Sage Journals: Discover world-class research

Abstract

The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy for adult, as well as pediatric, patients with asthma. However, the use of LABAs has raised safety concerns, especially the potential for severe asthma exacerbations (SAEs) resulting in hospitalizations or even death. Meanwhile, the use of inhaled corticosteroids (ICSs), a cornerstone in the treatment of mild-to-severe persistent asthma, has been associated with growth suppression in children. The purpose of this review was to identify and discuss the major published safety studies surrounding LABA, ICS, and combined LABA/ICS usage in children. By way of a critical search for influential published clinical trials, meta-analyses, and observational studies, six studies relevant to the safety of LABA monotherapy, seven studies relevant to ICS monotherapy, and four studies on the subject of LABA/ICS combination usage were identified and reviewed. Based on the reviewed literature, the controversy surrounding these anti-asthma medications was clearly exposed. On the one hand, there is some evidence that LABA monotherapy may be associated with SAEs and asthma-related death, while ICS monotherapy may be associated with a higher risk of growth suppression. On the other hand, the concurrent use of a LABA with an ICS has been associated with positive outcomes including symptom reduction and reduced rate and severity of exacerbations. Further clinical research is warranted and has been called for by the US Food and Drug Administration.

Keywords

Drug safety growth suppression inhaled corticosteroids long-acting beta-agonists pediatric asthma serious asthma exacerbations

Introduction

Asthma, a chronic inflammatory disorder associated with variable airflow obstruction and bronchial hyperresponsiveness, is the most common chronic lower respiratory disease in children worldwide. It presents with recurrent episodes of wheeze, cough, shortness of breath, and chest tightness [Papadopoulos et al. 2012]. In the United States in 2011, there were an estimated 7.1 million pediatric patients suffering from asthma (representing a 9.5% prevalence rate) who accounted for 27.3% of the total asthma-patient population in the US [Centers for Disease Control and Prevention, 2011].

Children with asthma are limited in their day-to-day activities such as sports, school, and playing with pets, significantly reducing quality of life. In addition, children with asthma can be distressed by asthma symptoms and can become frightened by asthma attacks or exacerbations [Juniper, 1997]. Meanwhile, parents or caregivers of children with asthma are affected by both absenteeism from and lost productivity at work [Wang et al. 2005]. Epidemiologic studies tend to show that children do not grow out of asthma. Even if the symptoms disappear, asthma tends to reappear in adulthood [Braman, 2006]. Moreover, some children with mild asthma as children will have severe disease as adults [Braman, 2006]. Pediatric asthma is estimated to be responsible for approximately 13 million missed school days annually in the US [Akinbami et al. 2010]. In 2004, pediatric asthma was responsible for 7 million ambulatory visits (to either physician offices or hospital outpatient departments), 750,000 visits to emergency departments, 198,000 hospitalizations, and 186 deaths [Akinbami, 2006]. The annual cost of pediatric asthma in the US has been estimated at US$3.2 billion [Weiss et al. 2000]. The lifetime cost of pediatric asthma for a cohort of people born in the year 2000 in the US is estimated to be US$7.2 billion, including US$3.2 billion in medical costs and US$4 billion in work/productivity loss experienced by both the patients and their parents [Corso and Fertig, 2009]. Asthma disproportionately impacts low-income children in the US relative to the pediatric population in general, partly because of the substantial exposure poor children have to asthma triggers, such as dust and dust reservoirs, dust mites, roaches, rodents, molds, and tobacco smoke, that could exacerbate their condition [Krieger et al. 2000].

