Nocturnal asthma: not a separate disease entity

Respiratory Medicine (1994) 88, 483-491

Topical Review

Nocturnal asthma: not a separate disease entity E. J. M. WEERSINK AND D. S. POSTing* Department of Pulmonology, University Hospital Groningen, The Netherlands

Introduction Increased nocturnal wheeze and cough have already been described as early as in the fourth century A D and many case reports about this subject stem from the 17th and 18th century (1). These symptoms have often been called 'nocturnal asthma'. Nocturnal asthma has long been regarded as a different type of asthma. Yet it has been suggested that these common characteristic symptoms such as nocturnal dyspnoea, cough, and wheezing are an expression of increased nocturnal airflow limitation and airway hyperresponsiveness. Although nocturnal dyspnoea in asthmatics has been recognized for a long period of time, it is only recently that some insight has been obtained in both endogenous and exogenous factors underlying the nocturnal fall in pulmonary function and increase in airway hyperresponsiveness. In this article, we will review these underlying factors, discuss how they may influence each other and demonstrate that 'nocturnal asthma' is only an expression of severe asthma and not a separate disease entity.

Epidemiology It is evident that the phenomenon of nocturnal dyspnoea attacks is a severe complication of asthma because most deaths due to asthma occur at night and in the early morning (2,3). Decrease in sleep quality and daytime cognitive performance, even without awakening are also important sequelae of nocturnal dyspnoea (4). Nocturnal worsening of asthma is still very common despite improvement of asthma therapy in the last decade. It is known that a poor agreement exists between subjective and objective assessments of nocturnal symptoms. *To whom correspondenceshould be addressedat: Departmentof Pulmonology,UniversityHospitalGroningen,Oostersinge159,9713 EZ Groningen,The Netherlands. 0954-6111/94/070483+09 $08.00/0

Falconer et al. (5) examined the relation between reported and recorded nocturnal cough in 15 children (age 7-14) and showed that cough was reported by 66%, while tape recorded cough was heard in 90%. This poor agreement may be partly an explanation for the frequently unrecognized nocturnal worsening of asthma by patients and therefore for the underdiagnosis and possible undertreatment by physicians. Turner-Warwick et al. (2) have studied the frequency of nocturnal symptoms in asthma in a primary care population, who received inhaled corticosteroids (n--7729). From the adult asthmatics, 39% woke up every night with chest tightness, wheezing or cough, 64% reported awakening at night at least three times a week and 74% reported awakening at night at least once a week. Dethlefsen et al. (6) showed in a population of 3129 asthmatics that episodes of dyspnoea occur about 40 times more frequently overnight than during the day. Meijer et al. (7) investigated 769 children, who had been visiting the outpatient clinic for a longer period (at least 6 months) and all had been instituted on therapy to minimize their symptoms. Nocturnal symptoms were scored by a questionnaire and the answers were given by the children and their parents. Fifty percent had no nocturnal symptoms, 34% had nocturnal symptoms at least once a week and 6% every night. Common symptoms resulting in awakening at night collected with this questionnaire are cough (32%), shortness of breath (26%), morning dyspnoea (25%) and wheezing (18%). In addition, they investigated a group of 106 children, who came for their first visit to the outpatient clinic. Although a comparable pattern of nocturnal symptoms was found, all complaints were significantly more frequently reported in the latter group than in the long standing treated group. The 106 children were treated with inhaled corticosteroids for at least 3 months, whereupon all symptoms had the same prevalence as in the long-standing treated group. Thus, still 50% woke up at night at least once 9 1994W. B. SaundersCompanyLtd

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Table 1

nocturnal airflow limitation, will be consecutively discussed (Fig. 1). Airway tone

Airway responsiveness NERVOUS SYSTEM

Exogenous factors Allergen exposure Viral infection Mucociliary clearance Gastric-esophageal reflux Non-specific stimuli

TT~" TT TTT T'~ TT

Ttt TTT ? T TT

Endogenous factors (24-h rhythm) Plasma adrenaline J,~$ Plasma cortisol ~ Histamine release TTT Vagal tone T~T Steep "~ i-NANC system ~,~ e-NANC TTT

.t~ ? TTT -? ~,~, ~T~

a week. Many asthmatics still suffer from nocturnal symptoms despite improved treatment.

