Childhood asthma is one of the most common problems managed by pediatricians. The diagnosis is usually straightforward and the management is often standard. However, there are a number of pitfalls that can complicate the management of childhood asthma. Allergies, sinusitis, and gastroesophageal reflux may confuse the diagnosis or cause additional difficulties with the treatment of asthma. Finally, while the medications for asthma continue to improve, adherence to treatment regimens remains poor. The goals of proper management of this disease remain to avoid hospitalizations, emergency department visits, and school absences, to ensure normal activities, and to avoid long-term lung damage due to airway remodeling. A classification system based on National Institutes of Health (NIH) guidelines,1 the history, and physical examination, as well as pulmonary function tests, can be very helpful in the management of the child's asthma.
Here we discuss the practical aspects of asthma management in school-aged children using the NIH guidelines. These guidelines divide childhood asthma into four categories:
Mild intermittent asthma. Children with mild intermittent asthma have normal pulmonary function tests, have never been hospitalized for wheezing, do not have emergent visits for acute wheezing, and do not miss school. These children with only mild symptoms, such as wheezing fewer than two times per week, may be treated with an inhaled ßagonist as needed for symptoms.
Mild persistent asthma. These children have symptoms more than twice per week but less than once per day. Acute exacerbations may affect activity and cause absences from school. There may be a history of occasional emergency department visits or even one or two hospitalizations. Nocturnal symptoms occur twice per month or more. Pulmonary function tests are normal but may decrease 20% to 30% from baseline with symptoms. Patients in this category may use an inhaled ß-agonist as needed for symptoms but also require a long-term maintenance medication. This may be either low-dose inhaled steroids (Table 1, page 21), an oral leukotriene antagonist, or inhaled cromolyn or nedocromil on a daily basis.
Moderate persistent asthma. These
children tend to have daily symptoms and require daily ß-agonist use. Occasional emergency care of their asthma may be required. Their exacerbations can last for several days or more. They miss considerable amounts of school, and asthma affects their activities. Nocturnal asthma symptoms occur more than once per week, and almost daily symptoms of coughing/wheezing occur. For these children, moderate doses of inhaled steroids are appropriate (see Table 2 for dosing equivalencies, page 24). If low-dose inhaled steroids are preferred, salmeterol or formoterol can be used to gain adequate control of asthma symptoms.
Another possibility for add-on therapy is montelukast at a dose of 5 mg/d through age 14. Advantages to the use of montelukast include an excellent safety profile and a high degree of patient adherence. Its taste and once daily dosing enhance adherence to montelukast. The NIH guidelines also list theophylline as a potential add-on therapy to low-dose inhaled steroids in the child with moderate persistent asthma. Consultation with an asthma specialist is recommended for children with moderate persistent asthma.
Severe persistent asthma. These children have almost continuous symptoms. Their activity is often severely limited. Hospitalizations are frequent and they may have a history of admission to the pediatric intensive care unit for severe exacerbations. They have frequent nocturnal symptoms. Children with severe asthma should be treated with high-dose inhaled steroids (Table 2). In addition, long-acting ß-agonists should be used for add-on therapy. They could be expected to need oral steroid bursts for asthma exacerbations. A small percentage of these children may require maintenance oral steroid therapy. Children falling into this classification are best managed with the partnership of an asthma specialist.
Regardless of the severity of the asthma and the initial choice of medication, if control is not achieved, therapy should be stepped up. For instance, if symptoms do not abate in the child with combination lowdose inhaled steroid and a long-acting ß-agonist therapy, the steroid dose should be increased into the moderate range. Once control of asthma symptoms has been achieved, treatment should be reviewed in 1 to 6 months to determine if a reduction in asthma therapy can be made.
ADVERSE EFFECTS OF CURRENT ASTHMA THERAPIES
While inhaled steroids remain the single most important therapy for the control of the inflammation of asthma, their use remains hindered by poor compliance. Many parents and physicians are concerned about the side effects of inhaled corticosteroids; in reality, these drugs are relatively free of significant side effects. Dysphoria, oral candidiasis, cough, and throat irritation constitute the majority of patient complaints. These local side effects are less common in children because of the increased use of spacers in this population. Potential concerns include long-term effects of inhaled steroids on adrenal and immune function, growth, and the development of cataracts.
