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The Proceedings of the American Thoracic Society 6:720-723 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200907-059DP
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Obstructive Lung Disease from Conception to Old Age

Differences in the Treatment of Adults and Children with Asthma

Paul M. O'Byrne1

1 Firestone Institute for Respiratory Health, St. Joseph's Hospital and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Correspondence and requests for reprints should be addressed to Paul M. O'Byrne, M.B., F.R.C.P.I., F.R.C.P.(C), F.R.C.P.E., Rm 3W10, McMaster University Medical Center, 1200 Main St. West, Hamilton, ON, L9G 4R7 Canada. E-mail: obyrnep{at}mcmaster.ca

ABSTRACT

Achieving asthma control is the focus of asthma management. Inhaled corticosteroids are the most effective treatment for asthma in children and adults, with no evidence that the magnitude of benefit differs between adults and school-aged children. Leukotriene inhibitors are more widely used in children than in adults. This may be because provoking stimuli, such as environmental allergens and frequent exercise, are more important asthma triggers in children or because parental concerns about the side effects of treatment with ICS. Inhaled corticosteroid/long-acting inhaled β2-agonist combinations may not be as effective in children as in they are adults in improving asthma control and reducing asthma exacerbations.

Key Words: inhaled corticosteroids • leukotriene inhibitors • long-acting inhaled β2-agonists • adults • school-aged children

Asthma is recognized as a chronic inflammatory disease of the airways, with structural changes occurring (i.e., airway remodeling) possibly as a result of the chronic airway inflammation. Airway inflammation and airway remodeling have been documented in children (1, 2) and adults with asthma (3, 4). Increases in airway reticular basement membrane, which is one of the features that characterizes airway remodeling in asthma, have been identified in very young children with a short history of asthma symptoms (5) and in adults with allergic rhinitis without asthma (6), although these changes seem to progress if asthma symptoms develop in these patients with allergic rhinitis (6). There have been no reports directly comparing the type and magnitude of airway inflammation or airway remodeling in adults and children with asthma in a single study; however, the magnitude of the increases in reticular basement membrane are similar in children with severe asthma (2) and adults with severe asthma (7). It is plausible that eosinophilic airway inflammation may be a more prominent feature of childhood asthma because most children with asthma are atopic, and allergen inhalation causes mainly an eosinophilic airway inflammatory response (8). Fewer patients with adult-onset asthma are atopic, and occupational asthma, which is an important cause of adult-onset asthma, is often associated with a neutrophilic airway response (9).

Achieving asthma control is the focus of asthma management, as identified by all recently developed asthma treatment guidelines (10–12). Asthma control consists of achieving day-to-day asthma control, indicated by the absence of asthma symptoms, minimal reliever use, normal activity levels, and lung function values close to normal (Figure 1). A second objective is to minimize future risk to the patient by ensuring the absence of asthma exacerbations, the prevention of accelerated decline in lung function over time, and no side effects from medications (Figure 1). These objectives of asthma management are applicable to all ages of people with asthma; however, there are differences, which are sometimes substantial, in the recommendations provided by the guidelines for the management of asthma in preschool children, school-aged children and adolescents, and adults. These differences are particularly marked between preschool children and the rest of the population with asthma. Indeed, the Global Initiative for Asthma has recently developed separate guidelines for preschool children (13). This review considers the differences between adults and school-aged children in the three most widely used treatment options for asthma. These are inhaled corticosteroids (ICS), leukotriene inhibitors, and combination inhalers containing ICS and long-acting inhaled β2-agonists (LABA).


Figure 1
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  		Figure 1. The goals of asthma treatment in school-aged children and adults.

 
INHALED CORTICOSTEROIDS

Inhaled corticosteroids are the most effective treatment for asthma and the most widely used regular treatment for airway disease (10, 11). They improve all of the symptoms and physiologic abnormalities that characterize asthma and markedly reduce the risks of patients experiencing severe asthma exacerbations (14). The changes in these parameters occur because of the antiinflammatory effects of ICS and in particular their ability to resolve eosinophilic airway inflammation (15) and airway edema (16). The physiologic changes that benefit from ICS include airflow obstruction and airway hyperresponsiveness (17). ICS improve many of the pathological abnormalities (airway remodeling) that characterize asthma, including the structural changes that occur within the airway epithelium (18) and the observed increased deposition of subepithelial collagen (19). ICS also cause a reduction in the airway neovascularization seen in asthma (20).