Circadian Rhythms in Endogenous Factors and Exogenous Factors There are circadian rhythms to many biologic functions and the respiratory system is not different in that respect. Circadian variation in airway diameter occurs in healthy subjects and asthmatics and is markedly exaggerated in asthmatics with nocturnal symptoms. In addition, airway hyperresponsiveness deteriorates more markedly overnight in asthmatics with nocturnal increase in airway obstruction compared to those who have minimal circadian variation in airway diameter (8-10). The nervous system, which consists of the fl-adrenergic, cholinergic, and non-adrenergic, non-cholinergic system (NANCsystem) has an important function to control the airway diameter. Moreover, it is generally accepted that airways inflammation influences airway diameter and airway responsiveness, but it is not fully clear whether and to what extent airway wall inflammation is more increased overnight in asthmatics with nocturnal airflow limitation. Other endogenous and exogenous factors, such as sleep (11), mucociliary clearance (11), gastric esophageal reflux (12), allergen exposure (13-16), and non-specific stimuli e.g. passive exposure to cigarette smoke (17) are likely to play a role in nocturnal airflow limitation (Table 1). In the following part available data about the nervous system and airway wall inflammation, which we consider to be as the most important factors for

~-adrenergic system There are hardly any fl-adrenergic nervous fibres in the lung. The adrenergic tone is largely governed by circulating adrenaline stimulating fl2-adrenergic receptors on smooth muscles. Stimulation of the fla-adrenergic receptor leads to an increase in intracellular cyclic-adenosine monophosphate (c-AMP) resulting in relaxation of airway smooth muscles. The observed coincidence of the trough in plasma adrenaline and the fall in peak expiratory flow (PEF) at 04.00h suggest a contribution of endogenous adrenaline to nocturnal airflow limitation, although a similar circadian pattern in plasma adrenaline has been shown for healthy subjects (18,19). Infusion with adrenaline to plasma levels comparable with those at 04.00h did not alter PEF fall overnight (20). After adrenaline infusion above physiological plasma levels it has been observed that the PEF fall at night was reduced (18). A case report (21) of a patient who had undergone bilateral adrenalectomy showed the development of asthma with morning dyspnoea and increased PEF-variation with morning dipping. Since adrenaline is a potent bronchodilator and its level decreases during the night, these findings suggest that adrenaline is an important cause of nocturnal airflow limitation. Nevertheless, it appears necessary to infuse a supraphysiological concentration of adrenaline before reduction of the circadian variation of PEF occurs. Based on above findings it has been thought that a fl2-adrenergic receptor dysfunction overnight may play a role in nocturnal worsening of asthma. Three aspects of dysfunction of the fl2-adrenergic receptor have been investigated: density, stimulation and affinity of the fl2-adrenoceptor. The dysfunction of fl2-adrenergic receptors was measured on blood leucocytes instead of airway smooth muscles. No difference in density was shown between asthmatics with and without nocturnal airflow limitation and healthy controls, although a circadian pattern in density was observed in both asthmatics and healthy controls (19,22,23). Stimulation of fl2-adrenergic receptors with isoprenaline increases c-AMP production. In asthmatics with nocturnal airflow limitation an impaired c-AMP response was observed both day and night. This response showed a circadian variation, which is the same for asthmatics without nocturnal airflow limitation and healthy controls. It has been suggested

