Why we must do a better job controlling asthma

David P. Skoner, MD

Improvements in understanding and treatment notwithstanding, asthma is often poorly controlled in children. To change that state of affairs, the author calls for better acquaintance with the inflammatory nature of the disease and with the evidence that suboptimal control can undermine your patients' overall health and quality of life.

Asthma is the most common chronic childhood illness. The estimated number of children younger than 14 years who have asthma was approximately 4.1 million in 1993­1994, a 1998 study revealed.¹ The incidence of pediatric asthma has increased strikingly over the past few decades. Between 1980 and 1994, there was a 160% increase in the incidence of asthma among children 4 years of age and younger (from 22.2 to 57.8 cases per 1,000), and a 74% increase among children 5 to 14 years old (from 42.8 to 74.4 cases per 1,000) (Figure 1).¹ Similar increases have been reported worldwide.

The hospitalization rate among children with asthma in the United States also has increased dramatically since the 1960s. According to recent data, the hospitalization rate for asthma remained relatively constant from 1980 to 1993 in the 5- to 24-year-old group but rose significantly in children younger than 1 year—from 35.6 to 64.7 per 10,000 hospitalized children younger than 1 year.² Through 1992, the rate in the 1- to 4-year-old group rose from 38.3 to 60.1 per 10,000 hospitalized children 1 to 4 years old.² Numerous smaller, hospital-based studies have demonstrated significant increases in hospitalization rates. The asthma hospitalization rate at Children's Hospital of Pittsburgh, for example, increased significantly between 1980 and 2000 (Figure 2).^3,4

Reasons for the rise in pediatric asthma have not been clearly defined, but they may include increased exposure to indoor allergens, especially dust mites, and increased exposure to air pollution as a result of greater urbanization.

Death from asthma is still relatively rare, but the mortality rate has increased greatly over the past two decades among patients 5 to 24 years of age. The annual age-specific death rate increased 118% from 1980 to 1993.² The mortality rate in two age brackets (5 to 14 years and 15 to 24 years) approximately doubled from 1980 to 1993, with the highest rate among black children.²

Severe asthmatics are at greatest risk of death, but risk extends to mild asthmatics.⁵ What's more, predicting those at risk is a challenge. In an Australian study, deaths from asthma in 51 patients 20 years of age or younger were evaluated over a three-year period.⁶ A significant percentage (33%) of deaths occurred in patients with mild disease; 22% were symptom free in the preceding three months, and 63% were judged to be stable or improving in the preceding year.

Because risk factors for death from asthma are largely undefined, it has been suggested that all exacerbations of asthma that last longer than a few days be considered potentially fatal.⁵ Patients' and clinicians' failure to recognize and respond appropriately to gradually worsening asthma has, in fact, been reported as a risk factor (Table 1).⁷ Education may be a key to preventing asthma-related fatalities insofar as it prompts patients and caregivers to seek intervention early during an episode. Furthermore, childhood asthma of any severity must be treated and monitored regularly.

TABLE 1
Risk factors for poor asthma outcome

History of mechanical ventilation or admission to the intensive care unit for acute asthma

Reliance of patient on crisis management in the emergency department

Failure of patient to respond to worsening asthma and long delays in seeking medical attention

Underuse of corticosteroids before hospital admission

Overuse of sedation

Poor assessment and management of acute attacks

Sources: McFadden ER et al,⁵ Turner MO et al⁷

Studies suggest, however, that many clinicians do not adhere to treatment guidelines for asthma. Few children, for example, receive long-term treatment with recommended anti-inflammatory agents— one reason that asthma is often poorly controlled (Table 2). Many families acclimate to asthma's damaging effect on their lives, unaware that better control of disease would enhance the patient's quality of life and overall health.

TABLE 2
The problem defined

What is "poorly controlled" asthma?*

Any of the following:

More than two days of symptoms in a week

More than two episodes of parental sleep interruption in a month

Pulmonary function lower than 80% of the predicted value

Limitation of physical activities because of symptoms

Need for urgent care visits

Increased need for short-acting inhaled ß₂-agonists

*May indicate need to increase long-term medications

Sources: Yamada EG et al³³; National Asthma Education and Prevention Program⁸

What leads to poor control of asthma?

Underappreciation of disease severity

Failure to follow treatment guidelines

Patient nonadherence

Difficulty using certain inhalation devices

This article looks at the inflammatory nature of asthma, the adverse effects of the disease, and the improvements in daily life when asthma is optimally managed.