Studies of the effects of inhaled steroids on the hypothalamic-pituitary-adrenal axis in children have shown that inhaled flunisolide and triamcinolone at doses up to 1000 ug/d and beclomethasone at doses up to 800 µg/d had no effect on urinary Cortisol excretion.2-3 The effect of inhaled steroids on growth in children has been a major concern since these medications became available. Studies on the effects of inhaled steroids on growth are complicated by the fact that many of the patients are receiving oral corticosteroids to relieve asthmatic exacerbations. A number of long-term longitudinal studies have shown no effect on growth with doses of beclomethasone up to 800 pg/d.4 The recent Childhood Asthma Management Program study5 compared inhaled budesonide, nedocromil, or placebo for 4 to 6 years in children 5 through 12 years of age with mild-to-moderate asthma. This study found that inhaled budesonide improved airway responsiveness and provided better control of asthma than placebo or nedocromil and that there was a small but transient reduction in growth velocity. There is little question that linear growth can be affected initially by inhaled steroids; however, there is no evidence that children who take inhaled steroids do not reach normal adult heights eventually. In addtion, it must be kept in mind that inadequately controlled asthma per se also affects stature.
Outpatient Asthma Treatment in Children +
The development of posterior subcapsular cataracts is strongly associated with long-term oral corticosteroid therapy. However, in a study of 95 children taking inhaled steroids, none had cataracts, including those receiving 2000 ug/d of beclomethasone for more than 10 years. This indicates that cataracts are no more than a rare complication of inhaled steroid use.6 In addition, no evidence exists that inhaled steroids affect the frequency or the course of viral or bacterial respiratory infections.7
Inhaled short-acting β-agonists provide rapid relief from asthma symptoms. The usual side effects of β-agonists include tremors, arrhythmias, central nervous system effects such as nervousness, and metabolic effects such as hypokalemia. As β-agonists have become more specific for the β2-receptor, these side effects have become much less common and are usually inconsequential. In addition, the inhaled form of these drugs has replaced the oral formulation. For these reasons, β-agonists are usually considered relatively benign medications. However, studies have shown an association among increased risk of death or near death, regular daily β-agonist use, and increased bronchial hyperreactivity.8 Because of these concerns, as well as the effect on increasing bronchial hyperreactivity, these medications are now used primarily on an "as needed" basis. Further, if as needed β-agonist use occurs more frequently than 2 to 3 times weekly, a drug that provides long-term control of the underlying inflammatory processes should then be prescribed.9
Complicating this issue is the development of the long-acting (12-hour) βagonists salmeterol and fomoterol. Shortly after its release, sudden severe asthma attacks, or deaths, associated with salmeterol were reported. There is no evidence that salmeterol itself leads to asthma exacerbation and subsequent death; however, monotherapy with salmeterol does lead to increased bronchial hypersensitivity. This medication should always be used for long-term control of asthma as an adjunct to inhaled corticosteroids. Specifically, if the child becomes asymptomatic after the addition of a long-acting β-agonist, the inhaled steroid should not be discontinued.10 Because of its slow onset of action, salmeterol should not be used to provide rapid relief from an acute asthma episode.
Theophylline is an older medication that until recently was a popular therapy for childhood asthma. Its use has decreased considerably in the United States primarily because of the availability of newer antiasthma drugs and concerns about toxicity. Theophylline has potential side effects ranging from mild nausea, insomnia, and nervousness to life-threatening cardiac arrhythmias and encephalopathic seizures. Most serious side effects occur when the serum concentration of theophylline exceeds 20 mg/dL. Factors such as diet, fever, viral infections, and drug interactions may affect the metabolism of this medication. Drugs that interact with theophylline include certain antibiotics such as ciprofloxacin, clarithromycin, and erythromycin as well as Cimetidine, verapamil, propranolol, and thiabendazole. Routinely monitoring serum drug levels is mandatory because reliance on symptoms is not predictive of elevated levels."
Leukotriene antagonists have been used primarily in children for the treatment of mild and moderate asthma,12 and for patients with asthma not completely controlled with moderate doses of inhaled corticosteroids. Experience with these medications in school-aged children suggests that they are tolerated extremely well with very few side effects. In adults, leukotriene antagonists have been associated with the development of Churg-Strauss syndrome, a rare form of vasculitic angiitis. This disorder has been exceedingly rare in school-aged children. So far, there is little if any evidence that Churg-Strauss syndrome in astiimatic patients is due to a direct drug effect.13 It appears that tapering of oral corticosteroids in these patients unmasks the disease.