Topical Review

that this circadian variation in isoprenaline-induced c-AMP response can be a reflection of circadian variation in density of/~2-adrenergic receptors. When ~]~e affinity of/]2-adrenergic receptors was investigated, no differences between day and night and no differences between healthy subjects and asthmatics without nocturnal airflow limitation have been observed when compared to asthmatic with nocturnal airflow limitation. So far the impact of a circadian variation in dysfunction of the fl2-adrenergic receptor in nocturnal airflow limitation is not clear. Moreover, the dysfunction of the fl2-adrenergic receptor on blood leucocytes does not necessarily reflect a dysfunction of fl2-adrenergic receptor on airway smooth muscles. However, incomplete resolution of the circadian PEF variation should be observed after treatment with fl2-agonists if a dysfunction of fl2-adrenergic receptor on airway smooth muscles is more pronounced at night than in daytime in asthmatics with nocturnal airflow limitation. The study of Rabe et al. (24) agrees with this assumption in that inhaled long-acting fl2-agonists improved morning PEF values, nevertheless, the circadian variation still existed though on a higher level. This is in contrast to a study with the oral long-acting fl2-agonist bambuterol which significantly reduced the circadian variation of PEF and FEVa-values (25). This difference can possibly be explained by different concentrations of the used fl2-agonists, which is higher in the latter study. In addition, Oosterhoff et al. (10) have shown that propranolol-induced bronchoconstriction is not decreased overnight in patients with and without nocturnal airflow limitation. The former group, however, was more sensitive to propranolol both at day and night compared with patients without nocturnal airflow limitation. In conclusion, a dysfunction of the fl2-adrenergic receptor on blood leucocytes and on airway smooth muscles may be present in asthmatic patients with nocturnal airflow limitation both day and night. A pivotal role of such a fl2-adrenergic receptor dysfunction and circadian variation in plasma adrenaline levels in the pathogenesis of nocturnal airflow limitation is still debatable, although it is presumable that the trough in plasma adrenaline superimposed on an impaired function of the fl2-adrenergic receptor is important in nocturnal airflow limitation. Cholinergic system

The dominant neural bronchoconstrictor pathway in the airways is the cholinergic system. The vagal neurotransmitter acetylcholine acts via at least three different muscarinic receptors (MI, M2, and M3) Ml-receptors in parasympathetic ganglia may facili-

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rate neurotransmission of the cholinergic nerves whereas Mz-receptors on postganglionic nerve terminals may inhibit the release of acetylcholine, thus reducing the stimulation of postjunctional M3-receptors which induce airway smooth muscles contraction. As increased vagal activity leads to bronchoconstriction, vagal tone may well be important in the pathogenesis of nocturnal airflow limitation. Postma et al. (26) investigated the circadian variation of the vagal tone in non-allergic patients with COPD, who had a significant overnight fall in FEV 1. They found an overall increase in vagal activity in the patients compared with healthy subjects, the difference being maximal at night. The exaggerated vagal tone correlated with nocturnal airflow limitation. The same phenomenon has been observed in adult allergic asthmatics (27). In contrast to these findings are the observations of van Aalderen et al. (28) who found no evidence for the increased vagal activity in allergic children with nocturnal airflow limitation. In addition, Sly et al. (29) failed to find any protection of inhaled ipratropium bromide on nocturnal airflow limitation in asthmatic children. In adults, however, inhaled ipratropium bromide shows some protection against nocturnal airflow limitation, which is dose-dependent (30). An almost complete reduction in nocturnal airflow limitation has been shown after infusion with atropine (30/~g kg 1), indicating that vagal mechanisms are at least fundamental in the pathophysiology of nocturnal airflow limitation in adults (31). The observed increase in vagal activity, which is maximal at night, may also be partly explained by the lower adrenaline plasma levels at 04.00h. These lower nocturnal levels may less counteract the acetylcholine-release at the smooth muscle via the fl2-adrenergic receptor on postganglionic nerve terminals (32). In addition, it is known from animal studies that the M2-receptor has also a negative feedback function to the acetylcholine release. A dysfunction of the M2-receptor may occur after allergen exposure by release of inflammatory mediators, especially from activated eosinophils (33). Therefore, it can be hypothesized that this impaired negative feedback mechanism is important in nocturnal airflow limitation since the numbers of activated eosinophils are increased in almost all asthmatics and possibly even more pronounced in those with more severe asthma or asthma at night (34,35). Recently M2-receptors have been detected in human bronchial tissue of healthy subjects (36) and in addition, a dysfunction of Mz-receptors has been observed in asthmatic patients as well. This has not yet been investigated in relation with nocturnal airflow limitation, and certainly needs further research.