Pharmacotherapy is fundamental to the treatment of pediatric asthma. Its goal is the control of symptoms and the prevention of exacerbations with a minimum of drug-related side effects. Short-acting inhaled β₂ agonists (SABAs) are the most commonly used reliever medications for pediatric patients with asthma for the treatment of intermittent and acute asthma episodes. For children with intermittent asthma, a SABA is the only asthma medication they may take. For children with persistent asthma, controller medications are used to reduce bronchial inflammation. Inhaled corticosteroids (ICSs) are used as first-line controller treatment. The patient is generally started at a low dose (200 µg BDP equivalent); if control is inadequate, the dose may be increased. Leukotriene receptor antagonists (LTRAs) are an alternative first-line therapy for pediatric patients between the ages of 5 and 11 years old with mild persistent asthma who cannot use ICSs or an add-on therapy for those children whose asthma is not adequately controlled with ICS treatment alone [Bacharier et al. 2008]. The benefit of LTRAs has been shown in children as young as 10 months, although Singulair was approved for patients 12 months and older for asthma [Straub et al. 2005]. For patients who remain uncontrolled, a long-acting β₂ agonist (LABA) may be added; in step therapy, at an earlier step for children aged 5–11 years, and a later step for children 0–4 years old [U.S. Department of Health and Human Services, 2007]. LABA/ICS combination drugs are also available and are an important treatment option at least for a subpopulation of older children [Lemanske et al. 2010]. For a list of anti-asthma medications, categorized by drug class, see Table 1.

Table 1.

Anti-asthma medications by drug class.

Drug class	Generic name	Brand name(s)
Short-acting beta agonists (SABAs)	Albuterol	Proventil®, Ventolin®
	Albuterol sulfate	Accuneb®,ProAir HFA®, Proventil-HFA®,Ventolin-HFA®,VoSpire ER®
	Albuterol sulfate / Ipratropium bromide	Combivent®, DuoNeb®
	Levalbuterol hydrochloride	Xopenex®
	Levalbuterol tartrate	Xopenex HFA®
	Metaproterenol sulfate	Alupent®
	Pirbuterol acetate	Maxair®
	Terbutaline sulfate	Brethaire®, Bricanyl®
Long-acting beta agonists (LABAs)	Aformoterol tartrate
	Formoterol fumarate	Foradil®, Perforomist®
	Salmeterol xinafoate	Serevent®
Inhaled corticosteroids (ICSs)	Beclomethasone dipropionate	Qvar®
	Budesonide	Pulmicort®
	Ciclesonide	Alvesco®
	Flunisolide	AeroBid®, AeroSpan HFA®
	Fluticasone propionate	Flovent Diskus®, Flovent HFA®
	Mometasone furoate	Asmanex Twisthaler®
	Triamcinolone acetonide	Azmacort®
LABA/ICS combination drugs	Formoterol fumarate dihydrate / Budesonide	Symbicort®
	Formoterol fumarate / Mometasone Furoate	Dulera®
	Salmeterol xinafoate / Fluticasone propionate	AdvairDiskus®, Advair HFA®
Leukotriene receptor antagonists (LTRAs)	Montelukast sodium	Singulair®
	Zafirlukast	Accolate®
	Zileuton	Zyflo®, Zyflo CR®
Other anti-asthma medications	Cromolyn sodium	Intal®
	Methylprednisolone	Medrol®, Solu-Medrol®
	Omalizumab	Xolair®
	Prednisolone sodium phosphate	OraPred®, OraPred ODT®
	Prednisone	Deltasone®, Rayos®

In terms of pediatric asthma management, physicians face a delicate balance between drug safety and efficacy to achieve optimal therapeutic benefits for individual patients. Although there are side effects, such as tachycardia, dizziness, and jitteriness, associated with SABAs, these drugs tend to have generally favorable safety profiles, even in very young patients [Bacharier et al. 2008]. LTRAs are also generally safe and well-tolerated with an overall incidence of adverse events similar to placebo [Knorr et al. 2001]. The most commonly encountered side effects with LTRAs are headache and gastrointestinal upset [Bacharier et al. 2008].The importance of LTRAs in the management of pediatric asthma as well as safety issues surrounding their use are discussed in a number of recent studies [Montuschi et al. 2007; Montuschi, 2008, 2011; Montuschi and Peters-Golden, 2010; Montuschi and Barnes, 2011].

