- Email: [email protected]
Nocturnal Asthma
Abbreviations: HLF ⫽ human lung fibroblast; IL ⫽ interleukin; SAC ⫽ segmental antigen challenge; SMA ⫽ smooth muscle actin; TGF ⫽ transforming growth factor
TGF-2, and IL-13 caused no significant dose-dependent increase in collagen III synthesis
Conclusions is characterized histologically by bronchial subA sthma epithelial fibrosis and increased numbers of myofibroblasts. It has been proposed that these myofibroblasts are responsible for the characteristic subepithelial collagen deposition seen in asthma. We hypothesized that the concentration of growth factors and cytokines that is important in asthmatic airway remodeling are elevated in BAL fluid after segmental antigen challenge (SAC). We further hypothesized that these growth factors and cytokines increase ␣-smooth muscle actin (SMA) and collagen III synthesis by human lung fibroblasts (HLFs).
Materials and Methods Transforming growth factor (TGF)-1, TGF-2, interleukin (IL)-4, and IL-13 concentrations were measured in BAL fluid concentrates from 10 asthmatic patients and 9 nonasthmatic control subjects before they underwent SAC and 1 day, 1 week, and 2 weeks after undergoing SAC. Five lines of HLF were stimulated by exogenous addition of TGF-1, TGF-2, IL-4, and IL-13 (range, 0.01 to 10 ng/mL) for 48 h. Harvested supernatants were analyzed for determination of collagen III levels. Cell lysates were tested for ␣-SMA by Western blot analysis.
Results Before SAC, there was no significant difference in the BAL fluid concentrations of TGF-1, IL-4, and IL-13 between asthmatic patients and nonasthmatic subjects. However, TGF-2 levels were higher in nonasthmatic subjects. In asthmatic patients, the BAL fluid concentration of these cytokines and growth factors increased significantly 1 day after undergoing SAC (p ⬍ 0.05). TGF1, TGF-2, and IL-13 concentrations returned toward baseline by 1 week after SAC, whereas IL-4 levels remained elevated until 2 weeks after SAC. In nonasthmatic subjects there was no significant change in the concentrations of these cytokines and growth factors after undergoing SAC. On stimulus of HLF by exogenous addition of these growth factors and cytokines, TGF-1 and IL-4 increased ␣-SMA levels in a dose-dependent manner (p ⬍ 0.05 for both). TGF-2 also significantly increased ␣-SMA expression at concentrations of 1 and 10 ng/mL (p ⬍ 0.01). In contrast, increasing concentrations of IL-13 had no effect on ␣-SMA expression. The analysis of collagen III revealed that only IL-4 increased collagen III synthesis in a dose-dependent manner (p ⬍ 0.05). TGF-2 increased collagen III synthesis at a concentration of 1 ng/mL. Increasing concentrations of TGF-1, *From Thomas Jefferson University, Philadelphia, PA. This research was supported in part by National Institutes of Health grants AI24509 and HL67663. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Stephen P. Peters, MD, PhD, FCCP, Wake Forest University Health Sciences Center, Center for Human Genomics, Medical Center Blvd, Winston-Salem, NC 27157; e-mail: [email protected] www.chestjournal.org
Our conclusions were as follows: (1) TGF-1 or ⌻GF-2 stimulation leads to phenotypic change of fibroblasts to myofibroblasts, however, this does not correspond to a dose-dependent increase in collagen III synthesis; (2) IL-13 has no direct role in these features of airway remodeling; and (3) BAL fluid concentrations of IL-4 remain elevated for at least 2 weeks after antigen challenge in asthmatic patients. IL-4 causes dosedependent increases in both ␣-SMA and collagen III synthesis. Therefore, IL-4 may be one of the important cytokines mediating airway remodeling in asthmatic patients.
