Asthma is a significant cause of morbidity and mortality in the pediatric population. It is estimated that 4% to 8% of all individuals have asthma of varying severity, and the incidence and severity of asthma seem to be increasing. This has resulted in publications sponsored by the National Heart, Lung, and Blood Institute (NHLBI): Guidelines for the Diagnosis and Management of Asthma} and the International Consensus Report on the Diagnosis and Treatment of Asthma.2 It is very disturbing that despite a better understanding of the pathophysiology of asthma and better asthma medications, there is still significant morbidity and mortality from asthma.
Thus, there have been increased efforts to better understand asthma and the most effective ways to implement asthma therapy. One of the most important aspects of treating asthma is having a comprehensive treatment plan. Prescribing the most appropriate medications for asthma will do very little good if the patient uses them incorrectly or does not take them at all. Thus, a well-developed comprehensive treatment plan is essential for the long-term management of asthma. A logical approach to this may be facilitated by answering a series of questions:
Is asthma an inflammatory disease, and what relationship does inflammation have on the airways?
Inflammation plays a very important role in the pathophysiology of asthma. Airways from patients with fatal asthma have inflammatory changes with edema, mucus plugging, and infiltration of the airway wall by eosinophils, plasma cells, and lymphocytes. Eosinophils contain a number of proteins in their granules that are capable of damaging the airway epithelium. This damage can expose sensory-nerve endings allowing activation of neurogenic inflammatory pathways resulting in the release of potent spasmogens into the tissues, increased vascular permeability, and increased mucus production. Thus, inflammation plays a major role in the development and severity of asthma, and the management of inflammation (either by prevention or treatment) plays a fundamental role in asthma management.
Figure. Asthma pathophysiology and approach to treatment.
How does inflammation develop in asthma» and how can the development of inflammation be minimized?
A combination of genetic and environmental factors lead to the development of asthma. As illustrated in the Figure, certain people are born with a genetic predisposition for asthma. Without environmental exposure, these individuals may not develop asthma. If, however, they have certain environmental exposures, they will develop inflammation. The inflammation causes the airways to be unstable or "twitchy." This is called increased bronchial responsiveness or airway hyperresponsiveness, which means that an asthmatics airways will constrict when exposed to nonspecific stimuli, such as cold air, smoke, or exercise. This responsiveness can be quantitated by challenge with exercise, cold air, methacholine, or histamine.3 As an asthmatics airways become more hyperresponsive, the asthma becomes unstable. This model of the development of asthma gives a framework from which to develop an overall asthma treatment plan.
What are the essential components of asthma therapy?
Using the model in the Figure, asthma therapy may be divided into four broad categories, as outlined in the NHLBI Guidelines.1 The four essential components of an asthma therapy plan must include the following:
* environmental control,
* objective measurements, and
* patient education.
As is seen in the Figure, all of these modalities of therapy interact with each other and complement each other.
What is the best way of approaching environmental control in asthmatics?
First, have all members of the family stop smoking in the home or car. Tobacco smoke is the dominant source of particulate matter in the air of homes of 65% to 70% of children.
Next, consider eliminating the most common allergens: dust mites, cats and dogs, fungi, and cockroaches. Dust mites are common in the bedroom. Mattresses and pillows should be encased in plastic. All bedclothes should be washed in 1300F water every 10 days. If possible, carpets should be removed. If not, then they should be vacuumed after treatment with benzyl benzoate powder, which can reduce mite levels by 80%. Fungi are a potential problem in any damp area. Humidity should be controlled and any material that fosters fungal growth removed. Showers should be cleaned with chlorine-containing solution. Washing the cat weekly will decrease levels of cat allergen in the home and has been shown to be effective. Parents should be advised to give the cat away or at least to not replace it if it dies or runs away. Frequent baths might cause the latter. The same advice should be given regarding dogs.
There are still many unanswered questions regarding environmental control. For instance, air filters may be effective in filtering the air, but there is scant data as to the actual impact air filters have on asthma control.
