OBJECTIVE. To review the use of inhaled corticosteroids on asthma control in children by using the new therapeutic paradigm outlined in the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma.
METHODS. A systematic review of the literature was performed by using the Medline and Embase databases (January 1996 to October 2007).
RESULTS. A total of 18 placebo-controlled, clinical trials in >8000 children (aged 0–17 years) with asthma met the criteria for evaluating monotherapy with inhaled corticosteroids: 13 double-blind studies of inhaled corticosteroids versus placebo and 5 controlled studies that compared inhaled corticosteroids to a nonsteroid antiinflammatory agent. The findings can be summarized as follows: (1) Compared with placebo, inhaled corticosteroid treatment was associated with reductions in both the impairment and risk domains. (2) Improvements in impairment and risk observed with inhaled corticosteroids were generally greater than those observed with nonsteroid antiinflammatory comparator medications. (3) Inhaled corticosteroids were well tolerated. (4) Small reductions in growth rates were evident when compared with placebo and/or comparator nonsteroid antiinflammatory medication use in the long-term (>1-year) studies, but when measured, the reductions diminished with time.
CONCLUSIONS. Treatment with inhaled corticosteroids improves the asthma-control domains of impairment and risk in children. Differences in study protocols make detailed comparisons difficult. Specific needs for additional trials include (1) more studies using appropriate indicators for impairment (eg, rescue-medication use; symptoms scores; asthma/episode-free days) and risk (eg, forced expiratory volume in 1 second in children who can perform spirometry; exacerbations requiring oral corticosteroids; urgent care usage) and (2) more studies evaluating adolescents; the majority of the data reported were for children up to the age of 12 years, and data for adolescents are often lost (either grouped with adults [eg, studies in patients ≥12 years old] or not included [eg, studies of school-aged children ≤12 years old]). Attention should be given to standardizing variables that will permit comparison of outcomes between trials.
The National Heart, Lung, and Blood Institute of the National Institutes of Health recently released an update of the US asthma clinical practice guidelines, Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma1 (EPR3). This new document incorporates an evidence-based assessment of former guidelines and current literature in revising the recommendations for practice.
The relative burden of asthma in relation to other chronic conditions remains high, particularly in children, despite better understanding of asthma, improved approaches to treatment, and modest gains in asthma morbidity.2 The prevalence of asthma in the United States is greater in children than in adults (8.9% vs 7.2%, 2005 data).3 Asthma affects >6.5 million children (0–17 years old); ∼1.4 million are <5 years old.3 Children are more likely to have suboptimally controlled asthma as demonstrated by exacerbations and use of urgent care services. The rates of asthma exacerbations reported in 2005 for the previous 12 months were 5.2% and 3.9% for children and adults with asthma, respectively.3 There were 103 emergency department (ED) visits per 10000 children compared with 50 ED visits per 10000 adults; hospitalization rates were 27 per 10000 children versus 14 per 10000 adults. Children <5 years old had the highest rates: 168 ED visits and 60 hospitalizations per 10000 children.3 Asthma resulted in ≥1 missed day of school for almost 13 million children (5–17 years old) in 2003.3
For most patients, asthma onset occurs early in life, and disease persistence is associated with recognizable risk factors including atopic disease, recurrent wheezing, and a parental history of allergy and/or asthma. Evidence indicates that therapy with current antiinflammatory medications does not prevent progression of the underlying disease.1 In contrast to previous guidelines that focused on reducing asthma severity, the new guidelines target asthma control as the primary goal for management. Classifying asthma severity to initiate treatment is differentiated from assessing asthma control for ongoing monitoring, and both are broken down to newly defined domains of impairment and risk to operationalize therapeutic targets (Table 1). 1
The goal of asthma therapy is to achieve asthma control by reducing impairment and risk on the basis of the criteria1 shown in Table 2. As in previous guidelines, inhaled corticosteroids (ICSs) are the preferred class of long-term controller medications to manage persistent asthma in all age groups. Numerous studies in children with asthma have established that ICSs improve pulmonary function, reduce the need for reliever medications, improve quality of life, enhance exercise tolerance, and reduce hospitalizations.1 Thus, although early intervention with ICSs for childhood asthma does not alter the natural history of asthma, these medications are important for gaining and maintaining asthma control.1 However, no review to date has examined the effect of ICSs on childhood asthma in terms of impairment and risk as defined in the EPR3. The purpose of this review is to evaluate the data on ICSs in childhood asthma with specific regard to the newly defined domains of risk and impairment.