Since their introduction, however, LABAs have been associated with very serious safety issues. Several studies have presented evidence of significant risk of exacerbations and asthma-related death associated with LABA use. Meanwhile, although serious side effects are unusual, ICSs are associated with at least temporary growth suppression [Bacharier et al. 2008]. This study describes and discusses the current state of the evidence regarding LABA and ICS safety in the pediatric patient population, by reviewing some of the most impactful clinical trials, meta-analyses, and observational studies. As will become clear from this review, some of the important studies included both adults and children, while some were pediatric-specific. None of the studies involved children younger than 4 years old, hence, safety evidence has been extrapolated to that very young patient population in various treatment guidelines. For a list of studies reviewed, see Table 2.

Table 2.

Summary of influential pediatric long-acting beta agonist ( LABA) and inhaled corticosteroid (ICS) safety studies.

Study	Study design	Drug class	Pediatric only	Time period	Sample size if applicable	Major findings
Allen et al. [1998]	Randomized, blinded, parallel group, placebo-controlled clinical trial	ICS	Yes	1 year	325	ICS-treated children grew at rates similar to placebo-treated control subjects
Bensch et al. [2002]	Randomized, blinded, placebo-controlled clinical trial	LABA	Yes	1 year	518	Incidence of hospitalizations for asthma higher in formoterol groups versus placebo group
Bisgaard [2003]	Meta-analysis covering 8 randomized, blinded, clinical trials for pediatric patients	LABA	Yes	≥6 weeks	2,401	LABA use did not protect pediatric patients from asthma exacerbations compared to patients receiving an ICS, short-acting inhaled β₂ agonist (SABA), or placebo; there was a significant increase in asthma-related hospitalizations for children taking a LABA
Castle et al. [1993]	Randomized, blinded, parallel group, clinical trial	LABA	No	16 weeks	25,180	Twelve asthma-related and respiratory deaths in salmeterol group versus two in salbutamol group
Childhood Asthma Management Program Research Group [2000]	Randomized, blinded, placebo-controlled, clinical trial	ICS	Yes	4–6 years	1,041	Children assigned to ICS had lower growth than those assigned to nedocromil (mast stabilizer) or placebo
Garcia Garcia et al. [2005]	Randomized, blinded, noninferiority, clinical trial	ICS	Yes	1 year	994	Children assigned to ICS had lower growth compared with those assigned an leukotriene receptor antagonist
Guilbert et al. [2006]	Randomized, blinded, placebo-controlled, clinical trial	ICS	Yes	2–3 years	285	Children assigned to ICS had lower growth than those assigned to placebo
Guo et al. [2011]	Retrospective population-based cohort study for Medicaid patients ≤40 years old	LABA	No	6 years	940,449	Relative to SABA-only use, LABA use is associated with a higher risk of hospitalization but lower risk of emergency-department visit
Malone et al. [2005]	Randomized, blinded, parallel group, active controlled, clinical trial	LABA/ICS	Yes	12 weeks	203	Safety profile for LABA/ICS treatment similar to that of ICS-only treatment
Nayak et al. [2002]	Randomized, blinded, parallel group, placebo-controlled, clinical trial	ICS	Yes	12 weeks	353	No difference in the incidence or nature of adverse events between ICS and placebo groups
Nelson et al. [2006]	Randomized, blinded, parallel group, placebo-controlled, observational study	LABA	No	28 weeks	26,355	Rate of asthma-related deaths or life-threatening experiences was significantly higher for patients on LABA therapy compared with placebo
Pauwels et al. [2003]	Randomized, blinded, placebo-controlled clinical trial	ICS	No	3 years	7,241	3-year growth in children was reduced in the budesonide group by 1.34 cm; reduction was greatest in the first year
Rodrigo et al. [2009]	Meta-analysis covering 92 randomized, blinded, clinical trials	LABA/ICS	No	≥4 weeks	74,092	LABA/ICS-versus-ICS studies showed that combination therapy reduced exacerbations and hospitalizations and was equivalent to ICS monotherapy in terms of life-threatening events and asthma-related deaths
Simons [1997]	Randomized, blinded, parallel group, placebo-controlled clinical trial	ICS	Yes	1 year	241	Growth was lower in children taking an ICS versus those on a LABA medication or placebo
Tal et al. [2002]	Randomized, blinded, parallel group, double-dummy clinical trial	LABA/ICS	Yes	12 weeks	286	Treatment groups were similar in terms of their adverse-event profile and rates of discontinuation
von Berg et al. [1998]	Randomized, blinded, parallel group, placebo-controlled clinical trial	LABA	Yes	1 year	426	Exacerbation rates did not vary between salmeterol and placebo groups
Zimmerman et al. [2004]	Randomized, blinded, parallel group, placebo-controlled clinical trial	LABA/ICS	Yes	12 weeks	302	No difference in asthma exacerbations between LABA/ICS and ICS-only groups