What is the optimal approach to asthma medications?
Asthma medications may be broadly divided into two categories: anti- inflammatory agents and bronchodilators (Table 1). The choice of medicatton(s) and schedule of therapy largely depends on the severity of asthma (Table 2) and the individual patient. Mild asthmatic children often may be easily treated with intermittent inhaled ß2 -adrenergic agents. If, however, the child's asthma is moderately severe, or an intermittent ß2'aa,fenergic agent does not control symptoms, an anti-inflammatory agent should be administered on a regular basis and a bronchodilator used intermittently (optimal) or routinely to control symptoms. Treating bronchospasm alone in these children will affect the symptoms of the disease but not the disease itself, and there are significant concerns that the routine administration of an inhaled bronchodilator may actually make a patients asthma worse.4
What anti-inflammatory medications are available in the United States and which should be used first in childhood asthma?
The anti-inflammatory agents currently available in the United States include cromolyn sodium (inhaled), nedocromil (inhaled), and corticosteroids (either oral or inhaled).
Cromolyn Sodium. Both the national1 and international2 guidelines for the treatment of asthma recommend the use of cromolyn sodium as the first-line medication for moderate childhood asthma. Cromolyn sodium has been shown to decrease the number of eosinophils recovered with lavage from the lungs of asthmatic patients,5 decrease bronchial hyperresponsiveness,6 and control symptoms of cough, wheezing, and nighttime awakening. Cromolyn sodium has been shown to be as effective as theophylline and inhaled steroids in controlling childhood asthma and is considered one of the safest asthma medications available.7,8
Cromolyn sodium can be used acutely to block exercise-induced asthma or prior to a specific antigen exposure, seasonally to block the increase in airway reactivity that occurs during a pollen season, or chronically in moderate and severe childhood asthma. Cromolyn is available in three different forms in the United States: spinhaler (20 mg/cap), nebulizer solution (20 mg/vial), and metered dose inhaler (1 mg/puff). It is important to realize that the dose delivered to the lungs with these three devices is about 12% to 15% of the original dose, and this figure is highly variable depending on patient factors. Thus, if a patient isn't responding, one might want to increase the number of puffs from the metered dose inhaler or switch to a nebulizer solution.
Generally, a patient should be started initially on cromolyn four times a day. If a patient has airway obstruction, this may be combined with routine aerosolized albuterol. If the obstruction is severe, nebulized cromolyn plus albuterol may be started, and as the patient improves, treatment can be changed to a metered dose inhaler. After about one month of cromolyn therapy, patients can often have the dosing frequency decreased to three times a day, and about 75% of patients can go down to two times a day. During a cold or pollen season the frequency and dose of cromolyn may need to be increased (2 vials or spinhalers/ treatment), or inhaled steroids may need to be added.
Nedocromil. Nedocromil is a new nonsteroidal anti-inflammatory that may be more potent than cromolyn sodium. It has only recently been released for use in the United States and thus the experience with it is limited. The role it may play in the management of chronic asthma is not clear at this time.
What role do inhaled corticosteroids play in chronic asthma therapy in children?
Numerous studies have documented that the routine use of inhaled corticosteroids in childhood asthma is effective in improving asthma symptoms, spirometry, peak flow, and airway responsiveness.9
Inhaled steroids should be used in any asthmatic pediatric patient in which cromolyn fails to control the asthma symptoms. In the initial therapy in some patients, the addition of inhaled steroids to cromolyn can bring the airway inflammation under control faster. Inhaled steroids also have a dose-response effect. The more frequently they are used, the more effective they are. Initially, inhaled steroids can be used three to four times a day, and when the asthma is under control reduce use to twice a day, increasing the frequency if the asthma worsens.