A systematic review of the literature was performed for randomized, placebo-controlled studies that evaluated monotherapy with ICSs in children. Searches of the Medline and Embase databases (January 1996 to October 2007) were performed by using the Medical Subject Headings (MeSH) terms asthma, beclomethasone dipropionate, budesonide, flunisolide, controlled clinical trials, fluticasone propionate, mometasone, randomized, controlled trials, and triamcinolone acetonide and the text words childhood asthma, pediatric asthma, persistent asthma, and ICS. Searches were limited to human subjects aged 0 to 17 years and English-language literature.
EFFICACY OF ICSs IN CHILDREN
According to the new guidelines, “ICSs are the most potent and consistently effective long-term control medication for asthma” for adults and children.1 They are the only medications consistently shown to meet the goals of pharmacotherapy for asthma:
control (ideally, prevent) asthma symptoms;
reverse airflow obstruction;
improve quality of life; and
decrease the number and severity of asthma exacerbations (and associated urgent medical care).
In the step-care approach to therapy, ICSs are the mainstay of treatment for all patients with persistent asthma (Fig 1, steps 2–6). Treatment for adolescents (12–18 years old) is the same as for adults; changes to the algorithm are shown for children <12 years old. Table 3 shows the currently available ICSs indicated for use in children in the United States.
Most of the clinical benefits observed with ICS treatment in children occur at low doses. However, similar to adults, the dose response to ICSs in children may vary according to the clinical outcome (eg, improvement in lung function, prevention of exacerbations) and patient characteristics. Children with more severe asthma may respond to higher doses, whereas those with mild or moderate asthma usually show a plateauing of effect at low and medium doses.8–11 Nonetheless, stepping up the ICS dose may provide added clinical benefit for some children with mild or moderate asthma during exacerbations or seasonal increases in symptom severity (eg, to allergens, respiratory viruses).1 This “flexible dose approach” to treatment suggests that ICS therapy may be increased temporarily in response to some index of worsening asthma, usually an increase in symptoms, nighttime awakenings, decrease in peak flow rate, or use of rescue medications; it remains subject to continued study and discussion.12–15 In the future, such dose adjustments may be based on measurement of a simple biomarker of airway inflammation in children; sputum eosinophils and exhaled nitric oxide are being studied but require further validation.16,17
USING ICSs IN INFANTS AND YOUNG CHILDREN (≤5 YEARS OLD)
As in older children and adults, the use of ICSs in infants and young children is directed toward symptom control, preventing exacerbations, and improving the child's (and family's) quality of life. Treatment with ICSs should not be initiated or prolonged to alter the progression or underlying severity of asthma.1
Data on the use of ICSs to treat asthma in young children, particularly infants, are limited. Most treatment recommendations are based on expert opinion and extrapolations from studies in older children and adults.1 The most common symptoms of asthma in this population are wheeze and cough, which are frequently associated with other conditions.18–20 A diagnostic trial of ICSs is recommended if asthma is suspected.
A predictive clinical index (the modified Asthma Predictive Index [mAPI]) to identify children ≤3 years old who might be at high risk for developing asthma has been developed and validated on the basis of data from the Tucson Children's Respiratory Study.18,21 In preschool-aged children a positive mAPI was associated with ≥4 severe wheezing episodes requiring use of oral corticosteroids (OCSs) in 12 months and increased hospitalizations and urgent care visits for asthma.21,22 The recommendation of the EPR3 regarding which young child is appropriate for ICS therapy builds on the mAPI (Table 4).
