The objective of this National Heart, Lung, and Blood Institute (NHLBI) workshop was to review and assess the current state of knowledge regarding the role of circadian rhythms and sleep in the pathogenesis of nocturnal asthma. Also, we sought to identify gaps in our knowledge and make recommendations for future research. Because mounting evidence exists that mechanisms of inflammation, growth, and cytokine production are under day–night control, a potentially important area of basic study would be establishing precisely how chronobiology and sleep influence asthma, particularly the overall inflammatory process. Knowledge gained from the study of circadian alterations in physiology and inflammation needs to be applied clinically, since recent findings have indicated that chronotherapeutic strategies are important to the efficacious treatment of nocturnal asthma.
The worsening of asthma at night, commonly referred to as nocturnal asthma (NA), has never been adequately defined. Thus, the NHLBI working group produced the following definition: Nocturnal asthma is a variable exacerbation of the underlying asthma condition associated with increases in symptoms, need for medication, airway responsiveness, and/or worsening of lung function. These changes are related to sleep and/or circadian events. Additional definitions that should be clarified in the medical literature are diurnal, meaning daytime; nocturnal, meaning nighttime; and circadian, meaning the 24-h cycle.
Circadian rhythms dominate our existence. The function of circadian regulation is to impose a temporal organization on physiologic processes and behavior. In addition to the sleep– wake cycle, other examples of circadian regulation occur in body temperature, multiple hormones, and the autonomic nervous system. Disorders of circadian regulation are typically expressed as sleep disorders. However, diseases may be promoted or exaggerated by normal circadian control, and alternatively, disturbances of circadian regulation secondary to disease processes may exaggerate manifestations of the disease. It is therefore necessary to understand circadian regulation in order to understand the pathophysiology and treatment of diseases that have a temporal expression.
Circadian rhythms have two principal features: they run freely in the absence of temporal cues, particularly the light-dark cycle; and under normal environmental circumstances they are entrained to the light–dark cycle (1). These features indicate that a neural system that expresses and regulates circadian function must have the following features: circadian pacemaker(s); photoreceptors and visual pathways that transduce photic information into neural information and transmit it to the pacemakers; and pacemaker output to the effector systems that express circadian function (1, 2). These effector systems then express physiologic control mechanisms. However, there is a paucity of information about the effect of this interaction on lung function and immunology.
The timing and duration of sleep appear to be regulated by the interactions of two processes: a homeostatic process and a circadian process (3). The homeostatic process corresponds to the intuitive observation that we become sleepier the longer we are awake, and we become less sleepy the longer we have slept. Circadian events, such as humoral and body-temperature alterations, change rhythmically over a day-night schedule.
When humans sleep in long nights, their sleep is fragmented, as occurs in many animals (4, 5). Bouts of sleep are interspersed with periods of rest and quiet wakefulness. However, the impact of modern life on rest and quiet wakefulness, which have virtually become extinct, is probably much more severe than its impact on sleep. This change may have potent physiologic consequences, in that prolactin levels during active wakefulness are half those during quiet wakefulness (4, 5). In contrast, sleeping in short nights is associated with peak levels of sleep-related growth-hormone secretion that are double those in long nights (4, 5).
The immune system plays a role in sleep control. It has been shown that sleep-promoting substances accumulate in cerebrospinal fluid (CSF) during wakefulness, and that when transferred to normal recipient animals, this CSF induces sleep (6). Within the past few years, several sleep-regulatory humoral agents have been identified, the cytokines interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are perhaps the best characterized. Administration of IL-1 or TNF-α induces increased intensity and duration of non-rapid-eye-movement (NREM) sleep (7, 8).
IL-1 and TNF-α are well characterized as immune-response modifiers. Of importance for asthma is that both IL-1 and TNF-α induce nitric oxide (NO) production, which plays a role in airway inflammation. Interestingly, administration of exogenous NO also enhances sleep. Data such as these, coupled with the recent availability of knockout strains of mice lacking one or more of the genes included in encoding the IL-1 and TNF families of molecules now allow a reductionalistic approach to unraveling of the biochemical events and pathways involved in sleep regulation.