Nocturnal Asthma* William J. Calhoun, MD, FCCP
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. (CHEST 2003; 123:399S– 405S) *From the Asthma, Allergy, and Airway Research Center, University of Pittsburgh, Pittsburgh, PA. This research was supported in part by grants HL-69130, HL/ AI-63738. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). 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@msx. upmc.edu CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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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
symptoms commonly affect patients with N octurnal 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. There remains controversy over whether nocturnal asthma represents a distinct entity or is simply a manifestation of more severe asthma. The evidence to date does not answer the question definitively, as important information from well-controlled studies has emerged on both sides of the controversy. An additional area of controversy relates to mechanisms. Are the mechanistic observations in nocturnal asthma a cause of or a consequence of nocturnal asthma, or are they associated features that are not causally related? 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 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
Table 1—Postulated Mechanisms of Nocturnal Asthma Airway cooling Allergen exposure Gastroesophageal reflux Obesity Increased tissue inflammation Decreased plasma epinephrine Decreased plasma cortisol Increased circulating eosinophils Increased cholinergic tone Polymorphisms of the -adrenergic receptor
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cough and morning phlegm production than were subjects without symptomatic GERD. Furthermore, physiciandiagnosed 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 sever-
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
ity. 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 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, ⱕ 15%; 15 patients) were evaluated by physiologic assessment, BAL, and bronchial biopsy. Asthmatic patients with high PEF variability had lower FEV1, lower provocative www.chestjournal.org
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 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. CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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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. Finally, Kraft and colleagues14 have studied the physiology of the distal lung in subjects with nocturnal asthma. Increased peripheral lung resistance was observed in subjects with nocturnal asthma, compared to healthy control subjects, and to asthmatic subjects without nocturnal worsening. However, no day-night differences in these parameters were seen, and the subjects with nocturnal asthma had considerably greater airway obstruction (as measured by FEV1) than did those subjects without symptoms nocturnal asthma.
Regulation and Consequences of Inflammation A number of studies now have confirmed that inflammation worsens in subjects with nocturnal asthma during
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 402S
the nighttime hours, compared to asthmatic subjects with comparable asthma severity. Parameters that increase at night include interleukin-1,15 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
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
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.
variant of GR that binds corticosteroids but signals poorly.28 In this follow-up study,28 GR expression was evaluated in asthmatic patients with and without nocturnal worsening. The increased expression of GR 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 GR at 4:00 am (0400 hours) compared to 4:00 pm (1600 hours).
Polymorphisms of the -Adrenergic Receptor
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, longacting  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
An intriguing area of investigation has been the identification of single-nucleotide polymorphisms in the coding region of the -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 agonistdependent down-regulation of -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 -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 GR, which is a splice www.chestjournal.org
Treatment of Nocturnal Asthma
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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 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.
