Putting Nocturnal Asthma to Rest

Putting Nocturnal Asthma to Rest

Page 47

Nocturnal Asthma

Putting Nocturnal Asthma to Rest

By Nina C. Ramirez, MD, and Richard F. Lockey, MD

It’s barely dawn as the asthmatic child awakens in a tangle of blankets after another slumber disturbed by wheezing and coughing. The significant nocturnal bronchoconstriction he is experiencing most likely represents inadequate control of his disease.

Nocturnal asthma is characterized by nighttime worsening of symptoms, which usually occur between 3 a.m. to 5 a.m. and manifest as wheezing, chest tightness, dyspnea, cough and increased early morning arousal. While it’s common in pediatrics, literature of the disorder in this population is limited. In addition, not all subjects or their parents report symptoms.¹

Therefore, physicians must be precise in identifying the large group of subjects experiencing nocturnal symptoms to provide the best comprehensive care possible.

Forty-seven percent of 796 asthmatic children in one study reported nocturnal or early morning shortness of breath, and 6 percent reported symptoms every night. Cough was the most frequently reported symptom, and the majority of these children had FEV₁ values >=90 percent predicted, indicating that daytime values of pulmonary function did not accurately predict nocturnal bronchospasm.¹

Another study of an outpatient population with asthma in the United Kingdom revealed that 39 percent of adults and children awoke every night, 64 percent awoke at least three nights per week, and 74 percent awoke at least one night per week due to symptoms related to their disease.²

This reduced sleep quality puts asthmatic children at risk for daytime sleepiness and fatigue. They could experience impaired neuropsychological functioning and academic performance. Evidence sug-gests improvement in behavior, cognitive function and mood occurs once pulmonary function is stable in asthma subjects.³

Already a marker for more severe disease, nocturnal asthma also is associated with increased mortality. A greater proportion of asthmatics die at night between midnight and 8 a.m. compared to the general population without asthma.

Pathogenesis
Clinicians can gain a better understanding of nocturnal asthma’s mechanisms through chronobiology, the study of the biologic rhythm of the physiologic and pathologic processes.

Circadian regulation affects the sleep-wake cycle, body temperature and circulating hormones (epinephrine and histamine) that may contribute to increased bronchial hyperactivity observed in asthmatics at night.⁴ Circadian variability in airway dimension with mild nocturnal bronchoconstriction occurs in healthy humans, yet the amplitude of the changes in pulmonary function in poorly controlled asthmatics is far greater.

Evidence suggests there may be differences in the pathogenesis of nocturnal asthma in adults vs. children.^5,6 Pediatric nocturnal airway obstruction symptoms include a blunted catecholamine response when challenged with allergen inhalation and exercise during the day. Reduction in levels or response to catecholamines may enhance the release of mast cell mediators and bronchial inflammation.⁶

The lowest values in healthy and asthmatic adults and children for urinary catecholamines have been observed at night, a time when histamine levels increase as well. Urinary levels of histamine degradation products were greater in children.

Urinary excretion of 17-hydroxycorticosteroid reaches its nadir between 10 p.m. to 1 a.m. Diminished suppression of airway inflammation a few hours later, because of this decrease in levels of glucocortico-steroids, provides another risk factor for nocturnal asthma. Lower endogenous levels of cortisol have been found in adult subjects with asthma. However, exogenously administered intravenous corticosteroids do not abolish the early morning airway narrowing. For this reason, it seems unlikely that circadian changes in circulating cortisol levels are important in the pathogenesis of nocturnal bronchial obstruction. The exact role in children remains unknown.⁶

Another symptom, increased vagal activity, occurs in COPD and asthmatic adults during the night. Intravenous atropine, a muscarinic antagonist, can reverse the resulting bronchoconstriction and airway obstruction. However, increased vagal activity has not been observed in asthmatic children, which may explain why inhaled anticholinergic medications do not entirely block this response.⁶

In addition, a genetic predisposition to nocturnal asthma may exist. Dysfunction of the beta₂-adrenoceptor and decreased beta₂-adrenoceptor activity during the night occurs in adults. Down-regulation of the receptor appears related to polymorphism in the coding region of the beta₂-receptor gene and previous therapy with beta₂-agonists.⁷

Airway Inflammation
In terms of airway inflammation in asthmatics, bronchoalveolar lavage fluid contains significantly more eosinophils and neutrophils at 4 a.m. compared to subjects without nocturnal asthma. Transbronchial biopsies reveal the presence of peripheral airway inflammation extending into alveolar tissue.