In the United States, there are currently three inhaled steroids available: beclomethasone (Vanceril, Schering Corp, Kenilworth, New Jersey; and Beclovent, Allen & Hanburys, Research Triangle Park, North Carolina) 50 µg/pup:; triamcinolone (Azmacort, RhônePoulenc Rorer Pharmaceuticals Ine, Collegeville, Pennsylvania) 100 µg/pufï; and flunisolide (Aerobid, Forest Pharmaceuticals, St Louis, Missouri) 250 µg/puff. It is important to realize that these are different medications, to start with the lowest dose, increasing it as needed to control the asthma. The dose can be decreased once the asthma is under control. It is important to use inhaled steroids with a spacer device as this decreases the oral/pharyngeal deposition of the medication and can decrease the side effect of hoarseness, which occurs because of weakening of the muscles that adduct the vocal cords. A new inhaled corticosteroid, budenoside, is scheduled for release in the United States soon. It may give good asthma control with minimal side effects and may be administered twice daily.
There are other anti-inflammatory agents occasionally used in severe asthma (Table 1), but these are reserved for the most severe asthmatic patients who cannot be controlled on standard therapy.
What are the complications of inhaled corticosteroids in asthmatic children?
Although using corticosteroids by the inhaled route greatly decreases their systemic absorption, they are not without systemic effects. Most studies of the effects of inhaled corticosteroids on growing children are shortterm. Long-term studies are necessary to determine if the chronic use of inhaled corticosteroids will cause significant adverse effects in growing children. The major concerns in children include impaired growth, decreased bone formation, adrenal suppression, cataracts, vocal cord dysfunction, and purpura. Thus, although inhaled corticosteroids are probably safe to use in asthmatic children, it is prudent to minimize the dose of inhaled corticosteroids as much as possible.
There are several factors to be weighed in minimizing systemic corticosteroid effects. Inhaled corticosteroids have fewer adverse effects than systemic corticosteroids; they should be used liberally in patients requiring continual systemic corticosteroids to control asthma and to avoid the use of systemic corticosteroids. Children with mild to moderate disease should be given a trial of cromolyn (or nedocromil) and should be placed on inhaled steroids only if this is ineffective. Many times inhaled steroids are only needed seasonally. The lowest dose that eliminates asthma symptoms and produces normal peak flow variability (less than 15% between morning and evening peak flows) should be used. Inhaled steroids should always be delivered with a spacer device, and mouth rinsing after use should be encouraged to minimize hoarseness and candidiasis.
What role do ß2-agonists play in chronic asthma?
There is good evidence that inhaled ß2-agonists are the most effective bronchodilators, and their judicious use in acute asthma episodes is not questionable. There is, however, growing concern with the use of ß2agonists. Several reports have suggested that their use may be detrimental to asthma patients. Adverse reactions from overuse may include paradoxical bronchoconstriction, tachyphylaxis, increased airway reactivity, poorer control of symptoms, and the development of life-threatening episodes of asthma.4 Possible explanations for worsening of asthma as a result of chronic inhaled ß2-agonists include down-regulation of the ß2 receptors, other materials (oleic acid and Freon) in the inhalers that may make asthma worse, and by better symptom control, greater exposure to triggers that increase inflammation since ß2-agonists do nothing to treat inflammation.
This has led to the concern that we should not use ß2-agonists. This is probably not warranted, but we should consider recommending their use more on an as-needed basis rather than regularly. Because ß2agonists produce immediate relief of asthma symptoms, patients tend to use them more than anti- inflammatory agents.
We should encourage our patients to use their anti-inflammatory medications regularly, and use ß2agonists on an as-needed basis. If patients require ß2-agonists more frequently than 2 to 3 times a day, their anti-inflammatory medications should be increased.
What ß2-agonists should be used?
Currently, the most effective ß2-agonist agents available in the United States are terbutaline and albuterol. There is very little advantage in using other ß2-agonist agents. Two long-acting ß2-agonists, formoterol and salmeterol, have been used in other countries and may be released in the United States in the future. What role these medications will have on chronic asthma is still unknown. Although they seem to be very effective in treating symptoms and have longer durations of action than the currently available agents, there is concern that their widespread use will lead to decreased use of anti-inflammatory agents and worsening of asthma.