In asthma, the relative role of circadian and sleep systems has been a subject of controversy (9-12), and this issue remains unresolved. Initially, it was suspected that sleep systems played the major role. In a study of shift-workers, there appeared to be an immediate phase shift in the circadian rhythm of peak expiratory flow (PEF) when subjects rotated shifts, such that the decline in airway function remained coupled to the sleep period (9). Studies with sleep deprivation during the nocturnal period have, however, led to different results and conclusions (10, 11). The most complete data on this topic have related to changes in lower-airway resistance across the night (12). In asthma, the resistance increases progressively across the night, whether subjects sleep or not, although the increase is much greater during sleep. These results are supported by the observations that the onset of asthmatic attacks is less common in the first part of the night (13).
These data allow us to reach certain conclusions. First, it seems likely that both circadian and sleep factors play a role in asthma. Also, the progressive decline in airway function across the night does not suggest a typical change in a neuronal control process coupled to sleep. Notably, airway function is maximal at the time of increased sleepiness during the afternoon (14), and declines as sleep pressure dissipates during sleep.
Although sleep seems to play a role in the pathogenesis of asthma, asthmatic individuals also have evidence of problems with sleep. Studies reveal that asthmatic individuals or those with obstructive lung disease complain frequently of: difficulty in maintaining sleep (15), poor sleep quality (15, 16), and excessive daytime sleepiness (15). However, studies in which these findings were made contained important confounders (i.e., differentiation of asthma from chronic obstructive pulmonary disease [COPD], the potential role of medications such as theophylline that might affect sleep, and the role of snoring/sleep apnea). A large recent study, however, showed that asthmatic individuals are at increased risk for complaints of difficulty with inducing sleep, early-morning awakenings, daytime sleepiness, and daytime tiredness even when controls are applied for many of the aforementioned confounders in the analysis. Studies also show no effect of asthma on sleep latency and no consistent effect on sleep-stage distribution, although there is a significant reduction in sleep efficiency in asthmatic as compared to normal individuals (13). Thus, asthmatic individuals suffer from reduced sleep efficiency.
There is a paucity of studies on how sleep disturbances resulting from nocturnal asthma affect daytime performance in adults, and there are such studies for children. With the decreased sleep efficiency in asthma, and reports of daytime tiredness/sleepiness, the possibility exists that performance at work or school will be affected.
A study of nocturnal asthmatic and control subjects demonstrated that the asthmatic subjects had increased scores for subjective sleepiness (16). This reflected decreased objective sleep quality. Interestingly, daytime cognitive performance was worse in the nocturnal-asthma group. This area of research needs further investigation.
The morbidity of ventilatory failure, and also the mortality in asthma (17), are linked to the nocturnal worsening of lung function, which may be related to a blunted arousal mechanism caused by fragmented sleep. Ballard and colleagues (18) determined the effect of sleep deprivation on the arousal response to induced bronchoconstriction during the next night's sleep. It was found that arousal responses are depressed by prior sleep deprivation. It is suggested that worsening sleep patterns develop in asthmatic individuals and can lead to sleep deprivation and blunted arousal mechanisms.
Interestingly, in one study of asthma mortality, 79% of the 168 patients who died had a sleep disturbance reported prior to the terminal event (17). This contrasts with the usually accepted mortality risk factors of a previous ICU admission (5% in the study cited ), more than two hospitalizations/emergency-room (ER) visits in the preceding year (28%), or psychologic disturbance (13%).
It has been shown that sleep enhances the nocturnal increases in airway resistance and also leads to marked reduction in the volume of hyperinflated lungs in patients with nocturnal asthma (12, 19). Such volume changes do not account directly for all of the nocturnal change in airway resistance. However, artificially reducing lung volumes in awake asthmatic individuals to their typical levels during sleep did trigger worsening of airway obstruction, suggesting that the effects of sleep on lung volume could contribute to the nocturnal worsening of asthma (20).