LABA studies

The Serevent Nationwide Surveillance (SNS) study was a randomized, double-blind, clinical trial with parallel groups over 16 weeks, which was designed to compare the safety of salmeterol (LABA) and salbutamol (SABA) in asthma treatment. There were 25,180 subjects, with approximately 6% between the ages of 12 and 18, who participated in treatment. The SNS study found no statistically significant differences between the two groups in terms of risk of hospital admission, risk of life-threatening event, or risk of other serious event. However, there were 12 asthma-related deaths in the salmeterol group versus 2 in the salbutamol group [Castle et al. 1993].

The Salmeterol Multicenter Asthma Research Trial (SMART) was a randomized, double-blind, parallel-group, placebo-controlled, observational study over 28 weeks involving 26,355 asthmatic patients at least 12 years old. The trial found that the rate of respiratory-related deaths or life-threatening experiences was not significantly different (relative risk [RR] = 1.40, 95% confidence interval [CI] 0.91–2.14) for salmeterol versus placebo patients. However, there was a statistically significant difference between salmeterol and placebo for asthma-related deaths or life-threatening experiences (RR = 1.71, 95% CI 1.01–2.89) [Nelson et al. 2006].

In a much smaller, but pediatric-focused, multicenter, randomized, double-blind, and parallel study by von Berg and colleagues, a total of 426 children aged 5–15 years were randomly assigned to receive salmeterol 50 µg or placebo twice daily. The study design included a 2-week baseline period, a 12-month treatment period incorporating a 2-week period ‘off treatment’ after 6 months, and a 2-week follow-up period at the end of the study. The study found that 109 (53%) patients assigned a placebo experienced an asthma exacerbation compared with 137 (62%) patients in the salmeterol group; this difference was not statistically significant (p = 0.2) [von Berg et al. 1998].

In a randomized, double-blind, placebo-controlled, multinational, multicenter study, Bensch and colleagues examined the efficacy and safety of formoterol dry powder in pediatric asthma patients. A total of 518 children aged 5–12 years were randomly assigned to receive 12 or 24 µg of formoterol dry powder or placebo twice daily for 12 months. Results showed 68 (40%) patients in the formoterol 24 µg group, 67 (39%) patients in the formoterol 12 µg group, and 71 (41%) patients in the placebo group experienced asthma exacerbations. Again, there was no statistically significant difference in the number of asthma exacerbations across the treatment groups [Bensch et al. 2002].

In a pediatric-specific meta-analysis, Bisgaard examined the asthma-related exacerbation rates of LABA drugs in pediatric asthma patients. Eight studies (including those by Bensch and colleagues and von Berg and colleagues mentioned above) were included, with a total of 2,401 patients 4–17 years old with mild-to-severe persistent asthma [Bisgaard, 2003]. The conclusion was that LABA treatment with either salmeterol or formoterol, among children taking an ICS, provided no additional protection from asthma exacerbation compared to children receiving a SABA or placebo. A significant increase in asthma-related hospitalizations (the RR ranged from 3.3 to 21.6 across the three studies that included hospitalizations as study endpoints) was, however, observed for children taking a LABA.