ICS provide clinical benefit in all categories of persistent asthma severity. Mild intermittent and persistent asthma constitutes the majority of patients with asthma. Patients with even mild persistent asthma are often not well controlled (21). Low doses of ICS can often provide ideal asthma control and reduce the risks of severe asthma exacerbations in children and adults with mild persistent asthma. Intermittent ICS therapy at the time of an exacerbation has also been suggested to be an effective treatment strategy for mild persistent asthma (22, 23) but may be less effective than low-dose regular therapy for most outcomes, where, although not directly compared with intermittent ICS therapy, marked benefit has been demonstrated in adults (24, 25) and in children (26).

Only one study has evaluated the benefits of ICS use for asthma over time in school-aged children and adults. The START (inhaled Steroid Treatment As Regular Therapy in early asthma) study was a large, worldwide, long-term, double-blind, placebo-controlled trial that was undertaken to determine whether early intervention with low doses of the ICS budesonide (200 µg once daily in children 5–11 years of age and 400 µg once daily for older children and adults) in patients with newly diagnosed persistent asthma would prevent severe asthma-related events and modify the decline in lung function (24). The occurrence of severe asthma exacerbations and the decline in postbronchodilator FEV1 were significantly reduced by early intervention with budesonide. There were no significant differences in the protection afforded by ICS on exacerbations in children and adults. The adult patients had a significant decline in postbronchodilator FEV1 that was significantly attenuated by the ICS treatment, but the decline was less (but not significantly so) in children 11 years of age or younger, and no decline in FEV1 was seen in the adolescent patients (27) (Figure 2), as was also described in the CAMP trial (26).


Figure 2
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  		Figure 2. The change in postbronchodilator FEV1 percentage of predicted after 3 years of treatment with inhaled budesonide or placebo in children younger than 11 years of age, in adolescents 11 to 17 years of age, and in adults 18 years of age or older at time of randomization. A significant treatment effect in postbronchodilator FEV1 percentage of predicted was demonstrated in adults (P < 0.001) but not in adolescents (P = 0.38) or in children (P = 0.31). Reprinted by permission from Reference 27.

 
There do not seem to be any important differences in the benefits achieved by ICS treatment for most outcomes between children and adults. Also, ICS is accepted as being the best treatment choice as a maintenance treatment even in preschool children (13). However, there can be reluctance by parents to use ICS in children. This is mainly caused by an inappropriate perception of the side-effects of low doses of ICS in children. Low doses of ICS (budesonide 400 µg/d or less) can cause slowing of growth in children (24, 28), but these doses do not appear to affect final height (29).

LEUKOTRIENE INHIBITORS

Cysteinyl leukotrienes are important mediators of asthmatic responses. They are the most potent bronchoconstrictors known (30). Their release is triggered by exposure to inhaled allergens (31), after exercise (32), and after aspirin ingestion by patients with aspirin-sensitive asthma (33). Cysteinyl leukotrienes promote inflammatory cell migration into the airways (34) and bone marrow eosinophilopoiesis after allergen inhalation (35). Leukotriene inhibitors are effective at attenuating asthmatic responses to all of these stimuli and have been demonstrated to reduce asthma symptoms, to reduce the need for rescue β2-agonist use, to improve lung function (36–39), and to reduce the risks of severe asthma exacerbations (36, 37, 40).

Several studies have directly compared the efficacy of low-dose ICS and leukotriene inhibitors in persistent asthma and have demonstrated overall greater efficacy of low-dose ICS for most outcomes of asthma control (41–43); however, there is variability in the individual responses of patients with asthma to these classes of antiasthma drugs, with evidence suggesting that higher bronchodilator use, bronchodilator responsiveness, higher exhaled nitric oxide levels, and eosinophil cationic protein levels and greater airway hyperresponsiveness and pulmonary function values are associated with a greater response to ICS treatment in children (42). Studies have consistently found clinical benefit when leukotriene inhibitors are added to ICS, but this benefit has been less than that demonstrated with LABAs as the add-on treatment (44, 45).