ICSs approved by the Food and Drug Administration (FDA) in the United States for young children (≤5 years old) include budesonide inhalation suspension (BIS), which is approved for children as young as 12 months, and fluticasone propionate (FP) dry powder inhaler (DPI) and hydrofluoroalkane formulations, which are approved for children as young as 4 years. Beclomethasone dipropionate (BDP) hydrofluoroalkane is only approved for children aged ≥5 years. Although not approved for young children and there are no data regarding dosing, efficacy, or safety in this population, many pediatricians will use a diagnostic trial of any of these ICSs as they deem necessary. Figure 2 presents an algorithm for a diagnostic trial of ICSs in infants and young children.
SAFETY OF ICSs IN CHILDREN
Regardless of age, few patients report serious adverse events (AEs) with ICSs at the recommended dosages, even with long-term use.23–26 Most clinical benefit with ICSs is achieved at relatively low doses, further reducing the potential risk of AEs.1 Nonetheless, as for any regularly used medication, children should be monitored regularly for potential systemic AEs, particularly because some children may be more susceptible to the effects of ICSs even at conventional doses. Suggestions for reducing AEs associated with ICSs are shown in Table 5.
Of greater concern has been the potential effect of ICSs on linear growth. Again, the available data for low- to medium-dose ICSs show a minimal effect on growth velocity: a reduction of ∼1 cm in the first year of treatment in some children. This decrease, when observed, usually does not progress over time, and long-term studies have indicated that these children attain their full adult height.18,28–32 All children using ICSs should be monitored by stadiometry and, if possible, measured by the same person at each clinic visit.1 Although no specific clinical cutoffs are provided in the EPR3, my approach in practice is to (1) reduce the ICS dose if there is slowing of growth at the 3-month visit and the child's asthma is stable and (2) stop ICSs and consider changing the medication or the device if the child is still not growing after 6 months. A reduction in growth velocity also results from inadequate control of asthma.1 Table 6 summarizes the evidence-based findings of the 2007 EPR3.
For children with difficult-to-control asthma, who require higher doses of ICSs, the use of adjunctive long-term control therapy is recommended to reduce the dose of ICSs and, thus, minimize possible dose-related long-term effects on growth (Fig 1).1 High doses of ICSs administered for prolonged periods of time (eg, >1 year), particularly in combination with frequent courses of OCSs, may be associated with adverse growth effects. However, the benefits of early intervention with ICSs may outweigh the potential small reduction in growth velocity in these children (Table 6).1,18,32
THE EFFECT OF ICSs ON THE DOMAINS OF IMPAIRMENT AND RISK IN CHILDREN
Eighteen randomized, placebo-controlled studies involving >8000 children (0–17 years old) met the criteria for reviewing monotherapy with ICSs: 13 double-blind studies of ICSs alone (Table 7) and 4 double-dummy studies comparing ICSs to a nonsteroid antiinflammatory agent (Table 8). One study, the Childhood Asthma Management Program (CAMP), was a double-blinded trial that compared nedocromil sodium (NED), budesonide, and matched placebos and is included in Tables 7 and 8. Approximately 4900 children were exposed to ICSs in these studies.
In most of the studies, the children had mild or moderate persistent asthma as defined by symptoms, use of short-acting bronchodilator (SAB), and/or need for daily asthma medications. At study entry all children were using ≥1 asthma medication, an SAB with or without a controller medication (ICSs, cromolyn sodium). For children who were able to perform spirometry, baseline forced expiratory volume in 1 second (FEV1) ranged from 70% to >90% predicted.
Study duration was ≥12 weeks, and dosing frequency for ICSs was twice or less daily.
Double-Blind, Placebo-Controlled Studies
A total of 6700 children received placebo (n = 2696) or an ICS (n = 4004) for ≥12 weeks. The ICSs included budesonide, 200 to 2000 μg/day (n = 2941), FP, 100 to 200 μg/day (n = 826), or BDP hydrofluoroalkane, 80 to 160 μg/day (n = 237).
