturnal asthma symptoms. Head-to-head comparisons now suggest that treatment with inhaled corticosteroids, followed by long-acting bronchodilators if needed, can reduce considerably the symptoms and consequences of nocturnal asthma.

	Newer Observations in Nocturnal Asthma

TOP Abstract Introduction Newer Observations in Nocturnal... Controversies in Nocturnal... Mechanisms of Nocturnal Asthma Treatment of Nocturnal Asthma Summary References

 
Clinical Associations
Gastroesophageal reflux disease (GERD) is commonly associated with nocturnal asthma symptoms. A recent cross-sectional study provides new information on these interactions. More than 2,600 subjects were evaluated, including > 450 who had an existing diagnosis of asthma. GERD symptoms were consistently defined, and they occurred in 4.6% of the sample population. Subjects with GERD were significantly more likely to have nighttime wheezing and breathlessness, and to report nocturnal cough and morning phlegm production than were subjects without symptomatic GERD. Furthermore, physician-diagnosed asthma was twice as prevalent in subjects with GERD (9%) compared to those without (4%; p < 0.05), and peak flow variability was significantly greater in subjects with symptomatic GERD. However, FEV₁ and methacholine hyperresponsiveness were not different between the groups.²

In a study of different design, Cuttitta and colleagues³ evaluated the relationship between GER, manifested as reduced esophageal pH, and lower respiratory resistance. By multiple stepwise regression analysis, the most important predictor of change in lower respiratory resistance was the duration of esophageal acidosis. Collectively, these data suggest that GERD aggravates lower airway obstruction and worsens nocturnal asthma.

Despite these compelling data linking the occurrence of GERD to symptoms of nocturnal asthma, proof of the concept that improvement in GERD will translate to improvement in nocturnal asthma is lacking. A recent systematic literature review⁴ (not strictly a meta-analysis) of the effects of treatment of GERD on asthma control found that neither medical therapy nor surgery for GERD was consistently related to improvement in measures of asthma control. Hence, treatment for symptomatic (and asymptomatic) GERD is generally recommended as an adjunctive management strategy for asthma, but evidence for its efficacy is lacking.

Obesity is also associated with nocturnal asthma.² Hakala and colleagues⁵ evaluated 14 obese asthmatic patients before and after significant weight loss. Diurnal and day-to-day variations in peak flow rates were significantly reduced by substantial weight loss. Of considerable interest, FEV₁ and midexpiratory flow rates also were increased, and airway resistance was reduced following weight loss. Thus, obesity, per se, contributes to peak flow variability and diurnal variation in lung function. Whether weight loss reduced unrecognized GERD or was an independent factor in improving lung function was not determined. If it is the latter, the mechanisms by which increased body mass increases markers of asthma severity have not been established but may include increased production of proinflammatory cytokines.

Effect of Age on Diurnal Variation in Lung Function
There are data emerging from the literature suggesting that the diurnal variation in lung function, and perhaps in the occurrence of nocturnal asthma, may be age-related. Studies⁶ of 29 asthmatic children who ranged in age from 8 to 13 years demonstrated minimal diurnal variation in respiratory system compliance and resistance, and suggested that the frequency of significant diurnal variation is only about one third. Furthermore, the magnitude of the changes was relatively small (20%).

A previous study in adults made a complementary finding. Bellia and colleagues⁷ evaluated two groups of otherwise similar asthmatic patients, who differed principally in mean age (35 vs 60 years) but otherwise exhibited comparable demographics and measures of asthma severity. Of note, aging appeared to increase the diurnal variation in airway function, as measured by peak expiratory flow (PEF), and was associated with an increased incidence of nocturnal symptoms.

These data suggest that age, independent of asthma severity, may be an important determinant of the prevalence of nocturnal asthma.

Consequences of Nocturnal Asthma
Nocturnal asthma is recognized as an indicator of uncontrolled asthma, but it also has important effects on quality-of-life (QOL) and psychometric indexes. A study by Diette and colleagues⁸ at Johns Hopkins University of > 400 asthmatic children and their parents demonstrated that 40% of children had experienced nighttime awakening within the previous 4 weeks. Moreover, those children with nocturnal awakenings also had demonstrated an increased number of days of school missed, increased symptom severity, and an increased use of reliever medications. In addition, the parents of these children with nocturnal asthma had an increased frequency of missed work days. Thus, nocturnal asthma impacts the QOL of both the patients and their families.