The effects of sleep on lung volume could be mediated by several different mechanisms including: (1) a sleep-associated reduction in inspiratory muscle tone; (2) a decrease in pulmonary compliance; and (3) an increase in intrapulmonary blood pooling. In particular, the effects of sleep on intrapulmonary blood volume (IPBV) are intriguing, since there is evidence that such pooling of blood can promote airway narrowing. Using capillary volume (Vc) as a surrogate marker of IPBV, it has been shown that Vc increased overnight in asthmatic individuals with nocturnal worsening of lung function (21). Upper-airway narrowing could impose a resistive load on ventilation that would augment IPBV (22, 23). However, if lung volume is maintained throughout sleep, the overnight decrease in lung function and increase in bronchial hyperactivity are not altered (24).
There is significant variation in gastrointestinal (GI) function during sleep. The circadian rhythm of human basal gastric-acid secretion is characterized by a peak in the early evening and a nadir between 5:00 and 11:00 in the morning (25). There are conflicting data as to whether esophageal acid causes a decrease in airway function. In one study of sleeping individuals with nocturnal asthma, no significant acute or sustained change was observed in airflow resistance relative to periods of increased esophageal acid content, suggesting that gastroesophageal reflux (GER) contributed little to the nocturnal worsening of asthma (26). However, another study showed that an esophageal acid infusion at 4:00 a.m. in asthmatic children with a positive Bernstein test produced changes in the respiratory pattern indicative of bronchoconstriction, as well as overt clinical wheezing (27). Although it appears that asthma is more responsive to the effects of GER during the diurnal cycle than during the nocturnal cycle, the exact role of circadian/sleep effects in esophageal acid-induced bronchoconstriction remains unclear.
Several studies have shown the asthmatic response to nonspecific and allergen challenges. For example, one study showed that the lowest histamine concentration leading to a 10% decrease in FEV1 was at night, rather than with daytime challenges (28). Another study evaluated methacholine challenge at 4:00 a.m. and 4:00 p.m., and demonstrated a significant correlation between the methacholine concentration causing a 20% decline in FEV1 (PC20) and the overnight decrease in peak flow (29). In addition, it was found that some subjects were extremely sensitive, to the extent that even a saline challenge led to a significant reduction in FEV1. Yet another study demonstrated that the PC20 for both histamine and methacholine showed significant circadian variation in subjects with nocturnal asthma (30). The amplitude of the PC20 was significantly greater and the maximum responsiveness occurred significantly earlier with methacholine (3:06 a.m.) than with histamine (4:54 a.m.). In a study of children with stable asthma, there was a significant difference between the mean troughs of FEV1 (5:06 a.m.) and PC20 (10:30 p.m.) following histamine challenge (31). It was suggested that the circadian variation in the nadir of bronchial responsiveness precedes that of bronchial caliber in asthma. On the basis of these as well as other observations, it seems that nonspecific airway responsiveness is enhanced at night, especially in patients who show a significant nocturnal increase in airway obstruction.
Allergen responsiveness has also been shown to be increased at night. A study using house-dust-mite challenge found that the greatest decrease in FEV1 occurred after a late-evening challenge (11:00 p.m.) (32). In addition, there was a greater persistence of airway obstruction after the 11:00 p.m. challenge (32). In a more recent study, the frequency, duration, and severity of the late asthmatic response (LAR) were evaluated in subjects with stable allergic asthma (33). A 40% LAR was observed following an 8:00 a.m. challenge, whereas an 8:00 p.m. challenge caused a 90% LAR. Furthermore, the duration and severity of the LAR were enhanced after the evening challenge, and an increase in the PC20 for methacholine was greater at 24 h after the evening challenge than at 24 h after the morning challenge. The findings of these as well as other studies suggest that the frequency, severity, and duration of late asthmatic reactions to allergen challenge are increased at night and result in further enhancement of bronchial responsiveness. This nocturnal increase in bronchial responsiveness can contribute significantly to the nocturnal worsening of asthma symptoms.