In a large, retrospective, cohort, database study with close to 1 million Medicaid patients (out of which there were 767,715 children less than 18 years old) in 10 states over 6 years, Guo and colleagues came to a similar conclusion regarding hospitalizations. Compared with patients taking a SABA only, LABA use in patients with pre-existing asthma was found to be positively associated with hospitalizations and intubations. On the other hand, the estimated hazard ratio for emergency-department visits was 0.68 (95% CI 0.63–0.73) for those same patients with pre-existing asthma. After controlling to the greatest extent possible for patient severity, patients taking a LABA were less likely to go to the emergency room than those on a SABA only [Guo et al. 2011].

ICS studies

A number of studies have reported a direct association between ICS use and short-term growth suppression. Simons and colleagues conducted a randomized, double-blind, placebo-controlled, parallel-group, 1-year study on the use of ICSs by 241 pediatric asthma patients. During the study period, height on average increased by 3.96 cm in the beclomethasone group (200 µg twice a day), which was significantly (at least statistically) less than both the average growth in the placebo group (5.04 cm, p = 0.018) and the average growth in the salmeterol group (5.40 cm, p = 0.004) [Simons et al. 1997].

The Childhood Asthma Management Program Research Group found similar results through a double-blind, placebo-controlled study. A total of 1,041 children, aged 5–12 years old, with mild-to-moderate persistent asthma, were randomly assigned to receive budesonide (200 µg), nedocromil (8 µg, a mast cell stabilizer), or placebo twice daily. The study participants were treated for 4–6 years. The children taking budesonide grew on average 22.7 cm, statistically significantly (p = 0.005) less than the average growth of 23.8 cm among the children assigned the placebo [Childhood Asthma Management Program Research Group, 2000].

Pauwels and colleagues again found lower average growth among asthmatic children taking an ICS during a randomized, double-blind clinical trial. A total of 7,241 asthma patients with mild persistent asthma in 32 countries were enrolled in the study. Among them were 1,974 children aged 5–10 years old and 1,221 children and adolescents aged 11–17 years old. They were randomly assigned to receive budesonide or placebo once daily for 3 years. Results showed that the mean growth difference was 0.43 cm (p < 0.0001) less per year in the budesonide group than in the placebo group [Pauwels et al. 2003].

Garcia Garcia and colleagues examined the efficacy and safety of fluticasone versus montelukast in a 12-month, multicenter, randomized, double-blind, clinical trial. Out of a total of 994 patients with mild persistent asthma who were 6 to 14 years old, 499 were assigned fluticasone (100 µg, twice daily), and 495 received montelukast (5 µg, once daily). The results showed that the average growth was statistically significantly lower (p = 0.018) in the fluticasone group (5.81 cm) than in the montelukast group (6.18 cm) over a year’s time [Garcia Garcia et al. 2005].

Finally, in a randomized, double-blind clinical trial, a total of 285 pediatric asthma patients were randomly assigned to receive either fluticasone (88 µg, twice daily) or placebo for 2 years, then were followed for an additional year without medication. Compared with the placebo group, patients in the fluticasone group grew an average of 1.1 cm less (p < 0.001) over the first 24 months. However, the height increase was 0.7 cm less (p = 0.008) by the end of study period [Guilbert et al. 2006].

Conversely, some studies have shown no statistically significant association between ICS use and growth suppression. Allen and colleagues conducted a double-blind, placebo-controlled study with 325 pediatric asthma patients, age range of 4 to 11 years old, who were randomly assigned to receive a low dose of fluticasone (50 µg), a higher dose of fluticasone (100 µg), or a placebo twice daily for 1 year. The results showed that, by the end of study period, mean height increased 5.94 ± 0.16 cm in the 50 µg fluticasone group, 5.73 ± 0.13 cm in the 100 µg fluticasone group, and 6.15 ± 0.17 cm in the placebo group (p = 0.308, overall) [Allen et al. 1998].