References 1 National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and prevention of asthma. Bethesda, MD: National Institutes of Health, April 1997; Publication No. 97– 405 2 Gislason T, Janson C, Vermeire P, et al. Respiratory symptoms and nocturnal gastroesophageal reflux. Chest 2002; 121:158 –163 3 Cuttitta G, Cibella F, Visconti A, et al. Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics. Am J Respir Crit Care Med 2000; 161:177–181 4 Coughlan JL, Gibson PG, Henry RL. Medical treatment for reflux oesophagitis does not consistently improve asthma control: a systematic review. Thorax 2000; 56:198 –204 5 Hakala K, Stenius-Aarniala B, Sovijarvi A. Effects of weight loss on peak flow variability, airways obstruction, and lung volumes in obese patients with asthma. Chest 2000; 118: 1315–1321 6 Tomalak W, Elbousefi A, Kurzawa R, et al. Diurnal variations of respiratory system resistance and compliance derived from input impedance in asthmatic children. Respir Physiol 2000; 123:101–108 404S
7 Bellia V, Cuttitta G, Cibella F, et al. Effect of ageing on peak expiratory flow variability and nocturnal exacerbations in bronchial asthma. Eur Respir J 1997; 10:1803–1808 8 Diette GB, Markson L, Skinner EA, et al. Nocturnal asthma in children affects school attendance, school performance, and parents’ work attendance. Arch Pediatr Adolesc Med 2000; 154:923–928 9 Weersink EJM, van Zomeren EH, Koeter GH, et al. Treatment of nocturnal airway obstruction improves daytime cognitive performance in asthmatics. Am J Respir Crit Care Med 1997; 156:1144 –1150 10 ten Hacken NHT, Timens W, Smith M, et al. Increased peak expiratory flow variation in asthma: severe persistent increased but not nocturnal worsening of airway inflammation. Eur Respir J 1998; 12:546 –550 11 Weersink EJM, Postma DS. Nocturnal asthma: not a separate disease entity. Respir Med 1994; 88:483– 491 12 Desjardin JA, Sutrarik JM, Suh BY, et al. Influence of sleep on pulmonary capillary volume in normal and asthmatic subjects. Am J Respir Crit Care Med 1995; 152:193–198 13 Irvin CG, Pak J, Martin RJ. Airway-parenchyma uncoupling in nocturnal asthma. Am J Respir Crit Care Med 2000; 161:50 –56 14 Kraft M, Pak J, Martin RJ, et al. Distal lung dysfunction at night in nocturnal asthma. Am J Respir Crit Care Med 2001; 163:1551–1556 15 Jarjour NN, Busse WW. Cytokines in bronchoalveolar lavage fluid of patients with nocturnal asthma. Am J Respir Crit Care Med 1995; 152:1474 –1477 16 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; 149:667– 672 17 Mackay TW, Wallace WAH, Howie SEM, et al. Role of inflammation in nocturnal asthma. Thorax 1994; 49:257–262 18 Kraft M, Djukanovic R, Wilson S, et al. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996; 154:1505–1510 19 Postma DS, Oosterhoff Y, Van Aalderen WMC, et al. Inflammation in nocturnal asthma? Am J Respir Crit Care Med 1994; 150:S83–S86 20 Oosterhoff Y, Hoogsteden HC, Rutgers B, et al. Lymphocyte and macrophage activation in bronchoalveolar lavage fluid in nocturnal asthma. Am J Respir Crit Care Med 1995; 151: 75– 81 21 ten Hacken NHT, van der Vaart H, van der Mark 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 22 Georges G, Bartelson BB, Martin RJ, et al. Circadian variation in exhaled nitric oxide in nocturnal asthma. J Asthma 1999; 36:467– 473 23 ten Hacken NH, Postma DS, Drok G, et al. Increased vascular expression of iNOS at day but not at night in asthmatic subjects with increased nocturnal airway obstruction. Eur Respir J 2000; 16:445– 451 24 Liggett SB. Polymorphisms of the beta 2-adrenergic receptor and asthma. Am J Respir Crit Care Med 1997; 156:S156 – S162 25 Turki J, Pak j, Green SA, et al. Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma: evidence that Gly16 correlates with the nocturnal phenotype. J Clin Invest 1995; 95:1635–1641 26 Ramsay CE, Hayden CM, Tiller KJ, et al. Polymorphisms in the beta2-adrenoreceptor gene are associated with decreased airway responsiveness. Clin Exp Allergy 1999; 29:1195–1203 27 Kraft M, Vianna E, Martin RJ, et al. Nocturnal asthma is associated with reduced glucocorticoid receptor binding af-
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
28 29
30 31 32
finity and decreased steroid responsiveness at night. J Allergy Clin Immunol 1999; 103:66 –71 Kraft M, Hamid Q, Chrousos GP, et al. Decreased steroid responsiveness at night in nocturnal asthma: Is the macrophage responsible? Am J Respir Crit Care Med 2001; 163:1219–1225 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 Selby C, Engleman HM, Fitzpatrick MF, et al. Inhaled salmeterol or oral theophylline in nocturnal asthma? Am J Respir Crit Care Med 1997; 155:104 –108 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 Wiegand L, Mende CN, Zaidel G, et al. Salmeterol vs theophylline: sleep and efficacy outcomes in patients with nocturnal asthma. Chest 1999; 115:1525–1532
Hypothalamic-Pituitary-Adrenal Axis Dysfunction During Sleep in Nocturnal Asthma* E. Rand Sutherland, MD, FCCP; Monica Kraft, MD, FCCP; M.D. Rex, BS; Misoo C. Ellison, PhD; and Richard J. Martin, MD, FCCP
ACTH Mean (⫾ SEM) ACTH levels in NA subjects were the highest at 4:00 am (28.5 ⫾ 3.9 pg/mL). Mean ACTH levels at 4:00 am in NNA subjects (14.3 ⫾ 3.2 pg/mL; p ⫽ 0.01, NA vs NNA group) and NL subjects, (16.0 ⫾ 3.8 pg/mL; p ⫽ 0.03, NA vs NL) were similar, lower than NA subjects. ACTH levels of NNA subjects did not differ from those of NLs (p ⫽ 0.74).
