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PRIORITY PRESS - 5th International Primary Care Respiratory Group World Conference

Toronto, Ontario / June 2-5, 2010

New-onset wheezing in children may be due to one of many etiologies, including viral or bacterial infections, but even persistent, chronic wheezing does not necessarily signal asthma, according to Dr. John Haughney, President, The International Primary Care Respiratory Group (IPCRG), Glasgow, UK. For example, some young children have viral infections with such frequency that wheezing appears to be chronic. For another, chronic airway problems may be produced by persistent exposure to an allergen, such as dander from a house pet. Asthma is a common disease, but it is also readily misdiagnosed, making definitive diagnostic tests essential.

Once the diagnosis of asthma is confirmed, the need to treat the underlying disease process, rather than symptoms alone, produces another significant challenge. According to 2007 data from the Asthma Society of Canada, only about half of children with a diagnosis of asthma meet criteria for good asthma control. Indeed, all countries report poor asthma control, including Sweden where, according to lead investigator, Dr. Bjorn Stallberg, Uppsala University, Stockholm, a six-year follow-up of an original cohort of 71 adolescents and young adults showed that roughly two-thirds of those in the follow-up cohort were not well controlled, possibly because of undertreatment with an inhaled corticosteroid (ICS).

In asthma, ICS is the first-line therapy for all patients with mild-to-moderate persistent asthma, including children, because this therapy treats the underlying inflammation. However, parents often believe absence of symptoms means the ICS agent, like short-acting beta agonists used for acute symptom control, can be tapered or stopped. Instead, consistent use of ICS is essential for optimal asthma control.

Risks of Non-Adherence

“Using conventional doses, all inhaled steroids need about six weeks to reach maximal effect,” cautioned Dr. Tom Kovesi, Associate Professor of Pediatrics, University of Ottawa, Ontario. Labelling the critical role of good adherence as an “inconvenient truth,” he cited data showing that some patients were still showing improvement in lung function one year after initiating ICS, which also places stress on the importance of daily therapy. The problem is that “in the real world, inhaled steroids are nearly always used intermittently.” For example, Dutch investigators reported here that only 22% of approximately 300 children between the ages of 0 and 17 with asthma received continuous medication with either a bronchodilator or a corticosteroid or both. Almost 5% of the same cohort received only continuous bronchodilator alone. In an assessment of “real-world” effectiveness of combination therapies vs. findings from randomized controlled trials, a retrospective study using the UK General Practice Research Database, only 17.4% of almost 7,000 adolescent and adult patients enrolled in the database met the composite measure for total control used by the Gaining Optimal Asthma Control (GOAL) RCT population and yearly exacerbation rates were considerably higher among “real-world” asthma patients compared to rates reported by GOAL investigators.

Even if children do receive the appropriate prescription, inadvertent or perhaps purposeful inhaler misuse is a major problem and clearly compromises asthma control, as noted by Jolyon Mitchell, Ph.D., Scientific Director, Trudell Medical International, London, Ontario. It is also suspected that parental resistance to ICS use in young children is a contributing factor to less than optimal ICS use. As Dr. Kovesi noted, parents are generally fearful of side effects from ICS due to systemic absorption, particularly the potential risk of growth delay.

However, it is important that parents understand that ICS agents act topically on the respiratory tract and do not require systemic absorption for efficacy. This means that steps taken to prevent systemic absorption will preserve the critical anti-inflammatory effect of these agents while circumventing risks. While Dr. Kovesi stressed that all ICS agents are equally effective, he cited two important factors for preventing systemic absorption. One is proper inhaler technique. This increases the proportion of ICS delivered to the lungs, where pulmonary absorption is low, and reduces the proportion that reaches the gastrointestinal (GI) tract, where risk of systemic absorption is increased. The other is selecting ICS agents with pharmacokinetic properties resulting in lower bioavailability following systemic absorption.

Pharmacokinetic and Pharmacodynamic Properties

Of pharmacokinetic properties, protein binding, speed of clearance, and half life are among relevant variables. These differ significantly (Table 1). While oral bioavailability signifies the estimated drug absorption once the ICS reaches the GI tract, high degree of protein binding is an advantage over lower protein binding even after absorption because it reduces the amount of free drug that is available for adverse effects, such as adrenal suppression. Similarly, rapid clearance is a relative advantage over slower clearance and shorter half-life is an advantage over longer half-life because it diminishes the opportunity for systemic exposure.

Several studies corroborate that these differences are clinically meaningful. For example, a study that compared the ICS budesonide and the ICS ciclesonide demonstrated similar efficacy but differences in hypothalamic-pituitary-adrenal axis (HPAA) function, which indicates systemic absorption (Von Berg et al. Pediatr Allergy Immunol 2007;18(5):391-400). In this study, 621 children (ages 6 to 11 years) were randomized to budesonide 200 µg or ciclesonide 160 µg given once daily by inhaler. At the end of 12 weeks, both produced comparable improvement in forced expiratory volume in 1 second (FEV₁), the primary end point, but HPAA function was significantly less affected by ciclesonide than budesonide (P<0.001). Budesonide also produced a significantly greater suppression of 24-hour urinary cortisol excretion.

In a similar study of 744 children, fluticasone 88 µg b.i.d. was associated with greater suppression of urinary cortisol excretion, an important marker of systemic activity than either 80 µg or 160 µg ciclesonide once daily even though relative improvements in airway function at the end of 12 weeks were comparable (Pedersen et al. Pulm Pharmacol Ther 2009;22(3):214-20).

The potential for reducing systemic risks by switching from one ICS agent to another with more favourable pharmacodynamics has been suggested by case examples. Discussing one published series (Heller et al. J Asthma 2010;47:337-9), Dr. Preetha Krishnamoorthy, Assistant Professor of Pediatrics, MUHC-Montreal Children’s Hospital, Quebec, singled out an example in which an infant admitted to a hospital with a morning cortisol excretion of only 8 nmol/L while taking fluticasone fully recovered cortisol excretion after
esonide (Figure 1).

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Growth Rate

In a Canadian study of 360 children between ages 6 and 9 years who were randomized to beclomethasone-CFC 200 µg b.i.d, placebo, or 5 mg montelukast, the mean growth rate was significantly less on beclomethasone (-0.78 cm) than on placebo or on montelukast (0.81 cm) (P<0.001 for both) (Becker et al. Ann Allergy Asthma Immunol 2006;96(6):800-7). While these types of studies alarm parents, Dr. Krishnamoorthy is among experts who have emphasized that control of asthma must be regarded as the first priority.

Specifically, Dr. Krishnamoorthy emphasized that parents should understand that asthma is a potentially fatal disease, making disease control far more important than an uncertain risk of adverse systemic effects, including growth delay. As a result, although parents should learn strategies for modifying the risk of systemic effects from ICS, they should also receive clear instruction on the need for rigorous adherence.

Summary

For long-term control of persistent asthma in children, physicians need not only ensure that patients are given an adequate prescription of ICS, a first-line and essential therapy for avoiding disease progression, but they must address parental concerns about the risks of ICS. Although ICS formulations are considered equally effective for symptom control, they differ in their relative risk of systemic absorption which may influence systemic risks, such as growth delay. Although no goal is more important than avoiding serious asthma exacerbations, selecting an ICS that poses the least risk for systemic absorption may provide an opportunity to increase the proportion of parents who ensure that their children adhere to a potentially life-saving therapy.