Potential causes for the increase in nonspecific and allergen-related airway responsiveness in asthma are not entirely clear. However, they include increased airway inflammation, decreased concentrations of circulating hormones (i.e., cortisol, epinephrine), enhanced cholinergic tone, and increased intrapulmonary blood pooling at night. Defining the exact etiology of the increase in airway responsiveness awaits further study.
There is evidence that upper-airway disease (i.e., allergic rhinitis, sinusitis, and nasal polyps) influences and may contribute to the intensity of lower-airway disease (34). Allergic rhinitis, for example, can intensify airway responsiveness and even provoke asthma symptoms. Data indicate that treatment of allergic rhinitis diminishes bronchial responsiveness and asthma (35). Active sinusitis can also cause an increase in the asthma process as shown in animal models, which appears to involve drainage of nasal mediators into the lower airway (36). Other processes that link the nasal sinus to the lung have been identified in studies of viral infections of the nose that produce an increase in lower-airway reactivity (37). Also, there is a day– night cycle in nasal patency and perhaps in inflammation. All of these data suggest an important interaction between the nasal sinus and lower-airway function.
Inflammation is now recognized as a cardinal feature of asthma. A central question is the role played by inflammation in nocturnal asthma. That is, are there aspects of inflammation that are unique to nocturnal asthma, or does nocturnal asthma represent a more severe degree of “usual” asthma? To address these questions, investigators have measured systemic markers in blood and urine and airway materials derived from bronchoalveolar lavage (BAL), and analyzed biopsy specimens of airway and peripheral lung tissue. These approaches offer distinct sets of advantages and provide complementary information.
In one study, circadian variation in peak flow, FEV1, blood eosinophil counts, and bronchial hyperresponsiveness to histamine inhalation were measured. Most significantly, peripheral-blood eosinophil counts correlated directly with bronchial hyperresponsiveness, airway obstruction, and circadian variation in peak flow (38). Another study demonstrated that patients with nocturnal asthma had an increased proportion of low-density eosinophils at 4:00 a.m. as compared with 4:00 p.m., and also as compared with that of asthmatic subjects without nocturnal asthma or of normal subjects (39). In further studies, plasma cortisol and epinephrine levels and eosinophil counts were measured, and clear circadian variation in eosinophil numbers, cortisol, and epinephrine was shown (40). These data support the concept that inflammatory cells in the circulation influence the function of the airway by mechanisms not yet fully clarified.
Studies have also evaluated the circadian urinary excretion of leukotriene E4 (LTE4) in relationship to variation in FEV1. Although one such study found no circadian variation in FEV1 or LTE4 excretion (41), another showed an increase in urinary LTE4 at night in patients with nocturnal asthma (42).
Studies using BAL have also provided significant insights into the question of airway inflammation in nocturnal asthma. Although there is interlaboratory variation, most investigators observe a circadian variation in the number of eosinophils in cases of such asthma. Cytokines in BAL fluid (BALF) also show a circadian alteration (43). Concentrations of IL-1β were higher in patients with nocturnal asthma, and were further increased at 4:00 a.m. as compared with 4:00 p.m. in these subjects. Other studies also suggest that cellular activation occurs at night in subjects with nocturnal asthma. Superoxide production was equivalent in patients with nonnocturnal asthma and those with nocturnal asthma at 4:00 p.m., but was significantly increased at 4:00 a.m. in patients with nocturnal worsening of their asthma. Moreover, the magnitude of the increase in superoxide release was correlated with the magnitude of the decrease in FEV1. These data suggest that circadian activation of inflammatory cells may occur to a greater degree in individuals with nocturnal asthma, and that such activation may play a pathogenic role in the development of nighttime airflow limitation.