Other research has studied the association between ICSs and other adverse events. Nayak and colleagues examined the efficacy and safety of beclomethasone dipropionate, formulated as an extra fine aerosol (hydrofluoroalkane-134a [HFA]-BDP), in children with moderate persistent asthma. A 12-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group study was conducted, with 353 children aged 5–12 years with persistent asthma enrolled. After a 2-week run-in period, children were randomized to receive low-dose HFA-BDP (80 µg), high-dose HFA-BDP (160 µg), or HFA-placebo twice daily. No statistically significant difference in the rate of adverse events was found across the groups [Nayak et al. 2002].

LABA/ICS combination studies

Although SMART was not designed to assess the effect of ICS use on asthma-related death or life-threatening experiences, post hoc analyses of the study results revealed that the higher risk of asthma-related deaths or life-threatening experiences held only for those not using an ICS at baseline. For those using an ICS, there was no statistically significant difference between the salmeterol and placebo groups [Nelson et al. 2006].

The meta-analysis by Rodrigo and colleagues also compared LABA/ICS combination therapy with ICS-only therapy. Their results showed that combination therapy could reduce exacerbations (RR = 0.73; 95% CI 0.67–0.79) compared with the ICS-only group. The results also showed there was no statistically significant difference between the LABA/ICS combination group and the ICS-only group (RR = 2.96; 95% CI 0.50–17.57) in asthma-related death [Rodrigo et al. 2009].

Zimmerman and colleagues conducted a double-blind, placebo-controlled, randomized, parallel-group, multicenter study. A total of 302 Canadian asthmatic children, aged 6–11 years, already taking an ICS medication, were enrolled in a 12-week study. The children were randomly assigned to receive either formoterol 4.5 µg, formoterol 9 µg, or placebo twice daily. A total of 19 asthma exacerbations occurred during the study, with no statistically significant difference across the groups [Zimmerman et al. 2004].

Malone and colleagues conducted a pediatric-specific randomized, double-blind, active-controlled, parallel-group study to compare the safety of inhaled fluticasone propionate with or without inhaled salmeterol. A total of 203 children aged 4–11 years were randomly assigned to receive salmeterol/fluticasone propionate (50/100 µg) or fluticasone propionate (100 µg) only twice daily for 12 weeks. The results showed that three (3%) patients in the salmeterol/fluticasone propionate group experienced asthma exacerbations, compared with eight (8%) patients in the fluticasone-propionate-only group [Malone et al. 2005].

Tal and colleagues conducted a double-blind, randomized, parallel-group, multicenter study, with 286 enrolled children, age 4-17 years old, with asthma. The asthmatic children were randomized to receive formoterol/budesonide (4.5/80 µg, twice daily) or budesonide (100 µg, twice daily). There were eight (5.4%) children in the formoterol/budesonide group who had asthma exacerbations, compared with four (2.9%) patients in the budesonide-only group [Tal et al. 2002], essentially the opposite of the result from the study by Malone and colleagues.

Discussion

Based on the results of the studies discussed in this article, as well as on its own research, the United States Food and Drug Administration (FDA) issued a safety announcement on February 18, 2010, regarding the use of LABAs in adults and children. The FDA’s announcement included the following: ‘Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure compliance with both medications’ [Food and Drug Administration, 2010]. At that time, the FDA also required a Risk Evaluation and Mitigation Strategy (REMS) for these products, which included a revised Medication Guide for patients and class-labeling changes. Although LABAs remain on the market, the FDA encourages them to be used at the lowest possible doses, for the shortest amount of time, and only in combination with ICSs [Food and Drug Administration, 2010].