In asthmatics with a nocturnal fall in FEV₁, higher numbers of eosinophils are present at night than during the day, but not in those without this phenomenon.⁸ Cytokines in bronchoalveolar fluid also demonstrate a circadian variability because a higher concentration of the pro-inflammatory cytokine, IL-1B, occurs in subjects with nocturnal asthma, especially around 4 a.m.⁴ To date, studies such as this have not been conducted in children.

Another determining factor is serum IgE, which is fivefold higher in asthmatics compared with non-allergic controls. Circulating IgE levels are highest around midday and fall during the night, just opposite to that observed with the hormonal changes described previously.

Serum histamine levels vary throughout the day, with peak levels at 4 a.m. (when nocturnal asthma occurs), suggesting mast cell activation is enhanced at night.⁹ Urinary leukotriene excretion of leukotriene E4 (LTE-4) is increased at night in nocturnal asthma sufferers as well, implying enhanced mast cell and inflammatory cell activation.¹⁰

Other Factors
Other contributing factors include indoor allergens, such as dust mites and pet dander, and secondhand tobacco smoke. Avoiding these allergens reduces circadian changes in peak flow rates and asthma’s frequency and severity. However, avoidance of indoor allergens does not completely abolish nocturnal airway narrowing.^4,5

Sleeping may be important in asthma’s pathogenesis too. Nocturnal asthmatics who are kept awake at night still experience nocturnal airway obstruction, as do subjects kept awake and maintained in the supine position for an entire 24 hours. However, there is little or no difference in the degree of airway narrowing among sleep stages.⁸

Gastroesophageal reflux disease (GERD) is common in subjects with asthma and often is implicated as a possible cause for nocturnal bronchospam. The exact role of circadian and sleep effects in reflux induced bronchoconstriction remains unclear. However, asthmatics with GERD should be treated appropriately, because GERD itself can exacerbate asthma.

Asthma Management
Treating asthma exacerbations is crucial in achieving sleep free of asthma. Avoiding offending environmental allergens, and recognizing and treating co-morbid diseases, such as allergic rhinitis, sinusitis and GERD, are necessary to ensure a successful outcome.

Some treatment medication options include:

Slow release beta-agonists: when administered orally, they can maintain bronchodilation for 10 to 12 hours and modify circadian variability in pulmonary function. However, tachycardia and hyperactivity are common side effects, especially in children. This makes the use of long acting inhaled beta₂-agonists a more attractive treatment because they are equally efficacious and have fewer side effects.

Salmeterol: a 12-hour inhalation beta₂-agonist, it provides good overnight protection. The dry powder formulation currently available is approved for use in children ages 4 and older. The dry powder and aerosol are used currently in children for long-term bronchodilation and nocturnal asthma control. However, they may down-regulate the beta₂-receptor, so more studies are necessary to determine whether the long-term use of beta₂-agonists could exacerbate nocturnal asthma.⁴

Corticosteroids: they are the cornerstone of asthma anti-inflammatory therapy. Oral administration at 8 a.m. and 3 p.m. is effective treatment for nocturnal asthma. However, oral corticosteroids are associated with suppression of the hypothalamic-pituitary adrenal axis, growth suppression and long-term side effects.

Inhaled corticosteroids, when appropriate, are safe and effective in reducing nighttime symptoms. When used at the recommended dosage, they’re not known to be associated with significant side effects.¹¹

Spacer devices enhance deposition of the aerosol while decreasing local side effects, such as thrush and dysphonia. For the very young child or those experiencing technical difficulty with a metered dose inhaler and spacer, the corticosteroid solution, budesonide, may be administered by wet nebulization.

Leukotriene antagonists: these are potent pro-inflammatory mediators involved in asthma’s pathogenesis. Urinary leukotriene excretion of LTE4, a marker of leukotriene production, is elevated in adults with nocturnal asthma.¹⁰ Leukotriene antagonists modify variability in pulmonary function in nocturnal asthma and appear promising in treating adult asthmatics with nighttime obstruction.¹² Its steroid sparing effect makes use in pediatrics attractive, yet further studies are needed to clarify its role in this group.