Long-term toll of asthma

Asthma is a chronic inflammatory disease of the airways—a fact that is reflected in treatment guidelines, which recommend daily anti- inflammatory therapy for persistent asthma and recognize that inhaled corticosteroids are the most effective anti-inflammatory agents available.⁸

Because of its well-established safety profile, cromolyn sodium has frequently been used as first-line therapy in children with mild to moderate persistent asthma. It is, however, less effective than inhaled corticosteroids in treating asthmatic children,^9­11 and current treatment guidelines recommend its possible use only in cases of mild persistent disease. (Table 3 classifies asthma severity.)

TABLE 3
Classifying asthma severity

Likewise, leukotriene modifiers have been shown to be less effective than inhaled corticosteroids, demonstrating less improvement in pulmonary function, asthma symptoms, need for rescue medication, and patient quality of life.^12,13 Although the precise role of leukotriene modifiers in asthma has not yet been established, they may potentially be used as add-on therapy, in place of long-acting ß₂-agonists, and as first-line treatment in a wheezy infant or toddler with mild recurrent symptoms for whom inhaled corticosteroids are not appropriate.¹⁴

Even in a mild asthmatic, repair of pulmonary damage caused by chronic inflammation leads to airway remodeling in the lungs, as injured tissue is replaced with parenchymal cells and connective tissue.¹⁵ Remodeling may establish an irreversible component to airflow obstruction, possibly related to the severity and duration of asthma.

Few studies have been conducted to document airway inflammation in children—unlike the case with adult asthmatics. The paucity of research likely relates to ethical issues. Two recent studies have, however, evaluated bronchial biopsy specimens and bronchoalveolar lavage fluid from asthmatic children.^16,17

In one study of patients between 1 and 15 years of age, nonbronchoscopic bronchoalveolar lavage was used to evaluate cellular components in 52 children with atopic asthma, 23 nonasthmatics with atopy, and 20 children with "viral-associated wheeze."¹⁶ The percentage of eosinophils and mast cells was significantly elevated in atopic asthmatics compared with the nonasthmatics and with viral-associated wheezers. These data demonstrate that airway inflammation is present in children with asthma and atopy but not in children with viral-associated wheeze or atopy alone.¹⁶

In the other study, 27 children, 1 to 12 years, were followed after bronchial biopsy was performed for various presenting respiratory symptoms.¹⁷ Patients in whom asthma was diagnosed at follow-up had a significantly greater number of eosinophils in the bronchial mucosa and a significantly thicker epithelial basement membrane than did patients whose original respiratory symptoms did not progress to asthma. The study demonstrates that inflammation and remodeling are present early in the course of childhood asthma.¹⁷

Of studies that have documented decreased pulmonary function early in the development of asthma in children, one provides evidence that such a deficit is a direct consequence of inflammation.¹⁸ In that study, pulmonary function in children with persistent wheezing was normal at birth but significantly reduced by 6 years of age.

Intervention: A matter of timing and continuity

Based on observations of early loss of pulmonary function, it has been hypothesized that a critical window of opportunity for therapeutic intervention may exist in young children who have asthma. Treatment initiated once the window has closed may never produce optimal results because of the irreversibility caused by remodeling.

In one of several clinical trials supporting early therapeutic intervention, 216 children with mild or moderate asthma were evaluated for one to two years before receiving treatment with budesonide (Pulmicort), an inhaled corticosteroid, and then followed for three to six years while receiving budesonide.¹⁹ Sixty-two control subjects receiving nonsteroid treatment were followed for three to seven years.

Control subjects exhibited a 1% to 3% annual decrease in percent predicted forced expiratory volume in one second (FEV₁), whereas budesonide-treated subjects exhibited significant improvement over baseline and compared with controls. Furthermore, the duration of asthma before treatment was associated with treatment response: Children who received inhaled budesonide within two years of asthma onset had a significantly greater increase in FEV₁ than children with a history of asthma longer than five years (Figure 3).¹⁹ This study supports the value of early intervention with an inhaled corticosteroid.

A decline in the hospitalization rate also has been associated with appropriate asthma therapy.^20­22 The hospitalization rate among asthmatic children 14 years of age or younger, which increased dramatically beginning in the mid-1960s in a number of countries, declined steadily in some countries after 1985—despite an increasing prevalence of asthma.