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Nonadrenergic, noncholinergic system The inhibitory (i)-NANC system is the only direct neural pathway of the smooth muscle which results in bronchodilation after stimulation of this system with capsaicin (37). Mackay et al. (38) have shown that in both normal and asthmatic subjects capsaicininduced bronchodilation (= i-NANC) is significantly greater at 16.00h than at 04.00h and no difference could be found between normals and asthmatics. Therefore, it is not clear whether this impaired bronchodilator function at night is important to counteract the increased nocturnal airway obstruction. Until now, no studies have been performed to investigate the role of the excitatory (e)-NANC system in nocturnal airflow limitation. The e-NANC system acts via irritant receptors and C-fibres and results in neurogenic inflammation and bronchoconstriction (axon reflex) after activation. It is possible that this neurogenic mechanism contributes to the increased bronchoconstriction at night. For instance the observed peak in histamine levels in plasma and bronchoalveolar lavage fluid at 04.00h, may result in stimulation or irritant receptors and release of neuropeptides of the e-NANC system. Moreover, the trough of plasma adrenaline at 04.00h may less counteract the release of these neuropeptides. Stimulation of the e-NANC system is possible with adenosine monophosphate (AMP) which leads to bronchoconstriction (39). It has been observed that a circadian pattern in AMP sensitivity existed with an increase at 04.00h in asthmatics with nocturnal airflow limitation compared to asthmatics without it (10). A larger change in circadian AMP sensitivity corresponded with a bigger circadian PEF-variation. These results together suggest that axon reflex mechanisms may be more susceptible to activation at night. INFLAMMATION

In the last decades, the pathophysiology of asthma has been characterized by an intermittent and potentially reversible airway obstruction superimposed on a background of airway wall inflammation. Airway wall inflammation has been implicated in the pathogenesis of airway hyperresponsiveness (40). Therefore, the observed increase in airway hyperresponsiveness overnight in asthmatics with nocturnal airflow limitation may be associated with an increase in inflammation of the airway wall at night. However, it is not clear which role airway wall inflammation plays in the observed nocturnal increase in airway hyperresponsiveness. It has been suggested that an increase in total numbers and/or activity of inflammatory cells can be observed at night.

Airway hyperresponsiveness In 1962 it has been shown that histamine-induced bronchoconstriction is increased at night both in atopic asthmatics and in patients with COPD (8). The same circadian pattern has been shown for methacholine-induced bronchoconstriction (9). Wempe et al. (25) have observed that a larger circadian variation for histamine-induced bronchoconstriction is associated with a larger circadian variation in PEF suggesting a relationship between airway hyperresponsiveness and nocturnal airflow limitation. However, it has been shown in children that the increase in airway hyperresponsiveness for histamine at night is not determined by the degree of nocturnal airflow limitation, since asthmatic children without nocturnal increase in airway obstruction do also show an increase in airway hyperresponsiveness at night (41). Though the degree of airway hyperresponsiveness is determined by the airway diameter, above findings show that this is only partially valid for the nocturnal increase in airway hyperresponsiveness in asthmatics. Thus, other factors than airway diameter are responsible for this nocturnal increase in airway hyperresponsiveness, suggesting a role for the inflammatory process in the airway wall at night. Airway hyperresponsiveness can also be measured by the so-called 'indirect' stimuli such as AMP and propranolol. AMP acts as an airway constrictor by release of histamine from mast cells in addition to stimulation of irritant receptors leading to neurogenic inflammation. The susceptibility to AMP is therefore more likely associated with the inflammatory state of the airways than the susceptibility to methacholine (39). Another evidence which supports this assumption is that inhaled corticosteroids (1600/lg for 14 days) have a greater reducing effect on AMP-induced bronchoconstriction than on methacholine-induced bronchoconstriction (42). This effect can be explained by the anti-inflammatory properties of corticosteroids, especially by reducing mast cell numbers in the bronchial mucosa, which may lead to a reduction in the amount of released inflammatory mediators. In patients with nocturnal airflow limitation PC2o AMP fell with three doubling dose steps at night compared to daytime values, being far more than the observed one dose step in PC2o methacholine. In asthmatic patients without a nocturnal increase in airflow limitation no changes in PC2o AMP and PC2o methacholine were observed (10) (Fig. 2). A striking observation was that, both day and night, responsiveness to AMP and Mch were significantly higher in asthmatics with nocturnal increase in airflow limitation than in those without.

