Despite their proven effectiveness, ICS are underused in the treatment of asthmatic children. As well, inappropriate devices and techniques result in suboptimal dosing.

Asthma is a common chronic illness affecting both adults and children. In the United States alone, asthma has been diagnosed in almost 9 million people less than 18 years old at some time during their lives,¹ and as many as 6.1 million children had active asthma in 2002 alone.¹ Asthma exacerbations resulting in emergency-department visits and hospitalizations were highest among children aged between 1 and 4 years, compared with all other age groups.¹ Among children who visit an emergency department with an asthma exacerbation, 10% to 13% return due to a recurrence within the first 2 weeks after discharge.^2,3

Asthma-related emergency-department visits and hospitalizations make up the single largest component of direct expenditures relating to asthma.⁴ A substantial proportion of these costs are attributed to the care of children; almost 48% of emergency-department visits and 35% of hospitalizations involve children.⁴ During a 1-year period, asthma-related events in children resulted in 727,000 emergency-department visits and 196,000 hospitalizations in the United States.¹

Inhaled Corticosteroids in Children
Inhaled corticosteroids (ICS) are associated with a 45% reduction in the risk of recurrent emergency-department visits⁵ and up to an 80% reduction in recurrent hospitalizations, compared with non-ICS use in patients with asthma.⁶ ICS use is recommended by the National Asthma Education and Prevention Program as the preferred therapy for control and long-term management of persistent asthma in children of all ages.⁷

Despite their proven effectiveness, ICS are underused in the treatment of children with asthma.⁸ Moreover, inappropriate devices and improper technique result in suboptimal dosing,⁹ thereby leading to less-than-effective treatment, decreased compliance, and treatment discontinuation.¹⁰ The three major treatment options available today are metered-dose inhalers (MDI), dry-powder inhalers (DPI), and nebulizers (see table). Patient age and ability to use a device correctly are important factors in choosing an appropriate device.¹¹

The aerosolized medication contained in an MDI is released in a puff upon actuation. Younger children, particularly those less than 5 years old, may not have the ability to coordinate actuation of the MDI and inhalation.⁹ Addition of a spacer device and face mask for young children may enhance drug delivery. Using a DPI requires inspiration of the medication upon actuation of the inhaler. This device is not suitable for children less than 4 years old, who may not have the necessary inspiratory force or coordination to use this device.⁹The third option for ICS delivery is a nebulizer. Aerosolized particles are dispersed continuously from the reservoir to a face mask or mouthpiece and are passively inhaled by the patient. The nebulizer is ideal for certain patients (such as infants and young children) because it does not require coordination between actuation of the device and inhalation.⁹

The theoretical advantages and disadvantages of the available devices have been examined in a real-world setting. Kofman et al¹² evaluated the inhalation technique of 150 children (aged 3 months to 18 years) using several different ICS delivery devices for the treatment of pulmonary diseases. More patients using nebulizers for delivering ICS had good technique (82%), compared with those using MDIs (64%) or DPIs (42%).

Budesonide Inhalation Suspension
Budesonide inhalation suspension (BIS) is the only ICS approved by the US Food and Drug Administration for use with a nebulizer. It is indicated for maintenance treatment of asthma and as a prophylactic therapy in children aged 12 months to 8 years. BIS was developed for use in young children and has been extensively studied in that population.

Szefler and Eigen¹³ provided a comprehensive review of studies evaluating the efficacy and tolerability of BIS in the control and maintenance of mild-to-severe, persistent asthma in infants and young children. Compared with placebo, treatment with once-daily or twice-daily BIS (0.25 to 1 mg) significantly improved pulmonary function; reduced symptoms, such as daytime and nighttime wheezing; and reduced asthma exacerbations and oral prednisone use. BIS was well tolerated, with an incidence of adverse events similar to that of placebo.

The comparative efficacy of a nebulized ICS versus a non-nebulized ICS for treatment of asthma has not been extensively studied in young children. Only one randomized, controlled trial¹⁴ and three retrospective studies are available for review.^15-18 Bisca et al¹⁴ compared the efficacy of beclomethasone dipropionate (800 µg per day or 1,600 µg per day delivered via MDI or nebulizer, respectively) in a 4-week to 8-week double-blind clinical study of 151 children, aged 6 to 16 years, who had moderate-to-severe asthma. Patients completing 4 weeks of treatment could continue at a half dose for an additional 4 weeks. At the end of the first 4 weeks, improvements over baseline in morning peak expiratory flow, the primary endpoint of the study, were similar in both groups. Improvements continued in patients treated for an additional 4 weeks. These results indicate that, under the tightly controlled environment of a clinical trial, the choice of device may not be a major factor affecting consistency of drug delivery to the lower airways in older children.