This decline has been attributed to more widespread disease control with inhaled corticosteroids in those countries.^21,22 A 60% decrease in the total number of hospital days for the treatment of acute asthma in children 2 to 18 years of age in Sweden, for example, was attributed to the continued use of inhaled corticosteroids.²¹

A recent report from the Childhood Asthma Management Program (CAMP) Research Group (a group in the United States that studied 1,041 children 5 to 12 years old) documented a significantly lower (43%) rate of hospitalization with budesonide (via Pulmicort Turbuhaler) than with placebo.²³ These data indicate that early intervention with inhaled corticosteroids and continued treatment of children with asthma may prevent a decline in pulmonary function and decrease asthma-related hospitalizations.

Two recent studies further illustrate the need for continued inhaled corticosteroid treatment to achieve disease control. One study evaluated a long-acting ß₂-agonist as replacement therapy for low-dose inhaled corticosteroid treatment. Patients 12 to 65 years old with persistent asthma that was well controlled with low-dose triamcinolone acetonide (Azmacort), experienced significantly fewer asthma exacerbations and treatment failures than those patients switched to salmeterol (Serevent) monotherapy.²⁴ The second study showed that the addition of salmeterol to triamcinolone acetonide therapy enabled a substantial (50%) reduction in the inhaled corticosteroid dose without significant loss of asthma control, but that total elimination of the inhaled corticosteroid led to marked treatment failure.²⁵

Growth impairment

Impaired growth has been demonstrated in children with chronic allergic disorders, including severe, poorly controlled asthma. In one study of 58 prepubertal asthmatic children before inhaled corticosteroid therapy was initiated, a significant association was demonstrated between height-velocity standard-deviation scores and degree of asthma control (Figure 4).²⁶ Scores were significantly higher in children with good asthma control compared with those with moderate or poor control—supporting a treatment-independent association between poorly controlled asthma and growth impairment.

Short-term studies showing growth impairment in children receiving inhaled corticosteroids have raised concern among clinicians about the potential for long-term growth effects. However, Agertoft and Pedersen recently reported the attainment of normal adult height in 142 asthmatic children treated with inhaled budesonide for a mean duration of 9.2 years.²⁷ A reduction in height velocity observed in the first year of treatment, which was consistent with the short-term studies, did not persist or affect the attainment of final adult height. The CAMP Research Group similarly documented an early, transient reduction in growth velocity with inhaled budesonide, but final height projections for children after four to six years of treatment were similar to those for children receiving placebo.²³

The quality-of-life gap

The impact of asthma on quality of life in a child is often underestimated. Such underestimation may relate to the difficulty of assessing symptom severity, especially nocturnal cough, and the child's adaptation of lifestyle to avoid symptoms. Assessment is complicated because parents may be unaware of important details of the child's condition: A prospective, two-month cohort study of assessments of asthma, for example, demonstrated important differences between parents and their asthmatic children 7 to 17 years of age in regard to perceptions of symptoms, disease control, and quality of life.²⁸

Clinicians' and children's perceptions of the effect of asthma on youngsters' quality of life often differ. Why? The answer may be, as one recent comparative treatment trial revealed, that clinical measures of asthma severity do not necessarily correlate with children's daily feeling of well-being and functional ability. Furthermore, their assessment of control varied greatly from that of clinicians, who relied on spirometric measures, percentage of symptom-free days or nights, and the use of rescue medication.²⁹ In general, physicians participating in the study tended to overestimate the degree of asthma control.

Restriction of physical activities—running, jogging, exercising, basketball, playing outside in cold weather or in grass or leaves, being around pets, and just horsing around—is frequently reported by young children with asthma. Better or longer performance of activities in which they already participate is a goal for these young children.

Asthma also has a major effect on the families of affected children. Family activities may be restricted to accommodate an asthmatic child. Outings or vacations may be limited to certain locations or times of the year to avoid known precipitants of attacks; visiting friends or family who own a pet may be impossible. Parents may also have to curtail social or business activities to care for a child experiencing asthma symptoms.

Concern over possible long-term treatment effects and medication side effects, and the inability to relieve a child's symptoms, constitute a significant parental burden. Parents who consistently deal with a child's nocturnal asthma lose sleep and become physically exhausted, and must often adjust their work schedule to accommodate missed school days.

Proper control of asthma with inhaled corticosteroids has been shown to improve the quality of life of asthmatic children and their parents.^30­32 In a double-blind, placebo-controlled trial that evaluated the effect of inhaled fluticasone propionate (Flovent) on functional status and sleep in children 4 to 11 years of age with mild or moderate asthma,³¹ treatment significantly improved functional status and decreased sleep disturbances in the treatment population over the one-year study period.³¹ These changes correlated with a significant decrease in parental burden, indicating that properly controlled asthma increases the quality of life of child and parent.