An earlier study by Weersink and colleagues⁹ made related observations. More than 40 asthmatic subjects underwent psychometric testing before and after randomized treatment with inhaled fluticasone, inhaled salmeterol, or a combination of the two agents. At baseline, asthmatic subjects demonstrated a variety of psychometric abnormalities compared to a control group. However, each treatment strategy was associated with an improvement in psychometric indices (to the normal range of findings) and an improvement in pulmonary function. No differences among the three strategies were observed for the outcomes measured. These data provide yet another important rationale for identifying and treating nocturnal asthma.

	Controversies in Nocturnal Asthma

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More Severe Asthma or a Separate Entity?
A key, and recurring, question in the field of nocturnal asthma is whether patients with nocturnal asthma simply have asthma that is more severe (with nocturnal symptoms being one indicator of severity) or have a qualitatively different disorder. Data exist on both sides of this question, so a definitive answer is not currently available.

The results of several studies have supported the concept that nocturnal asthma is simply asthma that is quantitatively more severe and is therefore more likely to be associated with increased variation in airway function and an increased frequency of nighttime symptoms. A study from the Netherlands was consistent with this concept. Healthy control subjects (n = 13), asthmatic patients with high PEF variability (ie, > 15%; 10 patients), and asthmatic patients with moderate PEF variability (ie, 15%; 15 patients) were evaluated by physiologic assessment, BAL, and bronchial biopsy. Asthmatic patients with high PEF variability had lower FEV₁, lower provocative concentration of methacholine causing a 20% fall in FEV₁, and lower concentration of adenosine monophosphate causing a 20% fall in FEV₁, all suggesting a greater degree of asthma severity.¹⁰ In these patients with high PEF variability, there were no differences in lymphocyte, mast cell, and eosinophil markers between 4:00 AM (0400 hours) and 4:00 PM (1600 hours). However, these measures of inflammation were significantly greater in subjects with high PEF variability compared to those with moderate variability, suggesting that nocturnal asthma was simply more severe asthma. In fact, this point of view has been clearly detailed.¹¹

The results of physiologic studies, which are detailed below, likewise have been equivocal. Desjardin and colleagues¹² specifically studied a group of asthmatic subjects, with and without nocturnal symptoms, who were well-matched for FEV₁, and demonstrated pulmonary capillary blood volume changes only in asthmatic subjects with nocturnal disease. This study is uncommon in the literature in that physiologically matched control subjects without nocturnal symptoms were included, and in that a specific distinction between patients with and without nocturnal asthma could be drawn. Studies by Irvin et al¹³ and Kraft et al,¹⁴ although provocative, did not include FEV₁ matched asthmatic control subjects without nocturnal disease.

It is in the area of cellular and molecular indexes of inflammation that nocturnal and nonnocturnal asthma can be most clearly differentiated (vide infra). Diurnal variations in alveolar tissue inflammation, cytokine levels, and reactive oxygen species levels have been demonstrated. However, it is also clear that many other studies have shown that nocturnal asthma is associated with increased numbers of markers of inflammation, suggesting increased disease severity, but that the measured inflammatory markers do not cycle with circadian timing.

Thus, although the literature does not at present distinguish between nocturnal asthma as a distinct entity vs a marker of severity, it is clear that asthmatic subjects with more severe asthma also may have a prominent nocturnal component to their disease. Understanding the mechanisms by which the "master clock" influences airway inflammation, airway function, and symptoms of asthma will undoubtedly lead to important insights into the pathogenesis of asthma.

	Mechanisms of Nocturnal Asthma

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Physiologic Insights
Desjardin and colleagues¹² evaluated the effect of sleep on pulmonary capillary blood volume (measured by CO diffusion) in healthy control subjects, subjects with nocturnal asthma, and subjects with asthma and no nocturnal worsening. No significant differences in awake physiology were seen between the two groups of asthmatic subjects. Only in subjects with nocturnal asthma were changes in capillary blood volume seen (ie, a 15% increase). The mechanism of this effect was not established, but the authors suggested that it may have reflected larger swings in intrathoracic pressure.