Allergic Rhinitis and Asthma
Allergic rhinitis is a contributing factor in the development and persistence of asthma. Both are manifestations of the same pathophysiology.14 Asthma and allergic rhinitis frequently coexist, with rhinitis symptoms reported among 19% to 94% of asthma patients, and asthma reported among 19% to 38% of those with allergic rhinitis.15 Allergic rhinitis often precedes asthma and has been shown to be a risk factor for the development of asthma. Nasal challenge with very low doses of allergen has been shown to increase pulmonary eosinophils.16
Treatment of concomitant allergic rhinitis also leads to improvement in asthma. Treatment of allergic rhinitis with intranasal steroids appears to decrease emergency department visits for asthma.17 Intranasal corticosteroids also have been shown to affect bronchial hyperresponsiveness in patients with seasonal allergic rhinitis.18,19 We recommend the aggressive treatment of allergic rhinitis in patients with asthma. Treatment with intranasal steroids and long-acting non-sedating antihistamines is required along with avoidance of exposure to allergic triggers. Antihistamines are not contraindicated in asthma. Those patients who do not respond to avoidance measures and medical management may benefit from allergy desensitization therapy.
Dosages of Inhaled Steroids
Avoidance of Viral Infections
Rhinovirus infection is responsible for most asthma exacerbations in children, but respiratory syncytial virus and influenza virus may also be triggers. To date, influenza is the only preventable viral infection. Annual influenza vaccinations are recommended for patients who have persistent asthma, especially in patients younger than age 10.
The child with moderate to severe asthma may have sinusitis as an etiologic trigger. Upper respiratory infections that last longer man the expected length of most viral illnesses (2 weeks) and exacerbate asthma should prompt an investigation for sinusitis. It should be noted that routine use of antibiotics in the child with acute asthma is not indicated, particularly for symptoms that last less than two weeks. A plain film (Water's view) or limited screening sinus computed tomography may assist in the evaluation. It should be remembered that acute sinusitis usually requires a minimum of 2 weeks of antibiotics for complete resolution. If nasal symptoms last longer than 4 to 6 weeks, therapy for chronic sinusitis should be initiated. Antibiotic therapy should be given approximately 3 to 4 weeks for chronic sinusitis. Add-on therapy of a topical nasal steroid has been shown to assist in a more rapid resolution of sinusitis.
Gastroesophageal reflux (GER) is also a profound trigger for asthma in children.20 Symptoms such as heartburn, abdominal pain, belching, and sour taste in the mouth may be clues to GER as an etiologic trigger of unstable asthma. However, a significant number of asthmatic children with unstable disease have silent GER. A pH probe is helpful in establishing GER as a possible asthma trigger.
EXERCISE AND ASTHMA
In determining the patient's asthma classification, the NIH guidelines do not distinguish between exercise and other triggers for asthma. Merely, the frequency of symptoms is the guide to therapy. Therefore, the track athlete wiüi daily symptoms from running would be classified as having moderate persistent asthma and an appropriate strategy would be to utilize a low-dose inhaled steroid with add-on therapy as discussed above. However, some athletic children still persist with exercise-induced symptoms despite maintenance therapy. The strategy for these children then becomes similar to that employed for children with only intermittent exercise-induced symptoms (ie, gym class once a week). Initial therapy usually consists of albuterol taken 1 5 minutes prior to exercise. This will provide adequate protection for the child to enjoy about one hour of exercise. In children whose exercise lasts longer than 1 hour, a longacting ß-agonist may be utilized. These medications provide approximately 6 hours of protected time against exerciseinduced symptoms. Salmeterol is dosed one hour prior to exercise and formoterol is dosed 15 minutes prior to exercise. For those children who are still inadequately protected from exerciseinduced symptoms, cromolyn at 2 to 4 puffs immediately prior to exercise can be added to the pre-exercise routine. Having me child do a mild warm-up routine immediately prior to the planned exercise will also improve exerciseinduced symptoms.
Physician/Patient/Family Partnership for Compliance
Recent data about the lack of compliance with asthma medications are alarming.21,22 Reasons for nonadherence range from improper use of delivery devices, inconvenient or frequent dosing regimens, the lag time required for medications to suppress inflammation, length of time for the reappearance of symptoms following discontinuation of the medication, and, perhaps most important, fear of side effects. All of these reasons seem to point to the need for greater patient education to overcome noncompliance.
When treating school-aged children and adolescents, educating patients about their disease is of paramount importance. The physician's goal should be to establish a partnership with the patient and the family beginning at the time of diagnosis. Patients and family should be given written information about asthma, along with an individualized daily treatment plan, that will allow them to understand the rationale for various therapies and pulmonary function monitoring. Patients and family members should be instrumental in developing the treatment goals and determining if they are being met. During subsequent appointments, the physician should encourage the patient and family to express concerns and ask questions about managing asthma.
Understanding the role of inflammation in childhood asthma has led to major changes in the approach to management of this disease. Based on the guidelines from the NIH, inhaled longterm control medications that target the underlying inflammatory processes in asthma are now recommended as the mainstay of drug treatment. Long-term control medications are recommended for all children who have asthma symptoms that occur more frequently than twice weekly or nocturnal symptoms more than twice monthly. Environmental control measures to decrease allergen exposure are important, as is attention to sinusitis and GER.