Meanwhile, a number of studies have now been devoted to understanding the effect of ICS utilization on adult height, arguably a more important endpoint than a short-term growth rate. Doull summarized the results from a number of longitudinal studies, concluding that the vast majority of asthmatic children will attain a normal adult height [Doull, 2004]. With few side effects at recommended dosages and growth suppression a temporary phenomenon, the benefits of ICS treatment seem to outweigh the costs.

In its February 2010 safety announcement, the FDA asked that the LABA manufacturers conduct additional clinical trials to evaluate further the safety of LABAs when used in combination with ICSs. It did not feel that there was enough known about their safety in children. This decision was consistent with the conclusion reached by Cates and colleagues in their recent review of reviews: ‘Regular combination therapy is likely to be less risky than monotherapy in children with asthma, but we cannot say that combination therapy is risk free. There are probably an additional three children per 1000 who suffer a non-fatal serious adverse event on combination therapy in comparison to ICS over 3 months. This is currently our best estimate of the risk of using LABA combination therapy in children and has to be balanced against the symptomatic benefit obtained for each child.’ [Cates et al. 2012, p. 2].

Concerns over the safety of asthma medication obviously make treatment more difficult. Moreover, pediatric asthma can be hard to diagnose in the first place because a number of other childhood conditions, such as rhinitis, sinusitis, and respiratory tract infections, can have symptoms similar to those caused by asthma and can co-occur with asthma. In children aged 6 and older, physicians diagnose asthma using the same tests, including spirometry, used to diagnose the disease in adults [Mayo Clinic, 2013]. For younger children, there is a focus on the frequency and severity of symptoms including wheeze, nocturnal cough, exercise-induced symptoms, persistence of cough with colds, and exposure to environmental factors including allergens [Bacharier et al. 2008]. Because asthma is characterized by clinical variation in presentation throughout the course of the disease, there is a strong need for noninvasive assessment of airway inflammation. Progress is being made in researching the use of exhaled breath concentrate (EBC) to study concentration of leukotrienes and other biomarkers in asthma [Montuschi, 2009]. However, EBC requires additional study before being introduced to everyday clinical practice.

Although we have focused on asthma treatment in developed countries, asthma is a common disease in both high- and low-income countries, with prevalence increasing rapidly in the latter. Although prevalence may be leveling off somewhat in the former, this is a recent event after decades of rising prevalence and severity [Greenwood, 2011]. In a large, global, multicenter study, the highest prevalence was found in the United Kingdom, Australia, New Zealand, and the Republic of Ireland, followed by countries in North, Central, and South America. The lowest prevalence was found in Eastern Europe, Albania, Greece, China, Taiwan, Uzbekistan, India, Indonesia, and Ethiopia [Pearce et al. 2007]. The high cost of ICSs is a major barrier to persistent asthma management in low- and middle-income countries [International Union Against Tuberculosis and Lung Disease and the International Study of Asthma and Allergies in Childhood, 2011].

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

Over the past 5 years, Dr Guo has received grant support from Bristol-Myers Squibb, Eli Lilly, Genentech, Janssen Ortho-McNeil, and Novartis. Dr Kelton has received grant support from Eli Lilly, Janssen Ortho-McNeil, and Novartis. Ms Xia, Mr Bian, Dr Xue, and Dr Wigle have no conflict of interest to report. The opinions and conclusions expressed in the article are solely those of the authors.

References

Akinbami

(2006) The state of childhood asthma, United States, 1980-2005. Available at: http://www.cdc.gov/nchs/data/ad/ad381.pdf (accessed May 2013).

Akinbami

Parker

Merkle

(2010) Factors associated with school absence among children with symptomatic asthma, United States, 2002–2003. Pediat Allergy Immunol Pulmonol 23: 191–200.

Allen

Bronsky

LaForce

Nathan

Tinkelman

Vandewalker

. (1998) Growth in asthmatic children treated with fluticasone propionate. J Pediatr 132: 472–477.

Bacharier

Boner

Carlsen

Eigenmann

Frischer

Götz

. (2008) Diagnosis and treatment of asthma in childhood: A PRACTALL consensus report. Allergy 63: 5–34.