The box below makes clear how inadequately controlled asthma often leads to low expectations and, in turn, a poor outcome.

Summing up: Low expectations = poor outcome

Treatment issues, future directions

Although asthma symptoms, exacerbations, and activity restrictions can be eliminated in most children, that goal has not been realized. The numbers of missed school days, sleep disturbances, and activity restrictions surpass limits established by the National Heart, Lung, and Blood Institute/National Institutes of Health. Because children at all levels of disease severity still die of asthma, health-care providers must do a better job assessing severity, educating families, and prescribing appropriate long-term control therapies.

Poor asthma control is attributed to underappreciation of disease severity, failure to follow treatment guidelines, patient nonadherence, and difficulties in using some inhalation devices. In the United States, recommended anti-inflammatory drugs are markedly underused in the treatment of pediatric asthma.

A recent study of 87 asthmatic children 3 to 12 years of age demonstrated a striking underuse of appropriate asthma therapy.³³ Inadequate control was defined as more than two days of symptoms a week, more than two episodes of parental sleep interruption a month, pulmonary function lower than 80% of predicted, or limitation of physical activities due to asthma symptoms. According to the report, disease was not adequately controlled in 84% of the 87 children, and more than 60% required a change of medication.

Underdiagnosis and undertreatment of asthma in minorities and the poor may be important factors in the disproportionately high mortality rate among black children in the United States.

Patient nonadherence may be an especially significant factor in the undertreatment of asthma in young patients, who often stop treatment when they are asymptomatic and resent having to take preventive medication. These attitudes must be reversed with proper education.

Poor inhaler technique and improper administration by caregivers—typically the result of inappropriate instruction—may also compromise therapeutic efficacy and disease control. Even health-care providers who know the appropriate techniques often fail to question, evaluate, and teach the patient. Development of simpler ways of administering inhaled therapy may lead to improved asthma control.

Great expectations

Optimal control of disease can diminish the substantial impact of asthma on childhood health. To this end, children who have asthma, and their parents, must be made aware of the consequences of poorly controlled disease, the treatable nature of asthma, and the high quality of life that accompanies optimal control.

A better outcome also depends on raising the expectations of asthmatic children and caregivers, educating them about disease management, and emphasizing adherence to therapy and proper use of inhalation devices. As for clinicians, careful assessment of disease severity is necessary to achieve optimal disease control, as is adherence to guidelines for treating asthma that recognize the importance of long-term anti-inflammatory therapy—in particular, the effectiveness of inhaled corticosteroids. Last, access to comprehensive care must be provided to all asthmatic children.

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4. Children's Hospital of Pittsburgh, 2001 (unpublished data)

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28. Guyatt GH, Juniper EF, Griffith LE, et al: Children and adult perceptions of childhood asthma. Pediatrics 1997; 99:165

29. Pedersen S: What are the goals of treating pediatric asthma? Pediatr Pulmonol 1997;15:22

30. Dukes E, Ollendorf D, Mellon M, et al: The impact of budesonide inhalation suspension on symptom-free days and use of asthma related services in young children with asthma [abstract]. Am J Respir Crit Care Med 1999; 159:A761

31. Mahajan P, Pearlman D, Okamoto L: The effect of fluticasone propionate on functional status and sleep in children with asthma and on the quality of life of their parents. J Allergy Clin Immunol 1998;102:19

32. Okamoto LJ, Noonan M, DeBoisblanc BP, et al: Fluticasone propionate improves quality of life in patients with asthma requiring oral corticosteroids. Ann Allergy Asthma Immunol 1996;76:455

33. Yamada EG, Roberto L, Sudhaker R, et al: Poor asthma control and inadequate medication regimens in a population of MEDI-CAL children with asthma [abstract]. Am J Respir Crit Care Med 1999;159:A267

THE AUTHOR is section chief, division of allergy, immunology, and infectious diseases, department of pediatrics, Children's Hospital of Pittsburgh. He received funding for this article from an unrestricted educational grant by AstraZeneca, Wayne, Pa. He is a consultant to, and grantee of, AstraZeneca, Aventis Pharmaceuticals, Forest Pharmaceuticals, Glaxo Wellcome, Key Pharmaceuticals, Merck, Pfizer Pharmaceuticals, and Schering Plough Laboratories.

David Skoner. Why we must do a better job controlling asthma.

Contemporary Pediatrics

2001;8:49.