Theophylline: a bronchodilator with some anti-inflammatory effects, theophylline has been part of a physician-recommended asthma therapeutic regimen for more than 65 years. It attenuates the late asthmatic response, and sustained release theophylline preparations given in the evening around 6 p.m. to 7 p.m. decrease nocturnal symptoms.⁴

Theophylline use has declined sharply within the past two decades because of its narrow therapeutic window, need for monitoring serum levels, multiple drug interactions and detrimental effects on cognitive function and mood in some children.³

Yet a study of nocturnal asthma in pediatrics showed a sustained release theophylline product given once daily at bedtime reduced the nighttime variability in pulmonary function. And, there were fewer adverse effects on behavior and cognition associated with the lower daytime theophylline level.¹³

Nocturnal asthma, a manifestation of increasing severity of the disease, is common in asthmatic children. While many treatments exist, more research is needed to investigate the problem of nighttime asthma in the pediatric population.

References
1. Meijer GG, Postma DS, Wempe JB, Gerritsen J, Knol K, van Aalderen WMC. Frequency of nocturnal symptoms in asthmatic children attending a hospital out-patient clinic. Eur Respir J. 1995;
8:2076-80.

2. Turner-Warwick M. Epidemiology of nocturnal asthma. Am J Med. 1998;85:6-8.

3. Stores GS, Ellis AJ, Wiggs L, Crawford C, Thomson A. Sleep and psychological disturbance in nocturnal asthma. Arch Dis Child. 1998;78:413-9.

4. Martin RJ, Banks-Schlegel S. Chronobiology of asthma. Am J Respir Crit Care Med. 1998;158:1002-7.

5. Menardo JL. Assessing nocturnal asthma in children. Pediatric Pulmonol. 1995;S11:38-9.

6. Meijer GG, Landstra AM, Postma DS, van Aalderen WMC. The pathogenesis of nocturnal asthma in childhood. Clinical and Experimental Allergy. 1998;28:921-6.

7. Hall IP. B2 adrenoceptor polymorphisms: are they clinically important? Thorax. 1996;51:351-3.

8. Silkoff PE, Martin RJ. Pathophysiol-ogy of nocturnal asthma. Annals of Allergy, Asthma and Immunology. 1998;81:378-83.

9. Barnes P, Fitzgerasl G, Brown M, Dollery C. Nocturnal asthma and changes in circulating epinephrine, histamine and cortisol. New Engl J of Med. 1980;303:263-7.

10. Bellia V, Bonanno A, Cibella F, Cuttitta G, Mirabella A, Profita M, et al. Urinary leukotriene E4 in the assessment of nocturnal asthma. J Allergy Clin Immunol. 1996;97:735-41.

11. Pincus DJ, Szefler SJ, Ackerson LM, Martin RJ. Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol. 1995;95:1172-8.

12. Wenzel SE, Trudeau JB, Kaminsky DA, Cohn J, Martin RJ, Westcott JY. Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma. Am J Respir Crit Care Med. 1995;152:897-905.

13. Bierman CW, Pierson WE, Shapiro GG, Furikawa CT. Is a uniform round-the-clock theophylline blood level necessary for optimal therapy in adolescent patient? Am J Med. 1988;85(suppl 1B):17-20.

Dr. Ramirez is an advanced subspecialty resident in allergy and immunology, in the allergy and immunology division of the University of South Florida College of Medicine and James A. Haley Veterans’ Hospital, Tampa, Fla. Dr. Lockey is professor of medicine in pediatrics and public health, director of allergy and immunology, and Joy McCann Culverhouse professor of allergy and immunology at the same facilities.

Table: Management Strategies for Childhood Nocturnal Asthma

1. Minimize exposure to indoor allergens
• Education about allergen avoidance
2. Avoidance of indoor tobacco smoke
3. Identification and treatment of co-morbid diseases:
• Allergic rhinitis
• Sinusitis
• Gastroesophageal reflux
4. Treatment strategies:

Inhaled long-acting beta₂-agonists:

• Salmeterol MDI (spacer if necessary)
• Salmeterol dry powder diskus

Inhaled corticosteroids:

• MDI (spacer if necessary)
• Budesonide solution via wet nebulization

Sustained release oral beta₂-agonists

• Albuterol sulfate extended tablets

Leukotriene antagonists and 5-lipoxygenase inhibitors:

• Montelukast (approved for ages 2 and older)
• Zafirlukast (not approved for ages under 12 years)
• Zileuton (not approved for ages under 12 years)
• Sustained release theophylline preparations

table/courtesy Nina C. Ramirez, MD, and Richard F. Lockey, MD