The main impediment to improved asthma care is poor patient compliance. Many patients do not understand the role and importance of prophylactic medications in asthma treatment. Further, inconvenient dosing regimens, difficulties with metered-dose inhalers, and fear of potential side effects have all contributed to poor patient compliance. Increased efforts at patient education are needed to improve adherence to asthma plans. These efforts at improving patient compliance, along with improved physician adherence to the guidelines from the NIH, are needed to decrease the morbidity and mortality of childhood asthma.
1. National Heart, Lung and Blood Institute, National Asthma Education Program, Expert Panel Report II. Guidelines for the Diagnosis and Management of Asthma. Update on Selected Topics 2002. Bethesda, MD: National Institutes of Health; 2002. NlH Publication 02-5075.
2. Sly RM, Imseis M, Frazer M, Joseph F. Treatment of asthma in children with triamcinolone acetonide aerosol. J Allergy Clin Immunol. 1976;62:76-82.
3. Bisgaard H, Damkjaer Nielsen M, Andersen B, et al. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide. J Allergy Clin Immunol. 1988;81:1088-1095.
4. Sodenberg-Warner M, Siegel S, Katz R, Rachefsky G. Treatment of chronic childhood asthma with beclomethasone dipropionate aerosols (BDA) IV. Longterm effects on growth. J Allergy Clin Immunol. 1979;63:164.
5. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl ] Med. 2000;343(15):1054-1063.
6. Simons FER, Persaud MP, Gillespie CA, Cheang M, Shuckett EP. Absence of posterior subcapsular cataracts in young patients treated with inhaled glucocorticosteroids. Lancet. 1993;342:776-778.
7. Hanania NA, Chapman KR, Kesten S. Adverse effects of inhaled corticosteroids. Am J Med. 1995;98:196-208.
8. Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med. 1992;326:501-559.
9. Furukawa CT, Kemp JP, Simons FE, Tinkelman DG. The proper role of beta 2adrenergic agonists in the treatment of children with asthma. Pediatrics. 1992;90:639-640.
10. American Academy of Allergy, Asthma, and Immunology, Committee on Drugs. Position statement: safety and appropriate use of salmeterol in the treatment of asthma. J Allergy Clin Immunol. 1996;98:475-480.
11. Melamed J, Beaucher WN. Minor symptoms are not predictive of elevated theophylline levels in adults on chronic therapy. Ann Allergy Asthma Immunol. 1995;75:516-520.
12. Knorr B, Matz J, Bernstein JA, et al. Montelukast for chronic asthma in 6- to 14year-old children: a randomized, doubleblind trial. Pediatric Montelukast Study Group. JAMA. 1998;279:1181-1186.
13. Jamaleddine G, Diab K, Tabbarah Z, Tawil A, Arayssi T. Leukotriene antagonists and the Churg-Strauss syndrome. Semin Arthritis Rheum. 2002;314:218-227.
14. Linneberg A, Henrik Nielsen N, Frolund L, Madsen F, Dirksen A, Jorgensen T. The link between allergic rhinitis and allergic asthma: a prospective population-based study. The Copenhagen Allergy Study. Allergy. 2002;57:1048-1052.
15. Vinuya RZ. Upper airway disorders and asthma: a syndrome of airway inflammation. Ann Allergy Asthma Immunol. 2002;88(Suppl 1):8-15.
16. Boulay ME, Boulet LP. Lower airway inflammatory responses to repeated very-low-dose allergen challenge in allergic rhinitis and asthma. Clin Exp Allergy. 2002;32:1441-1447.
17. Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST. Intranasal steroids and the risk of emergency department visits for asthma. J Allergy CHn Immunol. 2002;109:636-642.
18. Foresi A, Pelucchi, Gherson G, et al. Once daily intranasal fluticasone propionate (200 ^g) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis. J Allergy Clin Immunol. 1996;98:274-282.
19. Corren J, Adinof AD, Buchmeier AD, et al. Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma. J Allergy Clin Immunol. 1992;90:250-256.
20. Patterson PE, Harding SM. Gastroesophageal reflux disorders and asthma. Curr Opin PuIm Med. 1999;5:63-67.
21. Zora JA, Lutz CN, Tinkelman DG. Assessment of compliance in children using inhaled beta-adrenergic agonists. Ann Allergy. 1989;62:406-409.
22. Bender BG. Overcoming barriers to nonadherence in asthma treatment. J Allergy Clin Immunol. 2002;109(Suppl):S554-S559.
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Dosages of Inhaled Steroids