In addition to changes in blood/air volume ratios, the mechanical coupling of the parenchyma to airways, which normally distends the airway at high lung volumes, may be abnormal in asthmatic subjects with nocturnal worsening of symptoms. Using a plethysmograph in which subjects could sleep in the supine position, the authors¹³ evaluated the relationship between lung volume and airway resistance. In asthmatic subjects with nocturnal worsening, the normal decrease in lung resistance with increased lung volume was not seen. Furthermore, during sleep, resting airway resistance was about twice that seen during awake breathing (Fig 1 ), and resistance during awake breathing was about twice that seen in other studies of healthy subjects. Moreover, longer sleep duration was associated with increased airway resistance. Although asthmatic subjects without nocturnal symptoms were not specifically studied, these data argue that asthma is associated with profound physiologic abnormalities during sleep that are plausibly linked to the pathogenesis of nighttime asthma symptoms.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. On the ordinate is total gas volume (TGV), and on the abscissa is measured lung resistance (Rla). Five asthmatic subjects with nocturnal worsening were studied. Awake airway resistance is increased about twofold compared to that in healthy control subjects (data not shown), and resistance is doubled again during sleep in asthmatic patients. During wakefulness, increases in lung volume are associated with decreased lung resistance. In contrast, during sleep, increases in lung volume do not produce the expected fall in lung resistance. Reprinted with permission from Irvin et al.13

Regulation and Consequences of Inflammation
A number of studies now have confirmed that inflammation worsens in subjects with nocturnal asthma during the nighttime hours, compared to asthmatic subjects with comparable asthma severity. Parameters that increase at night include interleukin-1ß,¹⁵ circulating eosinophils,¹⁶ BAL eosinophils and lymphocytes,¹⁷ and alveolar eosinophils, but not airway eosinophils.¹⁸ In fact, studies that have shown no differences in inflammation are the exception.^{19 20} The question that remains controversial however, is why inflammation cycles have a diurnal rhythm. Most investigators view the circadian cycles of cortisol, cholinergic tone, histamine, and epinephrine as having theoretical relevance to inflammation, but the specific and detailed mechanistic links between these cycling biological processes and the control of inflammation remain incompletely defined.

Nitric Oxide
Exhaled nitric oxide (eNO) has been suggested as a noninvasive marker of airway inflammation. The accuracy of this assertion remains controversial. However, it is clear that nitric oxide (NO) levels increase in patients with asthma compared to healthy control subjects, rise further after allergen challenge or asthma exacerbation, and fall with inhaled steroid therapy. It is therefore of interest to evaluate eNO in the context of nocturnal asthma. The literature is controversial on whether eNO levels, and those of the synthetic enzyme responsible for the presence of the majority of NO in exhaled breath, the inducible form of NO synthase (iNOS), rise and fall in circadian fashion.

In a study of six asthmatic patients with nocturnal symptom, and eight asthmatic patients without nocturnal symptoms, ten Hacken and colleagues²¹ evaluated the variability of eNO in relationship to diurnal changes in airway function from 4:00 AM (0400 hours) to 4:00 PM (1600 hours). Compared to healthy volunteers, the eNO level in asthma patients was higher. Those asthmatic subjects with nocturnal asthma showed increased eNO levels compared to asthmatic subjects without nocturnal asthma. Furthermore, there was a significant positive correlation between circadian peak flow variability and eNO levels, suggesting that asthma severity was linked to increased eNO levels. However, no circadian variation of eNO was observed in any subject group (ie, healthy volunteers, asthmatic subjects without nocturnal asthma, or asthmatic subjects with nocturnal asthma).