Cortisol Although NA subjects had the highest mean cortisol levels at 4:00 am (17.1 ⫾ 3.7 g/dL), they were not significantly greater than the levels of NNA subjects (13.3 ⫾ 2.2 g/dL; p ⫽ 0.31). The cortisol levels of NA subjects were higher than those of NLs (7.4 ⫾ 2.5 g/dL; p ⫽ 0.01), but those of NNA subjects were not (p ⫽ 0.08).
ACTH/Cortisol Correlation Within-group correlations between ACTH and cortisol levels were (in ascending order) as follows: NA group, r ⫽ 0.71 and p ⫽ 0.0005; NNA group, r ⫽ 0.74 and p ⫽ 0.0001; and NL group, r ⫽ 0.82 and p ⫽ 0.0001.
Conclusions (CHEST 2003; 123:405S) Abbreviations: ACTH ⫽ corticotropin; NA ⫽ nocturnal asthma; NL ⫽ control subject; NNA ⫽ nonnocturnal asthma
Although subjects with NA demonstrate significantly increased ACTH levels at night, these were not accompanied by a commensurate cortisol response. The adrenal response to ACTH may be blunted in NA subjects, permitting increased airway inflammation in these subjects.
with nocturnal asthma (NA) have increased P atients airway inflammation at night, a phenomenon not seen
in patients with non-NA (NNA). We hypothesized that alterations in hypothalamic-pituitary-adrenal axis function may be of importance in the pathogenesis of NA.
Materials and Methods Subjects with NA (four subjects), NNA (six subjects), and healthy control subjects (NL; six subjects) maintained a miniconstant-sleep-wake routine for 8 days. On day 8, serum samples were drawn every 2 h over a 24-h period (12 samples per subject) and were analyzed for circadian differences in corticotropin (ACTH) and cortisol levels. Between-group comparisons were made at each time point during the hours of sleep (ie, 10:00 pm to 6:00 am) using repeated-measures analysis of variance.
Results During sleep, there was a linear increase in both ACTH and cortisol levels in all three groups (p ⬍ 0.004). *From the National Jewish Medical and Research Center, Denver, CO. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: R.J. Martin, MD, FCCP, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206; e-mail: [email protected] www.chestjournal.org
Severe/Fatal Asthma* Sally Wenzel, MD, FCCP
Severe asthma is poorly understood clinically, physiologically, and pathologically. While milder forms of asthma are generally easily treated, more severe forms often remain refractory to the best current medical care. Although some patients with severe asthma have had severe disease for most of their lives, there appears to be a second group that develops severe disease in adulthood. Additionally, it is not clear which genetic and environmental elements may be the most important in the development of severe disease. Physiologically, these patients often have airtrapping and may have loss of elastic recoil, as well. The pathology demonstrates a heterogeneity of findings, including continued eosinophilic inflammation, structural changes, distal disease, and, in at least one third of patients, a different pathology. Treatment remains problematic and likely will remain so until a better understanding of this disease develops. (CHEST 2003; 123:405S– 410S) CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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TGF-2, and IL-13 caused no significant dose-dependent increase in collagen III synthesis
Conclusions is characterized histologically by bronchial subA sthma epithelial fibrosis and increased numbers of myofibroblasts. It has been proposed that these myofibroblasts are responsible for the characteristic subepithelial collagen deposition seen in asthma. We hypothesized that the concentration of growth factors and cytokines that is important in asthmatic airway remodeling are elevated in BAL fluid after segmental antigen challenge (SAC). We further hypothesized that these growth factors and cytokines increase ␣-smooth muscle actin (SMA) and collagen III synthesis by human lung fibroblasts (HLFs).
Materials and Methods Transforming growth factor (TGF)-1, TGF-2, interleukin (IL)-4, and IL-13 concentrations were measured in BAL fluid concentrates from 10 asthmatic patients and 9 nonasthmatic control subjects before they underwent SAC and 1 day, 1 week, and 2 weeks after undergoing SAC. Five lines of HLF were stimulated by exogenous addition of TGF-1, TGF-2, IL-4, and IL-13 (range, 0.01 to 10 ng/mL) for 48 h. Harvested supernatants were analyzed for determination of collagen III levels. Cell lysates were tested for ␣-SMA by Western blot analysis.