Direct assessment of pulmonary tissue by bronchial and transbronchial biopsy has provided yet another perspective on the role of inflammation in nocturnal asthma (44). First, the intensity of inflammation was greater in transbronchial lung biopsies than in endobronchial biopsies, regardless of the time (4:00 p.m. and 4:00 a.m.) of sampling. Second, endobronchial biopsies did not differentiate nocturnal asthma from nonnocturnal asthma. Third, biopsy of either lung or bronchial mucosa at 4:00 p.m. did not distinguish the two types of asthma. Only transbronchial biopsy, performed at 4:00 a.m., showed a difference between asthmatic subjects with and without nocturnal worsening of their condition, and with more than a twofold difference in the magnitude of daytime and nighttime eosinophilic inflammation. This study strongly suggests that an important region of investigation with regard to understanding the pathophysiology and chronobiology of asthma consists of the very distal and alveolar area segments of the airway.
Bodily functions have been incorrectly assumed to be relatively constant throughout the 24 h of the day and other periods of time. Numerous studies have shown that the kinetics and dynamics of pharmacotherapies vary significantly according to the biologic time of administration during the 24 h-cycle, menstrual cycle, or annually, owing to the cumulative effect of endogenous rhythms in crucial physiologic and biochemical functions. Chronotherapeutics is the synchronization of medication levels in time with reference to need, taking into account biologic rhythms in the pathophysiology of medical conditions, and/or rhythm-dependencies in patient tolerance for given chemical interventions. Chronotherapeutics can sometimes be achieved by the judicious timing of conventional sustained-release (SR) formulations, although reliance on special drug-delivery systems seems to constitute a more dependable means of matching drug level to biologic need and tolerance (45).
Certain SR formulations of theophylline can be administered so that a rising blood level of the drug occurs when airway obstruction is increasing, while adverse effects are reduced. For this purpose, SR theophylline is administered once daily, in the evening, for the management of nocturnal asthma (46).
Another aspect of theophylline therapy is how it can work in conjunction with inhaled corticosteroids as part of a chronotherapeutic regimen. This interaction is important, since inhaled corticosteroid therapy used in patients with moderate to severe asthma failed to control a significant percentage of nocturnal asthmatic symptoms (47).
Various tablet formulations for the sustained-release of β-agonists have been used in a chronotherapeutic fashion for the management of asthma (48). As with theophylline, very little information exists about comparing the effects of or adding a long-acting β2-agonist oral preparation to an inhaled corticosteroid using chronotherapeutic techniques.
The long-acting inhaled β2-agonists salmeterol and formoterol have been studied for the treatment of nocturnal asthma (49, 50). These agents have a lower adverse-effect profile than do long-acting oral agents (51, 52). Salmeterol has been shown to control symptoms of nocturnal asthma to a substantial degree, and to improve sleep quality and daytime cognitive performance in patients with chronic asthma (49, 53). It is important to note that any advances in β2-agonist therapy will need to take into account the downregulation of the β2 receptors that occurs at night in nocturnal asthma (54), and which is related to glycine 16 polymorphism (55).
Drugs that antagonize the vagal nervous system should be useful in the management of nocturnal asthma as a means of counteracting the enhanced nocturnal parasympathetic tone that occurs in the disease (56). Studies have shown that inhaled cholinergic antagonists such as ipratropium bromide and oxitroprium bromide have reduced the morning decline in airflow in asthmatic individuals (57, 58).
Corticosteroids have been used in a chronotherapeutic manner, with the finding that their long-term oral administration at 8:00 a.m. and 3:00 p.m. was more effective in controlling nocturnal asthma than the same doses given at 3:00 p.m. and 8:00 p.m. (59). Other studies have shown that a single 3:00 p.m. dose of prednisone improved lung function and reduced airway inflammation more effectively than the same single dose given at 8:00 a.m. and 8:00 p.m. (60). Not only can oral steroids be dosed chronotherapeutically, but inhaled corticosteroids can also be efficacious when used in this manner (61).
Although the leukotriene-active drugs, including zileuton, zafirlukast and montelukast, are new in the treatment of asthma, they have been shown to alleviate the symptoms and the decrement in lung function seen in nocturnal asthma. It has been shown that zileuton in particular decreased nighttime increases in leukotriene B4 (LTB4) and (LTE4) while improving lung function (62). Zafirlukast has also been shown to decrease nighttime awakenings and improve morning PEF rates (63). Although these agents have only been studied at set doses and times regardless of the presence or absence of nocturnal asthma, the improvements observed were significant, and it is likely that these agents will prove very useful in the treatment of nocturnal asthma when used chronotherapeutically.