What is the current role of theophylline in the management of chronic asthma?
The national guidelines for the management of asthma1 recommend theophylline as an alternative therapy for moderate asthma. Theophylline has been shown to be an excellent bronchodilator, but its effect on reducing airway inflammation and decreasing bronchial reactivity have not been completely studied.
Theophylline is inexpensive and can be taken once or twice daily. It is, however, difficult to use in children under 5 and particularly so in infants. There have been conflicting reports of the adverse effects of theophylline on behavior and learning. A major disadvantage of theophylline is that it has a narrow therapeutic range. A number of factors can slow its metabolism and increase its serum concentrations. Recent recommendations are to aim for lower serum levels (5 to 15 µg/mL). Theophylline may be started at a low dosage (12 to 14 mg/kg/day) to a maximum of 300 mg/bid. If this is tolerated for 3 days, it can be increased to achieve clinical control of asthma with blood levels of 10 to 15 µg/mL. Blood levels should be obtained 4 to 6 hours after the fourth dose (this gives a peak level at a steady state) and then adjusted for clinical effect, with blood levels monitored at 3- to 12 -month intervals.
The American Academy of Pediatrics has recommended reducing the dose of theophylline by half in children with a fever that lasts longer than 24 hours and to avoid the concurrent administration of erythromycin, Cimetidine, and ciprofloxacin. The most commonly used preparations in children are: Slo-bid Gyrocaps (theophylline, Rhône-Poulenc Rorer Pharmaceuticals Ine, Collegeville, Pennsylvania) as sustainedrelease capsules and Theo-Dur (theophylline, Key Pharmaceuticals Ine, Kenilworth, Pennsylvania) as sustained-release tablets. Slo-bid Gyrocaps may be sprinkled on food for use in small children and can be given every 12 hours. Liquid preparations are not widely used and, although different preparations may have similar names, they vary widely in concentration and sugar and alcohol content.
What role do objective measurements play in the chronic management of asthma?
Just as physicians would not attempt to manage diabetes or hypertension without serially following objective measures (blood sugar and blood pressure), the management of asthma is incomplete without objective measures of lung function. Although some measures of lung function are more difficult to determine in children than in adults, with the proper methods they may be performed in virtually all patients 5 years of age and older. Objective measurements serve several functions. First, they give an objective determination of lung function that the physician can assess in the office. During acute exacerbations, objective measures at home allow families to assess the severity of airway obstruction. Also, using objective measures of lung function allows parents to determine specific triggers that precipitate episodes of asthma when the relationship between the trigger and the episode is not entirely clear. Lastly, objective measures of lung function allow patients to better understand their disease and thereby improve self-management and compliance.
What is the most effective objective measure with which to follow chronic asthma patients over time?
The most commonly used objective measures of lung function used in childhood asthma are spirometry and peak expiratory flow rate (PEFR) measurements. Spirometry is useful in the initial assessment of asthma and gives a good assessment of both large and small airway function. Periodic measurement of spirometry is useful in assessing overall lung function. Peak expiratory flow rate monitoring, although not as sensitive as spirometry, has more widespread applicability in chronic asthma management.
Monitoring PEFR at home is the best way to follow asthmatics. This monitoring should be linked with a written action plan. Objective measurements of airflow obstruction in asthma are useful because neither physicians nor patients can accurately assess early airway obstruction by subjective assessment of physical signs such as dyspnea and wheezing.10 Monitoring PEFR can be used in several ways:
* to assess the severity of an asthma episode,
* to assess the degree of diurnal variation in lung function, which correlates with the degree of airway hyperresponsiveness,
* to monitor response to therapy during an acute exacerbation,
* to detect asymptomatic deterioration of lung function in the home and office and to enable intervention before it becomes more serious,
* to monitor response to long-term therapy and provide objective justification for continued therapy, and
* to identify triggers such as exercise and exposure to cold air.