Three studies evaluated >2 years of treatment with budesonide (n = 1951) or FP (n = 143).18,29,33 Five studies evaluated young children and/or infants (mean age: <5 years).18,34–37 The results were comparable to the studies conducted in school-aged children (mean age: >5 years).
Treatment with ICSs clearly improved measures of impairment. Benefits in the risk domain were also observed, where reported.
Significant improvements in symptoms with ICSs compared with placebo were evident as mean reductions in symptom scores and increased numbers of days free from asthma (symptoms) or “episode-free days.”18,29,33–43 In young children (<30 months old), significantly less daytime and nighttime wheezing (P < .05 and P < .01, respectively) were reported with BIS versus placebo, but the specific scores and/or between-treatment changes were not provided.35 A similar population had significant increases in the percentage of days without cough (P = .011) or wheeze (P = .002) when treated with FP.37 Improvements in symptoms were maintained with long-term treatment (≥2 years).18,29,33
The symptom improvements were observed regardless of the patient's therapy before randomization. In some studies, patients were allowed to use their regular asthma medications (including ICSs) up to the point of randomization; other studies were conducted in steroid-naive patients or required a steroid-free run-in period before trial entry. In the studies reported by Baker et al34 (1999) and Peden et al41 (1998), children were permitted to use their regular asthma medications through the run-in period; in these studies, 31% and 45% of children used ICSs up to random assignment to BIS and FP, respectively. Shapiro et al43 (2001) specifically evaluated the ability of once-daily (qd) budesonide to maintain asthma control in children who had been previously receiving ICSs; all children used their maintenance ICSs up to random assignment, and 87% were using ICSs twice daily (bid). In most studies, all controller medications were withdrawn before random assignment. However, Chen et al33 (2006) reported a subanalysis of data for 5- to 10-year-olds in the Steroid Treatment as Regular Therapy (START) trial, a 3-year study in which budesonide was added to the usual care of patients diagnosed with mild asthma who had not regularly used ICSs.32,33 Added medications were tracked, but changes in usual care medications were not.32,33
Concomitant with fewer symptoms, ICS use was associated with significant reductions in daily and/or as-needed (prn) SAB.29,34,36–43 deBlic et al35 (1996) observed a slightly shorter duration of nebulized albuterol in infants treated with BIS compared with placebo, but the difference was not statistically significant. Although use of prn SAB was not reported, young children treated with FP for 2 years required less added controller medication (montelukast [P < .001] or additional FP [P < .001]) than placebo-treated children.18 A similar trend was observed in older children treated with budesonide for 3 years in the START trial; again, specific use of prn SAB was not reported.33
It is difficult to make comparisons between the studies regarding degree of symptom improvement because of differences in populations and study design. Presumably, for the patients who used ICSs through the run-in period, any statistically significant between-treatment differences resulted from deterioration of asthma control in the placebo group rather than substantial increases in asthma control with the ICSs. However, no subanalyses were performed, leaving this to speculation.
Eight of the ten 12-week studies reported pulmonary function test results.34,36,38–43 In all cases, children treated with ICSs had small but significant increases in FEV1 compared with placebo-treated children regardless of ICS use before random assignment.
Two of the long-term studies included children who were able to perform spirometry: CAMP and START. In both studies, ICS use was associated with slight improvements in FEV1 in the first year that gradually decreased throughout the treatment period so that no significant between-treatment differences were evident at trial end.29,32,33
Five studies assessed exacerbations or worsening of asthma requiring a short course of OCSs.18,29,35,40,42 Children treated with ICSs required significantly fewer courses of OCSs regardless of whether they were ≥5 or <5 years old.18,29,35 Although significance was not noted, 2 studies reported more OCSs for “worsening asthma” in school-aged children treated with placebo or usual care compared with budesonide.33,42 More infants and preschoolers (<48 months old) were “exacerbation-free” with FP treatment compared with placebo treatment (P = .033).37
Nayak et al40 (2002) noted a trend toward later onset of “time to first exacerbation” with hydrofluoroalkane-BDP, but statistical significance was not reached. The addition of qd budesonide to usual care was associated with a significant increase in the time to first severe asthma-related event (SARE) in children between 5 and 10 years of age in the START trial.33 The risk of an SARE decreased by 40% with the addition of budesonide to usual care (hazard ratio: 0.60; P = .012).33
Children treated with budesonide had significantly fewer hospitalizations and urgent care visits than placebo-treated children during the 4 to 6 years of the CAMP.29 Fewer hospitalizations were also reported during 2 years of FP, although statistical significance was not achieved.18 In the START trial, adding budesonide to usual care was associated with a 50% reduction in hospitalizations and a 34% decrease in emergency visits over 3 years; statistical significance was approached but not achieved.33,44 Additional comparisons are difficult because of differences between studies in both design and study population.