Topical Review

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-I- receptor more stimulated at night --

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Fig. 1 An overview of how the different parts of the nervous system are involved in nocturnal airflow limitation. M 1receptor ([~), Ms-receptor (0) and NK2-receptor (A) are more stimulated at night, ultimately resulting in bronchoconstriction. M2-receptor (9 and/~2-receptor( 9 are less stimulated at night, resulting in less counteracting of the increase in bronchoconstriction. (Ach=acetylcholine, Adr=adrenaline, NKA=neurokinin A, SP=substance P, CZS=central nervous system).

This suggests that, both day and at night, an increased inflammation of the airways determines the occurrence of nocturnal airflow limitation in asthmatic individuals. Cortisol The circadian rhythm of adrenal glucocorticosteroid secretion has been suggested to be another cause for nocturnal airflow limitation. The fall in plasma cortisol at midnight, by the 4 h time lag in its effect, may result in less suppression of airway inflammation, especially around 04.00h. However, 24-h cortisol infusion in order to reduce this midnight fall, did not prevent the dip in PEF at 04.00h in asthmatics with nocturnal airflow limitation (43). Therefore, it is not yet clear whether there is a causal role for

circulating cortisol in the increased inflammation at night. Wempe et al. (25) have shown that 4 weeks of treatment with inhaled budesonide (800/~g) reduces the fall in PEF and improves airway hyperresponsiveness and FEV 1 both day and night, although a total reduction in circadian variation was not observed. This sustained circadian variation was still greater in asthmatics with than without nocturnal airflow limitation after the same treatment period. It has been reported that a 14-year-old boy with Addison's disease developed asthma with nocturnal symptoms, and became asymptomatic after treatment with continuous replacement of glucocorticosteroids (44). Thus, a role for cortisol in nocturnal airflow limitation is likely, but whether this role is a principle one is not clear.

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Fig. 2 Airway hyperresponsiveness to methacholine (a), propranolol (b) and AMP (c) at 16.00 and 04.00h in the group

with nocturnal airflow limitation (NA +) and the group without nocturnal airflow limitation (NA-). Individual values are represented by dots. Mean values, expressed as geometric mean, are represented by horizontal bars. A change of 1 unit in log2 PC20 equals a change of 1 doubling concentration. (Oosterhoff et al. Am Rev Respir Dis 1993; 147: S12-S17). Inflammatory cells

Many cells contribute to the inflammatory process in the airways of asthmatics: mast cells and eosinophils are considered as principle effector cells in this respect. Involvement of mast cells in nocturnal airflow limitation is only provided by indirect evidence. There exists a circadian variation in plasma and urinary histamine concentrations in atopic asthmatics, the highest values coinciding with maximal nocturnal airway obstruction. In healthy subjects there is no nocturnal rise in plasma histamine levels, presumably because unsensitized mast cells or basophils are more stable (18). Van Aalderen et al.(28) reported that in allergic asthmatic children urinary N ~-

methylhistamine excretion was increased at night compared with daytime levels, while in controls no variation was shown. This contrasts to the study of Fitzpatrick et al. (45) but individuals included in this study were nonatopic. Furthermore, an increase in histamine in bronchoalveolar lavage (BAL) fluid has been observed in allergic asthmatics at 04.00h, who had a mean fall in FEV1 of 29%. The decline in FEV1 inversely correlated with the histamine level ( r = - 0'64) (46). A specific mediator of activated mast cells, P G D 2 (prostaglandin D2) is also increased in BAL-fluid at night compared with daytime values. However, daytime values of P G D 2 are increased as well when compared with values in healthy controls