As a result of the workshop, we formulated the following recommendations for future research directions.
The working group felt it imperative to separate the effect of circadian rhythms from sleep on the immunology of the lung. This is important in order to understand how the inflammatory process is turned “on” and “off” over the 24-h cycle. This would not only aid in the understanding of nocturnal asthma in terms of the physiologic and hyperresponsive alterations that occur in this condition, but would also shed light on inflammation, which is characteristic of all asthma. The location of the immunologic response in the lung also appears to be important in regard to resultant physiologic alterations. Once the chronoimmunologic sequence is understood, new and innovative modalities could be instituted for the treatment of asthma. Additionally, knowledge gained in this area could be applied to other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, which are also marked by chronobiologic alterations.
It was felt that a multidimensional investigation should be done, since it is important to bring together investigators with expertise in asthma, immunology, physiology, sleep, chronobiology, and neuropsychology. In this manner, a concentrated effort could be applied to the question(s) relating to nocturnal asthma so as to maximize the effort and outcomes of its management.
Unanswered questions remain about the role of inflammation in nocturnal asthma. First, does nocturnal asthma represent a unique manifestation of inflammation, either in timing or character? Second, the specific contributions of various inflammatory cells putatively related to asthma (eosinophils, macrophages, lymphocytes) have not been well characterized with respect to nocturnal asthma. In addition, the compartment (i.e., air space, bronchial mucosa, pulmonary tissue, or blood) most relevant to the process has not yet been established. In this context, there also remains controversy over the specific biochemical markers that best reflect the inflammatory process. Additionally, mechanisms by which the central biologic clock interfaces with and controls the immune–inflammatory cascade must be identified and characterized.
Better insight needs to be gained into problems of daytime sequelae of nocturnal asthma. Little is known about how disordered sleep resulting from nocturnal asthma affects daytime performance. The available studies strongly suggest that cognitive performance in adults is decreased. One may surmise that this holds true for school performance in children, but no data are available for this important group.
The physiologic interaction between sleep-associated changes in upper-airway caliber and lower-airway responses needs to be better defined. This is important for neuroreflex mechanisms and for increasing intrapulmonary blood volume with the resultant potential for bronchoconstriction from “engorgement” and the presentation of increased numbers of inflammatory cells and mediators to the lung.
The mechanism by which rhinosinusitis influences asthma needs to be identified. Asthma and rhinosinusitis have always been linked, but the exact mechanism of their linkage is in doubt. Allergic rhinitis/nasal inflammation has a circadian pattern similar to that of asthma. Thus, studying this process in patients with and without asthma may shed light on how or if rhinosinusitis interacts with the chronobiology of asthma.
Continued understanding of the chronobiology of asthma and the development of chronotherapeutic principles related to this are needed. As newer agents are developed for the treatment of asthma, chronotherapy may be important for increasing treatment efficacy while decreasing side effects. This has already been shown for several asthma medications.
Although a legion of articles have been written on the relationship of GER and asthma, and current data suggest that the effect of GER plays a more important role in the diurnal than in the nocturnal cycle, further investigation could solidify the exact role of circadian/sleep effects in bronchoconstriction related to GER.
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List of participants: Susan P. Banks-Schlegel, Ph.D., and Richard J. Martin, M.D., Chairs; Robert D. Ballard, M.D., Bruce G. Bender, Ph.D., William W. Busse, M.D., William J. Calhoun, M.D., Gilbert E. D'Alonzo, D.O., Susan M. Harding, M.D., Erhard Haus, M.D., Ph.D., Nizar N. Jarjour, M.D., Monica Kraft, M.D., James M. Krueger, Ph.D., Robert Y. Moore, M.D., Ph.D., Allan I. Pack, M.D., Ph.D., Michael H. Smolensky, Ph.D., Thomas A. Wehr, M.D., David P. White, M.D.
Workshop supported by the Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, September 15–16, 1997.