All ICSs used in these studies were well tolerated, and there were no serious AEs related to any of the study medications. Seven studies evaluated hypothalamic-pituitary-adrenal axis function.34,36,38–41,43 No ICS-specific changes were observed except for a small decrease in urinary cortisol reported in some children treated with FP who had previously used ICSs.38
No changes in growth with ICSs were reported in two 12-week studies.34,35 However, small decreases in growth with ICSs were reported in the 3 long-term studies.18,29,32 Compared with usual care alone, children treated with budesonide showed a reduction in growth of 0.43 cm/year (P < .001) in the START trial regardless of dosing at 400 or 200 μg/day.32 In the CAMP, the mean increase in height was also lower (by 1.1 cm) with budesonide.29 The long-term study of FP showed a small but significant difference in height percentiles after 2 years (FP: 51.5%; placebo: 56.4% [P < .001]).18 Where assessed, these changes in growth rates were predominant during the first year of treatment, and all groups had similar rates of growth at the end of the treatment periods.18,29 “Catch-up growth” was not evaluated. No other systemic effects were observed in these studies.
Controlled Comparisons With Nonsteroid Antiinflammatory Medications
Five placebo-controlled studies comparing an ICS to a nonsteroid antiinflammatory medication are described in Table 8.29–31,45–47 These studies included 2806 children: 1222 were exposed to ICSs (budesonide, 200 μg bid [n = 311]; FP, 50–100 μg bid [n = 908]), and 1216 received comparator nonsteroid medications (NED, 8 mg bid [n = 312]; montelukast, 5–10 mg qd [n = 904]). The CAMP included matching placebos for budesonide and NED (n = 418).29 In addition, 1 of the trials comparing FP and montelukast included a third group of children who were treated with the combination of FP and salmeterol, 100 μg/50 μg in the morning and salmeterol alone, 50 μg, in the evening.31
Each trial was unique, which makes comparisons difficult. Treatment duration ranged from 12 weeks to 6 years. The inhaled medications were given twice daily; montelukast (tablet or sprinkles) was given once per day, usually in the evening. All children were only using an SAB at random assignment.
Overall, treatment with ICSs improved measures of impairment and risk to a greater extent than the nonsteroid antiinflammatory medications.
Impairment was evaluated by symptom scores, episode-free days (or asthma-control days), and rescue-medication use. Compared with montelukast, FP-treated patients had more asthma-control days, episode-free days, and rescue-free days.30,31,45,46 Ostrom et al45 (2005) also reported significant reductions in nighttime asthma symptoms (P < .001) and rescue albuterol use (P = .018) with FP compared with montelukast.
In the CAMP, both NED and budesonide improved asthma symptoms, episode-free days, and albuterol use compared with placebo treatment.29 Differences between the active treatments did not reach statistical significance, but the clinical improvements were consistently greater with budesonide; only budesonide attained statistical significance compared with placebo.29
Improvements in asthma exacerbations favored FP over montelukast when measured as the time to first prednisone burst (P = .002)31 or worsening of asthma requiring a short course of OCSs (P = .019; P = .001).30,46 Compared with placebo, both budesonide and NED significantly reduced the number of prednisone courses per 100 person-years and the number of asthma-related urgent care visits.29 The decreases were greater with budesonide, but the differences were not statistically significant. Only budesonide significantly decreased the number of asthma-related hospitalizations.29
All treatments in the comparator studies were well tolerated, with no significant between-treatment differences for AEs and no serious AEs related to any of the study drugs. Small reductions in growth rates were observed with ICSs versus the comparator medications in the 2 long-term studies.29–31 No other systemic effects were observed.