Findings from a more recent study²² of five patients with nocturnal asthma and five asthmatic patients without nocturnal worsening were somewhat at variance with those from the study by ten Hacken et al.²¹ Nocturnal asthmatic subjects did have increased eNO levels compared to asthmatic subjects without nocturnal symptoms, but a circadian variation was observed only in subjects with nocturnal asthma. The peak eNO level was achieved at 4:00 PM (1600 hours), compared to 10:00 PM (2200 hours) and 4:00 AM (0400 hours). Curiously, this peak corresponded to the time of best pulmonary function.²²

Perhaps in support of the findings of Georges et al,²² ten Hacken and colleagues²³ quantitated iNOS expression in blood vessels in 25 asthmatic patients using bronchial biopsy. The expression of iNOS on blood vessels was greater in asthmatic subjects than in control subjects. In a post hoc separation of asthmatic subjects by the magnitude of PEF variability, those subjects with PEF variability of > 10% showed significantly greater expression of iNOS in blood vessels at 4:00 PM (1600 hours) compared to 4:00 AM (0400 hours). Thus, the same group has shown circadian variation in the levels of synthetic enzyme iNOS but no variation in the levels of eNO. Clearly, the field of investigation of eNO is currently underdeveloped, and the implications of the observations remain somewhat obscure.

Polymorphisms of the ß-Adrenergic Receptor
An intriguing area of investigation has been the identification of single-nucleotide polymorphisms in the coding region of the ß-adrenoceptor gene, which result in amino acid changes in the extracellular, transmembrane, and intracellular portions of the resulting protein.²⁴

Of these, the substitution of glycine at position 16 for arginine has been studied in the context of nocturnal asthma. This polymorphism results in increased agonist-dependent down-regulation of ß-receptor expression and therefore is plausibly linked to asthma. In a seminal study by Turki and colleagues,²⁵ the phenotype of nocturnal asthma was significantly linked to homozygosity for glycine 16. However, Ramsay and colleagues²⁶ failed to demonstrate a linkage between the glycine 16 polymorphism and any asthma phenotype. The variance with the study of Turki et al²⁵ is likely the result of different genetic backgrounds of the patients studied, and it highlights the difficulty of identifying specific genetic causes for complex diseases like asthma. The role of other ß-receptor polymorphisms, and particularly their interactions, will require additional study of large groups of well-characterized patients with asthma.

Abnormalities of Corticosteroid Signaling
A very intriguing area of research in nocturnal asthma is that of glucocorticoid resistance and signaling. Ongoing allergic inflammation can result in impaired function of the glucocorticoid receptor (GR). In this context, Kraft and colleagues²⁷ studied the binding affinity and function of the GR in asthmatic patients with nocturnal symptoms (11 patients) and without nocturnal symptoms (12 patients). Compared to healthy control subjects, asthmatic patients without nocturnal worsening showed significantly impaired glucocorticoid binding to GR (increased Kd). In patients with nocturnal asthma, the abnormality was seen only at 4:00 AM (0400 hours), and GR binding was normal at 4:00 PM (1600 hours). This diurnal variation did not occur in the other subject groups. Functional data supported the biochemical analyses. The inhibition of lymphocyte proliferation by therapy with dexamethasone and hydrocortisone required an approximately 10-fold greater concentration of steroids at 4:00 AM (0400 hours) compared to 4:00 PM (1600 hours), suggesting a resistance to the effects of steroid therapy at 4:00 AM (0400 hours). The mechanisms by which these effects are mediated may include the increased expression GRß, which is a splice variant of GR that binds corticosteroids but signals poorly.²⁸ In this follow-up study,²⁸ GRß expression was evaluated in asthmatic patients with and without nocturnal worsening. The increased expression of GRß was seen in nocturnal asthmatic subjects compared to nonnocturnal asthmatic subjects, and diurnal variation was evident only in the nocturnal asthmatic subjects, with further increased expression of GRß at 4:00 AM (0400 hours) compared to 4:00 PM (1600 hours).

	Treatment of Nocturnal Asthma

TOP Abstract Introduction Newer Observations in Nocturnal... Controversies in Nocturnal... Mechanisms of Nocturnal Asthma Treatment of Nocturnal Asthma Summary References

 
According to current US guidelines,¹ nocturnal symptoms of asthma occurring more often than once weekly may indicate inadequate control of asthma. Because most patients with nocturnal asthma have symptoms at least this frequently, it follows that most patients with nocturnal asthma have persistent asthma of moderate or severe levels of severity, as determined by the guidelines. Furthermore, the preferred treatment for persistent asthma of these levels of severity is inhaled corticosteroids. Thus, most patients with clinically important nocturnal asthma should probably be receiving an inhaled steroid as the primary controller agent.