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and with allergic asthmatics without nocturnal airflow limitation (Y. Oosterhoff, personal communication). Another finding suggesting that mast cells are less stable at night is the increase in AMP-induced airway constriction at night. It is known that AMP acts partly via mast cells resulting in histamine release. The lower stability of mast cells can be explained by a higher allergen load and by lower plasma adrenaline levels at night. Although the stability of mast cells is also decreased in daytime, this is more pronounced at night in asthmatics with nocturnal airflow limitation compared to asthmatics without nocturnal airflow limitation (10,18). It has been shown by Barnes et al. (18) that the nocturnal peak in plasma histamine disappeared after infusion of adrenaline above physiological levels, which also resulted in a reduction of PEF variation. This finding suggests that an acute stabilization of the mast cell is effective in nocturnal airflow limitation. In contrast, the effect of a single high dose of nebulized sodium cromoglycate did not reduce the overnight fall in FEV 1 (47). Therefore, Morgan et al. suggested that mast cell degranulation may not be important in the pathogenis of nocturnal airflow limitation. This is in agreement with the finding that treatment with an oral histamine antagonist (terfenadine, 120 mg) did not have a protective effect in nocturnal airflow limitation. This may also be due to a smaller effect of oral histamine antagonists compared with an inhaled one, or an insufficient dose, because terfenadine (180 mg q.d.) did protect against histamine-induced bronchoconstriction (48). Results so far suggest that mast cells in allergic asthmatics with nocturnal airflow limitation may be less stable both day and night. The circadian variation of circulating eosinophil granulocytes is similar for healthy subjects and asthmatics, although higher numbers are found in the asthmatic group (49). No significant differences have been found between numbers of eosinophils in serum and in BAL-fluid both day and night in asthmatics with and without nocturnal airflow limitation. But the observed numbers of eosinophils in the two asthma groups were significantly higher than in healthy controls. (35). Other studies concern the activity of eosinophils and provide evidence that asthmatics with nocturnal airflow limitation have an increase in eosinophil activity in peripheral blood at night indicated by a rise in eosinophil cationic protein (ECP) and the presence of hypodense eosinophils (50,51). The eosinophil activity is also increased at daytime in these asthmatics. Direct evidence for involvement of eosinophils and other inflammatory cells in nocturnal airflow limitation is supplied by BAL-fluid findings at night as investigated by Martin

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et al. (34). The overnight fall in PEF rate (40%)

correlated with the increase in eosinophils and neutrophil granulocytes in BAL-fluid at 04.00h (r = 0.62) and r=0-66 respectively), but not with Tlymphocytes. In contrast, Jarjour et al. (46) reported that total cell numbers of eosinophils and neutrophils did not increase in BAL-fluid at night, which is in agreement with the study of Oosterhoff (35). Nevertheless, spontaneously increased production of superoxide at 04.00h by BAL-fluid cells, an activation parameter of the inflammatory airway cells, has been associated with the overnight fall in FEV 1 (29%) (46). The discrepancies in results in the above mentioned studies may be explained by different patient characteristics. For instance, the study of Martin et al. entered more severe asthmatic patients (higher circadian PEF variations at home) than the other two studies. Overall, there is no clear evidence for a circadian pattern in total numbers and/or activity of inflammatory cells, although it could be suggested that in more severe asthmatics, with a greater fall in PEF-values at night, a circadian pattern in inflammation can be observed. Conclusion

From the available data we conclude that patients with nocturnal symptoms have clinical characteristics belonging to more severe asthma. Nocturnal symptoms such as nocturnal cough, wheezing and awakening are associated with nocturnal airflow limitation and increase in airway hyperresponsiveness at night; a complex often called 'nocturnal asthma'. It seems likely that nocturnal symptoms are the reflection of deterioration of asthma. Hypothetically, the circadian pattern of the cholinergic-system (increase at night) and the e-NANC system (increase at night) and at the other hand the adrenergic-system (decrease at night) and the i-NANC-system (decrease at night) may lead to nocturnal symptoms in asthmatics, who have an exaggerated inflammatory state of their airways both day and night. Only in the most severe asthmatics a circadian pattern of the airway wall inflammation can be observed. It appears that 'nocturnal asthma' is not a separate disease entity. We propose to replace it by 'asthma characterized by nocturnal symptoms', which is due to nocturnal airflow limitation, as a consequence of circadian variations in the nervous system superimposed on exaggerated airway wall inflammation. References

1. Hetzel MR. The pulmonary clock. Thorax 1981; 36: 481486.

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