Children with asthma remain a significant challenge, particularly as the relationship between early treatment of asthma symptoms and the development of adult disease is not yet clearly delineated. ICSs are recommended as the primary controller medication for children (as well as adults) with asthma. The efficacy and safety of ICSs to treat children has been well documented, although the data are more limited than for adults.1 When used at indicated doses, ICSs are safe. However, efficacy with dose plateaus; thus, when a child is symptomatic, it may be better to add another medication rather than increase the dose of ICSs beyond medium.1 Discussion of what to add is beyond the scope of this article. The evidence reviewed in the EPR3 suggests that the addition of a long-acting bronchodilator (LABA) provides greater asthma control than increasing the dose of ICSs or adding a leukotriene modifier.1 However, adjunctive therapy for children between 5 and 11 years of age has not been well studied, and data are lacking for younger children.1 The reader is directed to the EPR3,1 and other resources for parents of children with asthma may be helpful.48
The National Asthma Education and Prevention Program guidelines continue to serve as a basis for treatment recommendations; the latest report describes a new paradigm targeting asthma control through the domains of impairment and risk.1 This systematic review strengthens previous evidence (reported in the EPR2 and clinical practice guidelines) supporting the safe and effective use of ICSs to treat children with asthma. In addition, the data provide new evidence linking ICS use in children with asthma to improved asthma control as now defined by the EPR3 according to the domains of risk and impairment. Data from placebo-controlled studies confirm that treatment with ICSs improves both domains in children (0–17 years old).18,29–43,45–47
Compared with placebo, ICS treatment was associated with reductions in the impairment domain reported as symptoms scores, specific symptom episodes, episode-free days (or asthma-control days), rescue-free days, and/or rescue-medication use.
Compared with placebo, ICS treatment was associated with reductions in the risk domain evident as increased FEV1 (in children able to perform spirometry), fewer courses of OCSs, decreased exacerbation rates, and/or less use of urgent care services.
The reductions in the impairment and risk domains observed with ICSs were generally greater than reductions observed with nonsteroid antiinflammatory comparator medications.
ICSs were well tolerated in all studies.
Small reductions in growth rates compared with placebo and/or comparator nonsteroid antiinflammatory medications were evident in several long-term (>1-year) studies.18,29–32 These changes decreased with time, and the clinical significance is unclear. Other data suggest that asthmatic children treated with ICSs attain their full adult height despite initial reductions in growth rates.29,49
More in-depth comparisons are difficult to make because of differences in study protocols.
Additional studies that use appropriate indicators for impairment and risk are warranted. For impairment, rescue-medication use, daytime and nighttime symptom scores, and asthma/episode-free days are recommended as indicators. For risk, FEV1 should be reported for children who can perform spirometry; exacerbations that require OCSs and urgent care usage are also suggested as indicators. Attention should be given to standardizing variables that can be used to compare outcomes between trials.
The majority of pediatric data are for children ≤12 years; only 5 of the 18 studies included adolescents (13–18 years old).30,31,38,43,46 Data for this population are lost when assessing childhood asthma, either grouped with adults (eg, studies in patients ≥12 years old) or not included (eg, studies of school-aged children ≤12 years old). More studies are needed to evaluate whether diagnosing asthma and starting therapy early affects the course of the disease in adolescence. More information is also needed to assess how treatment can better meet the needs of the adolescent patient.
The evidence presented in this systematic retrieval and review of the literature is not ranked, because this is the work of a single author and not a committee. However, the studies chosen were separated according to design: double-blind, placebo-controlled studies and randomized, controlled, comparison trials. No nonrandomized trials or observational studies were included. Thus, all of the data collected in this review would fall into category A and B evidence according to the definitions in the EPR3.1
Asthma is a complex and heterogeneous disease. Many factors affect impairment and risk and influence choice of therapy. Not addressed in this article but of significant impact are adherence with treatment, environmental control, comorbid conditions, differences in delivery devices, and penetration of medication into the small airways. The reader is directed to the EPR3 for additional information.1
In summary, the available data indicate that ICSs improve asthma control in children by reducing both impairment and risk associated with the disease and support current recommendations for treatment.