Results Before SAC, there was no significant difference in the BAL fluid concentrations of TGF-1, IL-4, and IL-13 between asthmatic patients and nonasthmatic subjects. However, TGF-2 levels were higher in nonasthmatic subjects. In asthmatic patients, the BAL fluid concentration of these cytokines and growth factors increased significantly 1 day after undergoing SAC (p ⬍ 0.05). TGF1, TGF-2, and IL-13 concentrations returned toward baseline by 1 week after SAC, whereas IL-4 levels remained elevated until 2 weeks after SAC. In nonasthmatic subjects there was no significant change in the concentrations of these cytokines and growth factors after undergoing SAC. On stimulus of HLF by exogenous addition of these growth factors and cytokines, TGF-1 and IL-4 increased ␣-SMA levels in a dose-dependent manner (p ⬍ 0.05 for both). TGF-2 also significantly increased ␣-SMA expression at concentrations of 1 and 10 ng/mL (p ⬍ 0.01). In contrast, increasing concentrations of IL-13 had no effect on ␣-SMA expression. The analysis of collagen III revealed that only IL-4 increased collagen III synthesis in a dose-dependent manner (p ⬍ 0.05). TGF-2 increased collagen III synthesis at a concentration of 1 ng/mL. Increasing concentrations of TGF-1, *From Thomas Jefferson University, Philadelphia, PA. This research was supported in part by National Institutes of Health grants AI24509 and HL67663. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Stephen P. Peters, MD, PhD, FCCP, Wake Forest University Health Sciences Center, Center for Human Genomics, Medical Center Blvd, Winston-Salem, NC 27157; e-mail: [email protected] www.chestjournal.org
Our conclusions were as follows: (1) TGF-1 or ⌻GF-2 stimulation leads to phenotypic change of fibroblasts to myofibroblasts, however, this does not correspond to a dose-dependent increase in collagen III synthesis; (2) IL-13 has no direct role in these features of airway remodeling; and (3) BAL fluid concentrations of IL-4 remain elevated for at least 2 weeks after antigen challenge in asthmatic patients. IL-4 causes dosedependent increases in both ␣-SMA and collagen III synthesis. Therefore, IL-4 may be one of the important cytokines mediating airway remodeling in asthmatic patients.
Nocturnal Asthma* William J. Calhoun, MD, FCCP
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. (CHEST 2003; 123:399S– 405S) *From the Asthma, Allergy, and Airway Research Center, University of Pittsburgh, Pittsburgh, PA. This research was supported in part by grants HL-69130, HL/ AI-63738. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). 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@msx. upmc.edu CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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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
symptoms commonly affect patients with N octurnal 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. There remains controversy over whether nocturnal asthma represents a distinct entity or is simply a manifestation of more severe asthma. The evidence to date does not answer the question definitively, as important information from well-controlled studies has emerged on both sides of the controversy. An additional area of controversy relates to mechanisms. Are the mechanistic observations in nocturnal asthma a cause of or a consequence of nocturnal asthma, or are they associated features that are not causally related? 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 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
Table 1—Postulated Mechanisms of Nocturnal Asthma Airway cooling Allergen exposure Gastroesophageal reflux Obesity Increased tissue inflammation Decreased plasma epinephrine Decreased plasma cortisol Increased circulating eosinophils Increased cholinergic tone Polymorphisms of the -adrenergic receptor
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cough and morning phlegm production than were subjects without symptomatic GERD. Furthermore, physiciandiagnosed 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 sever-
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
ity. 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 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, ⱕ 15%; 15 patients) were evaluated by physiologic assessment, BAL, and bronchial biopsy. Asthmatic patients with high PEF variability had lower FEV1, lower provocative www.chestjournal.org
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 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. CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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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. Finally, Kraft and colleagues14 have studied the physiology of the distal lung in subjects with nocturnal asthma. Increased peripheral lung resistance was observed in subjects with nocturnal asthma, compared to healthy control subjects, and to asthmatic subjects without nocturnal worsening. However, no day-night differences in these parameters were seen, and the subjects with nocturnal asthma had considerably greater airway obstruction (as measured by FEV1) than did those subjects without symptoms nocturnal asthma.
Regulation and Consequences of Inflammation A number of studies now have confirmed that inflammation worsens in subjects with nocturnal asthma during
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 402S
the nighttime hours, compared to asthmatic subjects with comparable asthma severity. Parameters that increase at night include interleukin-1,15 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
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
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.
variant of GR that binds corticosteroids but signals poorly.28 In this follow-up study,28 GR expression was evaluated in asthmatic patients with and without nocturnal worsening. The increased expression of GR 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 GR at 4:00 am (0400 hours) compared to 4:00 pm (1600 hours).