We recently performed a retrospective longitudinal study¹⁵ to evaluate the effect of nebulized BIS, in the real world, in reducing the recurrence of emergency-department visits and hospitalizations in children aged 8 or fewer years who had asthma. The children were identified from a managed care database. The study population included children with one or more asthma-related emergency-department visits or hospitalizations (index events) during the period from July 2000 through June 2001; the children also had a prescription claim for an ICS (including BIS) within 30 days of discharge. Risk of a recurrence from day 31 to day 180 in patients receiving BIS was compared with risk in those receiving a non-nebulized ICS.

During the 6-month follow-up period, approximately 10% of patients had a recurrent asthma-related emergency-department visit or hospitalization.¹⁵ Of 749 patients with a prescription claim for an ICS, 270 (36%) had claims for nebulized BIS.¹⁵ Patients receiving BIS were 56% less likely to experience a recurrence (hazard ratio, 0.44; 95% confidence interval [CI], 0.26 to 0.72) compared with those receiving a non-nebulized ICS.

We replicated this study using an additional year of patient data.¹⁶ Our previous results were confirmed in a total of 10,176 patients identified with one or more index events and an asthma-related prescription claim within 30 days of the event (July 2000 through June 2002). During the 6-month follow-up period, 13% of patients had a recurrence. Among patients who received a controller medication within 30 days of discharge after the event, BIS was the only medication associated with a significantly lowered risk of asthma exacerbation recurrence (hazard rate, 0.71; 95% CI, 0.57 to 0.89).¹⁶

Of the subset of patients receiving only an ICS (n=1,552), 729 had a prescription claim for BIS and 823 for a non-nebulized ICS, but not both.¹⁷ Recurrence of an emergency-department visit or hospitalization was 12.4% during the 6-month follow-up period. Patients using BIS had a 53% risk reduction for emergency-department visit/hospitalization recurrences, compared with patients using non-nebulized ICS (hazard ratio, 0.47; 95% CI, 0.28 to 0.78).¹⁷ Analysis of the data by age group found that patients aged 4 or fewer years receiving nebulized BIS (n=480) had a 62% reduction in the risk of recurring emergency-department visits or hospitalizations (hazard ratio, 0.38; 95% CI, 0.21 to 0.69), compared with patients receiving non-nebulized ICS (n=292). A 52% risk reduction (hazard ratio, 0.48; 95% CI, 0.16 to 1.46) was seen in the subgroup of patients 5 to 8 years old receiving BIS, compared with those receiving non-nebulized ICS.¹⁷ This study suggests a significant benefit for nebulized BIS (instead of non-nebulized ICS) in the reduction of asthma-related emergency-department visits or hospitalizations among infants and young children. Although the explanation for this BIS advantage is not yet known, it may be due to improved technique resulting in more consistent dosing or drug delivery.

Data from a similarly designed retrospective longitudinal study¹⁸ of a large Medicaid population also suggested that BIS was more effective in reducing recurrence of asthma exacerbations, compared with other asthma medications, in young children. Patients aged 8 or fewer years were identified from the Florida Medicaid population database. Of 10,976 children identified, 20% had a subsequent hospitalization or emergency-department visit during the 1-year follow-up period. Patients receiving BIS within 30 days of the event had a 43% reduction in recurrent exacerbations (requiring hospitalization, an emergency-department visit, or oral corticosteroid use) compared with patients not given BIS (odds ratio, 0.57; 95% CI, 0.43 to 0.78).¹⁸ These results are consistent with those of the prior study and support treatment of children 8 or fewer years old using nebulized BIS.

Summary
ICS use is effective in reducing asthma-related emergency-department visits and hospitalizations. The choice of device has little impact on most patients. An ICS delivered via nebulizer in children aged 8 or fewer years is associated, however, with a greater reduction in emergency-department visits and hospitalizations than an ICS delivered via other devices. BIS is specifically formulated for use with a nebulizer, thereby facilitating the delivery of an ICS in infants and children. BIS, administered once or twice daily, is an effective controller and is well tolerated in young children with persistent asthma. Age should be an important factor in choosing the delivery device for an ICS, and recent studies15-18 suggest that the nebulizer is the most effective delivery device for infants and young children.

Carlos A. Camargo, MD, DrPH, is director, EMNet Coordinating Center, Department of Emergency Medicine, Massachusetts General Hospital, Boston. Pankaj Patel, PharmD, is Senior Manager of Health Economics & Outcomes Research, TAP Pharmaceutical Products Inc, Lake Forest, Ill.

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