Leukotriene inhibitors are more widely used in children than in adults to treat asthma. There are no studies available directly comparing the efficacy of leukotriene inhibitors in adults and children, but it is plausible that leukotriene inhibitors are more effective in the management of childhood asthma because allergen inhalation plays an important role in causing symptoms in children and because exercise is more likely to be an important part of daily life in children than in adults; both of these provoking stimuli for asthma are partially attenuated by leukotriene inhibitors. Another likely reason for the relatively common usage in childhood asthma is the perception by parents of unacceptable side-effects in their children from ICS use. Although these concerns are unfounded for the low doses of ICS that the majority of children would need for asthma control (46), leukotriene inhibitors are seen as a safer (albeit less effective) alternative as the initial maintenance treatment for asthma.

COMBINATION INHALERS CONTAINING ICS/LABA

Patients whose asthma is not ideally controlled on low-dose ICS therapy can be considered to have moderate persistent asthma. In adult patients, the combination of low-dose ICS and LABA (usually in a single inhaler) is better than increasing the dose of ICS to achieve better asthma control (47) and reduce exacerbation risks (25, 48), and these combinations are recommended in asthma treatment guidelines as the next treatment option after low-dose ICS (10, 11). There is much less compelling information regarding the clinical benefit of the regular use combinations of ICS/LABA in school-aged children (49). Therefore, some treatment guidelines recommend doubling the maintenance dose of ICS in school-aged children whose asthma is not controlled on low-dose ICS (10); however, the NAEPP asthma management guidelines support the use of ICS/LABA combinations in school-aged children with chronic impairment on low-dose ICS treatment (11). The reasons for these differences in school-aged children and adults are not known. Speculation has focused on the possibility that airway smooth muscle mass may be less in children with asthma compared with adults, who often have had the disease for a longer time, and LABAs relax constricted airway smooth muscle as part of their main mechanism of action. However, there is no direct evidence to support this speculation.

One study has compared the combination of budesonide/formoterol used as maintenance and rescue treatment in adults and children with very difficult-to-control asthma (50). The study examined the ability of this combination of ICS/LABA to reduce the risks of severe asthma exacerbations, and it demonstrated that the benefit in this regard was as least as good in school-aged children as in adults (51). Thus, for children with severe asthma, as identified in this study (51), this treatment approach may be beneficial. There are no studies of the use of these combinations in children under 5 years of age. Thus, recent Global Initiative for Asthma guidelines for the management of asthma in patients under 5 years of age recommend doubling the dose of ICS or adding a leukotriene modifier to low-dose ICS if the low-dose ICS alone does not provide asthma control (13).

CONCLUSIONS

ICS remain the most effective treatment for asthma in children and adults. There is no evidence to suggest that the magnitude of clinical benefit differs between school-aged children and adults. Leukotriene inhibitors are more widely used in children than in adults. The reasons for this may be that provoking stimuli, such as environmental allergens and frequent exercise, which are ameliorated by leukotriene inhibitors, are more important asthma triggers in children or parental concerns about ICS side effects. Maintenance dosing with ICS/LABA combinations are generally not as effective in children as they are in adults; however, the combination of budesonide/formoterol may be as effective in school-aged children as it is in adults in reducing the risks of severe asthma exacerbations when used as maintenance and relief medication.

FOOTNOTES

Conflict of Interest Statement: P.M.O. has received reimbursement for consultancies with AstraZeneca (AZ) ($10,001–$50,000) and has served on advisory boards with Acetelion ($1,001–$5000), Asmacure ($5,001–$10,000), GlaxoSmithKline (GSK) ($5,001–$10,000), Merck ($5,001–$10,000), and Topigen ($5,001–$10,000). He has received honorarium for lectures with AZ ($10,001–$50,000), Chiesi ($5,001–$10,000), and Ono Pharma ($1,001–$5000). He has also received funding for research with Altair ($100,001 or more), AZ ($100,001 or more), Genetech ($100,001 ore more), GSK ($100.001 or more), Wyeth ($100,001), Medimmune ($100,001 or more), Merck ($100,001 or more), and Pfizer ($100,001 or more).

(Received in original form July 6, 2009; accepted in final form September 2, 2009)

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