Monitoring PEFR should be performed in patients who are 4 to 5 years and older and who are taking daily medications.
Peak expiratory flow rate is measured by having the patient take a deep breath and blow out a short maximal blast of air. Ideally, PEFR should be measured twice daily, immediately upon arising and 10 to 12 hours later before and after using a bronchodilator. The day-to-day variability of PEFR provides an index of asthma stability and shouldn't vary more than 20% between A.M. and P.M.
To help patients understand and use PEFR, a system of zones has been established linked to traffic lights: green zone (80% to 100% of predicted or personal best) means everything is fine - no changes are necessary; yellow zone (50% to 80% of predicted or personal best) means that the asthma is worsening and that action is needed; red zone (<50% predicted or personal best) means danger and that immediate action is needed.
Since the clinic time is limited, is patient education that necessary?
Asthma is a chronic disease and much education (coaching) is needed to assure compliance with medications. An effective education program for asthmatic patients and their families is essential for adequate management.
The following are some suggestions for patient education:
* Prescribe anti-inflammatory therapy in moderate and severe asthmatic patients.
* Write a crisis plan for acute exacerbations.
* Check aerosol use technique regularly.
* Monitor PEFR at home.
* Give ongoing parent and patient education.
Other useful guidelines to assist in the development of a plan for patient education are listed in the Appendix and in additional references.11'13
In conclusion, most asthmatic children can be successfully managed through a comprehensive management plan that includes an understanding of the diseases pathophysiology, the effective use of the available medications, institution of reasonable environmental controls, objective measurement of lung function, and patient and parent education.
1. National Heart, Lung, and Blood Institute National Asthma Education Program, Expert Panel Report. Guidelines for the Diagnosis and Management of Asthma. Washington, DC: US Government Printing Office; 1991. US Dept of Health and Human Services publication 91:3042.
2. National Heart, Lung, and Blood Institute, National Institutes of Health. InternaDonai Consensus Report on tne Diagnosis and Treatment of Asthma. Washington, DC: US Government Printing Office: 1992. US Dept of Health and Human Services publication 92:3091.
3. Ferguson AC, Wong FWM. Bronchial hyperresponsiveness in asthmatic children. Chest. 1989;96:988-991.
4. Spitzer WQ Suissa S, Ernst P, et al. The use of ß-agonists and the risk of death and near death from asthma. N Engl; Med. 1992;326:501-506.
5. Kay AB, Walsh GM, Moqbel R, et al. Disodium cromoglycate inhibits activation at human inflammatory cells in vitro. Allergy Cim Immunol. 1987;80:1-8.
6. Hoag JE, McFadden ER. Long-term effect of cromolyn sodium on non-specific bronchial hyperresponsiveness: a review. Ann Allergy. 1991;66:53-63.
7. Settipane GA, Klein DE, Boyd GK. Sturam JH1 Freye HB. Weltman JK. Adverse reactions to cromolyn. JAMA. 1979;23:81 1 -881 .
8. Wass U, Piaschke P, Bjorkander J, Belin L. Assay of specific IgE antibodies to disodium cromoglycate in serum from a patient with an immediate hvpeisensitiviry reaction. ] Allergy CUn Immunol. 1988:81:750-757.
9. Van Essen-Zandvliet E, Hughes MD, Waallcens JH, et al. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. Am Ree Respfr Dis. 1992;146:547-554.
10. McFadden ER, Kiser R, DeGroot WJ. Acute bronchial asthma: relations between clinical and physiologic manifestations. N Engt J Med. 1973;288:221-225.
11. Murphy S, Kelly HW. Evolution of therapy for childhood asthma. Am Rev Respfr Dis. 1992;146:544-546.
12. Larson GL Asthma in children. Review article. N Engl J Med. 1992;326:1540-1544.
13. McFadden ER, Gilben IA. Medical progress: asthma. N Engl J Med. 1992:327:19281937.