Polymorphisms of the -Adrenergic Receptor
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, longacting  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
An intriguing area of investigation has been the identification of single-nucleotide polymorphisms in the coding region of the -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 agonistdependent down-regulation of -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 -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 GR, which is a splice www.chestjournal.org
Treatment of Nocturnal Asthma
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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 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.
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Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
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Hypothalamic-Pituitary-Adrenal Axis Dysfunction During Sleep in Nocturnal Asthma* E. Rand Sutherland, MD, FCCP; Monica Kraft, MD, FCCP; M.D. Rex, BS; Misoo C. Ellison, PhD; and Richard J. Martin, MD, FCCP
ACTH Mean (⫾ SEM) ACTH levels in NA subjects were the highest at 4:00 am (28.5 ⫾ 3.9 pg/mL). Mean ACTH levels at 4:00 am in NNA subjects (14.3 ⫾ 3.2 pg/mL; p ⫽ 0.01, NA vs NNA group) and NL subjects, (16.0 ⫾ 3.8 pg/mL; p ⫽ 0.03, NA vs NL) were similar, lower than NA subjects. ACTH levels of NNA subjects did not differ from those of NLs (p ⫽ 0.74).
Cortisol Although NA subjects had the highest mean cortisol levels at 4:00 am (17.1 ⫾ 3.7 g/dL), they were not significantly greater than the levels of NNA subjects (13.3 ⫾ 2.2 g/dL; p ⫽ 0.31). The cortisol levels of NA subjects were higher than those of NLs (7.4 ⫾ 2.5 g/dL; p ⫽ 0.01), but those of NNA subjects were not (p ⫽ 0.08).
ACTH/Cortisol Correlation Within-group correlations between ACTH and cortisol levels were (in ascending order) as follows: NA group, r ⫽ 0.71 and p ⫽ 0.0005; NNA group, r ⫽ 0.74 and p ⫽ 0.0001; and NL group, r ⫽ 0.82 and p ⫽ 0.0001.
Conclusions (CHEST 2003; 123:405S) Abbreviations: ACTH ⫽ corticotropin; NA ⫽ nocturnal asthma; NL ⫽ control subject; NNA ⫽ nonnocturnal asthma
Although subjects with NA demonstrate significantly increased ACTH levels at night, these were not accompanied by a commensurate cortisol response. The adrenal response to ACTH may be blunted in NA subjects, permitting increased airway inflammation in these subjects.
with nocturnal asthma (NA) have increased P atients airway inflammation at night, a phenomenon not seen
in patients with non-NA (NNA). We hypothesized that alterations in hypothalamic-pituitary-adrenal axis function may be of importance in the pathogenesis of NA.
Materials and Methods Subjects with NA (four subjects), NNA (six subjects), and healthy control subjects (NL; six subjects) maintained a miniconstant-sleep-wake routine for 8 days. On day 8, serum samples were drawn every 2 h over a 24-h period (12 samples per subject) and were analyzed for circadian differences in corticotropin (ACTH) and cortisol levels. Between-group comparisons were made at each time point during the hours of sleep (ie, 10:00 pm to 6:00 am) using repeated-measures analysis of variance.
Results During sleep, there was a linear increase in both ACTH and cortisol levels in all three groups (p ⬍ 0.004). *From the National Jewish Medical and Research Center, Denver, CO. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: R.J. Martin, MD, FCCP, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206; e-mail: [email protected] www.chestjournal.org
Severe/Fatal Asthma* Sally Wenzel, MD, FCCP
Severe asthma is poorly understood clinically, physiologically, and pathologically. While milder forms of asthma are generally easily treated, more severe forms often remain refractory to the best current medical care. Although some patients with severe asthma have had severe disease for most of their lives, there appears to be a second group that develops severe disease in adulthood. Additionally, it is not clear which genetic and environmental elements may be the most important in the development of severe disease. Physiologically, these patients often have airtrapping and may have loss of elastic recoil, as well. The pathology demonstrates a heterogeneity of findings, including continued eosinophilic inflammation, structural changes, distal disease, and, in at least one third of patients, a different pathology. Treatment remains problematic and likely will remain so until a better understanding of this disease develops. (CHEST 2003; 123:405S– 410S) CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
405S