A website for HK Thoracic Society, ACCP HK & Macau Chapter

2010 - Nocturnal Asthma and Chronotherapy

Dr Yu Chin Wing, Department of Medicine, North District Hospital

Definition and prevalence of nocturnal asthma
The National Heart, Lung, and Blood Institute working group had defined nocturnal asthma as 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.1

Nocturnal worsening of asthma is a common problem among asthmatics. According to a survey of 7,729 non-hospital-based asthmatic patients in the United Kingdom reported in 1988, 64% of the patients woke up at least 3 nights per week and 74% woke up at least 1 night per week.2 About half of the patients used inhaled corticosteroids in this study.

The factors associated with nocturnal worsening of asthma may include airway cooling, allergen exposure, gastroesophageal reflux (GERD), increased cholinergic tone, hormonal change and so on. The mechanisms are not entirely understood. Both healthy individuals and subjects with nocturnal asthma have circadian variation in lung function, which is best around 4pm and worst around 4am. However, the variation of airway caliber size in subjects with nocturnal asthma is more pronounced and usually exceeds 20%.3-4

Although airflow limitation at 4am improves with bronchodilator in many patients, this response is attenuated in nocturnal asthmatics. Hendeles et al. had demonstrated a slower response to albuterol in them.5 A study showed that nocturnal asthmatics had increased airway hypersensitivity, as reflected by a decreased in methacholine PC20 FEV1 at 4am compared to 4pm.6 They have significant circadian difference in leukocyte beta-adrenergic receptor density and function.7 The beta-receptor polymorphism of the Gly 16 allele is more prevalent in subjects with nocturnal asthma.8 Glucocorticoid receptor binding characteristics and steroid responsiveness are also altered in nocturnal asthmatics, with a significantly lower binding affinity at 4am compared to 4pm.9 In a study designed to evaluate pituitary-adrenal axis function, the peak level (at around 6am) and overall corticotrophin were significantly increased in subjects with nocturnal asthma, although a commensurate increase in cortisol levels was not observed. That suggested the adrenal responsiveness to corticotrophin was blunted.10

Abnormal response to melatonin may also play an important role in nocturnal asthma. A study showed that the peripheral blood mononuclear cells (PBMCs) from nocturnal asthmatics produce significantly greater amounts of IL-1, IL-6 and TNF-α in response to melatonin at 4pm. However, at 4am, their PBMCs were unable to be stimulated further, despite the melatonin level was higher.11

Leukotriene B4 has been implicated in the airway inflammatory response in nocturnal asthma.12 It is an attractant for neutrophils and it induces T-lymphocyte production of interleukin-5, which has been correlated with eosinophilia in asthma.

The relative role of circadian and sleep systems has been a subject of controversy. There were changes in lung volumes in nocturnal asthmatics during sleep and it had been shown that sleep would enhance the nocturnal increases in airway resistance in them.13

Inflammation in distal lung
The site of inflammation of nocturnal asthmatics is in the distal airways and alveolae. Monica Kraft et al. had demonstrated that nocturnal asthmatics exhibited more eosinophils, macrophages and CD4+ lymphocytes in the alveolar tissue obtained by bronchoscopy at 4am compared with 4pm. The number of eosinophils per volume of alveolar tissue was greater in nocturnal asthmatics at 4am compared with non-nocturnal asthmatics. Comparison with the eosinophilic inflammation in the larger airway specimens did not show significant difference, suggesting a circadian difference in distal lung.14 A higher nitric oxide level in alveolae, corresponding to the site of inflammation, was also demonstrated in nocturnal asthmatics.15

Concomitant conditions
Concomitant illnesses, such as OSAS, GERD and rhino-sinusitis, may worsen nocturnal asthma and should be treated if present. CPAP can improve the nocturnal symptoms in patients with nocturnal asthma and OSAS.16 High dose proton pump inhibitors was shown to improve the PEFR in patients with concomitant nocturnal asthma and GERD, but not in nocturnal asthmatics without GERD or patients with GERD but no nocturnal asthma.17

Chronotherapy is based on the importance of biologic rhythms in the pathophysiology of medical conditions and uses the timing of medications to provide maximal efficacy and minimal toxicity.18 The principle is important in managing patients with nocturnal asthma.

Corticosteroids have been shown to effectively reduce large circadian fluctuations in lung function of asthmatics. Beam et al. showed that a single dose of prednisolone 50mg at 3pm decreased the reduction of overnight percentage of FEV1. There was improvement in 4am FEV1, but the effect was not seen when prednisolone was given at 8am or 8pm. Following the 3pm prednisone dose, blood eosinophil counts were significantly reduced at both 8pm and 4am. Also, the 3pm dosing resulted in a pan-cellular reduction in bronchoalveolar lavage cytology.19 For inhaled corticosteroids, single daily administration of inhaled triamcinolone at 3pm had been shown to produce similar improvement in efficacy variables to QID administration without increased side effects.20

Once-daily evening dose of controlled-release theophylline preparation achieves peak blood concentrations at 10-12 hours after dosage. An evening dose of theophylline chronotherapy has been prophylactically used for nocturnal asthma attacks.21 Morning PEF was slightly but significantly higher with evening dose controlled-release theophylline (average dosage 650mg) than with controlled-release terbutaline (7.5mg) in nocturnal asthmatics. Feelings of dyspnoea on waking in the morning were also less pronounced with theophylline.22

According to a review study, long-acting beta-2 agonists are more effective than theophylline in improving morning and evening PEF, but are not significantly different in their effects on FEV1. Fewer adverse events occurred in participants using long-acting beta-2 agonists (salmeterol and formoterol) as compared to theophylline.23 In patients with nocturnal symptoms despite low to high doses of inhaled corticosteroids, the addition of salmeterol has been demonstrated to be superior to doubling the inhaled corticosteroid dose.24 Salmeterol can decrease both day-time and night-time short-acting beta-2 agonist requirement and reduce the number of nocturnal awakenings. However, it did not alter airway hyperresponsiveness or any bronchoscopic measure of inflammation,25and hence the need for LABA to be used in conjunction with corticosteroids. Leukotriene modifiers, such as Zileuton which is a 5-lipoxygenase inhibitor, is able to decrease the eosinophil percentages in both bronchoalveolar lavage fluid and blood at 4am.26 Montelukast administered at bedtime was shown to be effective in reducing peripheral blood eosinophil counts, nocturnal awakenings and asthma attacks.27

Nocturnal asthma is a common problem in our daily practice although its underlying mechanisms are complex. Chronotherapeutic principles should be considered in its management so as to maximize the therapeutic effects of medications.


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