Many industry-sponsored clinical trials of controller medications (eg, inhaled steroids, leukotriene modifiers, long-acting ß agonists, and theophylline) have used nighttime symptoms as an index of efficacy. Without reviewing those trials in detail, it is clear that each of these strategies can reduce nighttime symptoms, and most can improve morning peak flow rates or FEV₁. These data suggest that control of the underlying processes of asthma will subsequently lead to improvements in nocturnal asthma. This kind of information, however, is subtly, but importantly, different than that from a focused investigation of nocturnal asthma in which all subjects have been selected for the presence of significant nighttime physiologic embarrassment.

Theophylline has long been regarded as an important therapeutic tool in managing nocturnal asthma, as it can improve pulmonary function for a 12-h period, particularly when administered in the evening. Moreover, theophylline reduces late-phase physiologic responses after allergen challenge and increases the dose of allergen tolerated in an experimental model.²⁹ However, as newer approaches have become available, the utility of theophylline therapy may be becoming more limited. Using a crossover design, Selby and colleagues³⁰ evaluated salmeterol and theophylline using psychometric and QOL outcomes. Improvements in pulmonary function, as measured by PEF rate, and most psychometric indexes were equivalently improved by either therapy. However, therapy with salmeterol outperformed that with theophylline in terms of the number of awakenings and arousals, and in QOL measures.³⁰

In the same year, Kraft and colleagues³¹ evaluated salmeterol therapy in treatment for nocturnal asthma in a double-blind, placebo-controlled trial. Salmeterol therapy improved the use of rescue therapy with albuterol and reduced the number of nocturnal awakenings, but, unsurprisingly, it did not alter airway hyperresponsiveness or any bronchoscopic measure of inflammation.

Finally, Wiegand and colleagues³² studied the effects of theophylline and salmeterol in a placebo-controlled, randomized trial. Outcomes included parameters of sleep, symptoms of asthma, and pulmonary function. Therapy with theophylline was equivalent to that with placebo in this trial, whereas therapy with salmeterol preserved pulmonary function during the night.

	Summary

TOP Abstract Introduction Newer Observations in Nocturnal... Controversies in Nocturnal... Mechanisms of Nocturnal Asthma Treatment of Nocturnal Asthma Summary References

 
Nighttime awakening is a common symptom in asthma patients, which are associated with asthma morbidity, increased asthma severity, and uncontrolled or undercontrolled disease. Nocturnal asthma remains an area of controversy on a number of fronts (Table 2). Considerable evidence has suggested that nighttime symptoms of asthma are associated with increased asthma severity, but several well-controlled studies have argued that nocturnal asthma may be a distinct entity. Whether or not nocturnal asthma is distinct, the clinical associations among GERD, increased morbidity, obesity, and impairment in psychometric and QOL indexes are clear, and they provide a compelling rationale for aggressive treatment of this disorder. Much of the existing literature on nocturnal asthma, but not all, is confounded by the existence of a greater degree of asthma severity in the nocturnal asthma group than in asthmatic patients who do not experience nocturnal worsening. Further research is needed in the following several areas: (1) elucidation of the mechanisms of the coupling of central master clock signals to the regulation of inflammation and airway physiology; (2) distinguishing the mechanisms that are causal for nighttime asthma from those that are a consequence of increased airway obstruction at night; (3) establishment of the most appropriate treatment strategy for nocturnal asthma symptoms, including effective treatment for GERD; and (4) matching asthma populations with and without nocturnal worsening for FEV₁ or other markers of asthma severity in order to better understand the immunologic, inflammatory, and physiologic features that are most directly related to nighttime worsening of airway function.

	Footnotes

 
This research was supported in part by grants HL-69130, HL/AI-63738.

Abbreviations: eNO = exhaled nitric oxide; GERD = gastroesophageal reflux; GR = glucocorticoid receptor; iNOS = inducible nitric oxide synthase; NO = nitric oxide; PEF = peak expiratory flow; QOL = quality of life

	References

TOP Abstract Introduction Newer Observations in Nocturnal... Controversies in Nocturnal... Mechanisms of Nocturnal Asthma Treatment of Nocturnal Asthma Summary References

 

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