This work was funded partially by an unrestricted educational grant from Teva Pharmaceuticals.
The expert research and technical support of Judith Farrar, PhD, is greatly appreciated; this publication would not have been possible without her editorial assistance.
- Accepted April 16, 2008.
- Address correspondence to Gary Rachelefsky, MD, FAAP, Executive Care Center for Asthma, Allergy, and Respiratory Diseases, Geffen School of Medicine at UCLA, 200 Medical Plaza, Suite 140-17, Los Angeles, CA 90095. E-mail:
The author has indicated he has no financial relationships relevant to this article to disclose.
- ↵National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health; 2007. Available at: www.nhlbi.nih.gov/guidelines/asthma. Accessed October 30, 2007
- ↵Centers for Disease Control and Prevention, National Center for Health Statistics. Summary health statistics for U.S. children: National Health Interview Survey, 2005. Available at: www.cdc.gov/nchs/data/series/sr_10/sr10_231.pdf. Accessed October 25, 2007
- ↵Centers for Disease Control and Prevention, National Center for Health Statistics. Asthma prevalence, health care use and mortality: United States, 2003–05. Available at: www.cdc.gov/nchs/products/pubs/pubd/hestats/ashtma03-05/asthma03-05.htm. Accessed October 25, 2007
- Holt S, Suder A, Weatherall M, Cheng S, Shirtcliffe P, Beasley R. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ.2001;323 (7307):253– 256
- ↵Masoli M, Weatherall M, Holt S, Beasley R. Systematic review of the dose-response relation of inhaled fluticasone propionate. Arch Dis Child.2004;89 (10):902– 907
- ↵Fabbri L, Burge PS, Croonenborgh L, et al. Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. International Study Group. Thorax.1993;48 (8):817– 823
- Gustafsson P, Tsanakas J, Gold M, Primhak R, Radford M, Gillies E. Comparison of the efficacy and safety of inhaled fluticasone propionate 200 micrograms/day with inhaled beclomethasone dipropionate 400 micrograms/day in mild and moderate asthma. Arch Dis Child.1993;69 (2):206– 211
- ↵van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiverman EJ, Pocock SJ, Kerrebijn KF. Effects of 22 months of treatment with inhaled corticosteroids and/or beta2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. The Dutch Chronic Non-specific Lung Disease Study Group. Am Rev Respir Dis.1992;146 (3):547– 554
- ↵Agertoft L, Pedersen S. Short-term knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose response study. Eur Respir J.1997;10 (7):1507– 1512
- ↵Garcia Garcia ML, Wahn U, Gilles L, Swern A, Tozzi CA, Polos P. Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study [published correction appears in Pediatrics. 2005;116(4):1058]. Pediatrics.2005;116 (2):360– 370
- ↵Chen YZ, Busse WW, Pedersen S, Tan W, Lamm CJ, O'Byrne PM. Early intervention of recent onset mild persistent asthma in children aged under 11 yrs: the Steroid Treatment as Regular Therapy in Early Asthma (START) trial. Pediatr Allergy Immunol.2006;17 (suppl 17):7– 13
- ↵Baker JW, Mellon M, Wald J, Welch M, Cruz-Rivera M, Walton-Bowen K. A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics.1999;103 (2):414– 421
- ↵Shapiro G, Mendelson L, Kraemer MJ, Cruz-Rivera M, Walton-Bowen K, Smith JA. Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules in young children with inhaled steroid-dependent persistent asthma. J Allergy Clin Immunol.1998;102 (5):789– 796
- ↵Rachelefsky G. Free Your Child From Asthma. New York, NY: McGraw-Hill; 2006
- Copyright © 2009 by the American Academy of Pediatrics