Bensch

Berger

Blokhin

Socolovsky

Thomson

Till

. (2002) One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma. Ann Allergy Asthma Immunol 89: 180–190.

Bisgaard

(2003) Effect of long-acting β₂ agonists on exacerbation rates of asthma in children. Pediatr Pulmonol 36: 391–398.

Braman

(2006) The global burden of asthma. Chest 2006; 130: 4S–12S.

Castle

Fuller

Hall

Palmer

(1993) Serevent nationwide surveillance study: Comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 306: 1034–1037.

Cates

Oleszczuk

Stovold

Wieland

(2012) Safety of regular formoterol or salmeterol in children with asthma: An overview of Cochrane reviews. Cochrane Database Syst Rev 10: CD010005. DOI: 10.1002/14651858.CD010005.pub2.

10.

Centers for Disease Control and Prevention (2011) FastStats asthma. Available at: http://www.cdc.gov/nchs/fastats/asthma.htm (accessed May 2013).

11.

Childhood Asthma Management Program Research Group (2000) Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 343: 1054–1063.

12.

Corso

Fertig

(2009) The long-term economic costs of asthma. Available at: http://www.readynation.org/uploads/20090708_asthmafinalformatted.pdf (accessed May 2013).

13.

Doull

(2004) The effect of asthma and its treatment on growth. Arch Dis Child 89: 60–63.

14.

Food and Drug Administration (2010) FDA drug safety communication: New safety requirement for long-acting inhaled asthma medications called long-acting beta-agonists (LABAs). Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm (accessed May 2013).

15.

Garcia Garcia

Wahn

Gilles

Swern

Tozzi

Polos

(2005) Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: The MOSAIC study. Pediatrics 116: 360–369. [Published correction appears in Pediatrics 116: 1058.]

16.

Greenwood

(2011) Why are asthma rates soaring? Sci Am 304: 32–33.

17.

Guilbert

Morgan

Zeiger

Mauger

Boehmer

Szefler

. (2006) Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 354: 1985–1997.

18.

Guo

Tsai

Kelton

Bian

Wigle

(2011) Risk of serious asthma exacerbations associated with long-acting beta agonists among patients with asthma: A retrospective cohort study. Ann Allergy Asthma Immunol 106: 214–222.

19.

International Union Against Tuberculosis and Lung Disease and the International Study of Asthma and Allergies in Childhood (2011) The global asthma report. Available at: http://www.globalasthmareport.org/sites/default/files/Global_Asthma_Report_2011.pdf (accessed May 2013).

20.

Juniper

(1997) How important is quality of life in pediatric asthma? Pediatr Pulmonol 24: 17–21.

21.

Knorr

Franchi

Bisgaard

Vermeulen

LeSouef

Santanello

. (2001) Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 108: E48.

22.

Krieger

Song

Takaro

Stout

(2000) Asthma and the home environment of low-income urban children: Preliminary findings from the Seattle-King County healthy homes project. J Urban Health 77: 50–67.

23.

Lemanske

Jr Mauger

Sorkness

Jackson

Boehmer

Martinez

. (2010) Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 362: 975–985.

24.

Malone

LaForce

Nimmagadda

Schoaf

House

Ellsworth

. (2005) The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma. Ann Allergy Asthma Immunol 95: 66–71.

25.

Mayo Clinic (2013) Childhood asthma. Tests and diagnosis. Available at: http://www.mayoclinic.com/health/childhood-asthma/DS00849/DSECTION=tests-and-diagnosis (accessed May 2013).

26.

Montuschi

(2008) Leukotrienes, antileukotrienes and asthma. Mini-Revs Med Chem 8: 647–656.

27.

Montuschi

(2009) LC/MS/MS analysis of leukotriene B₄ and other eicosanoids in exhaled breath condensate for assessing lung inflammation. J Chromatography B 877: 1272–1280.

28.

Montuschi

(2011) Pharmacotherapy of patients with mild persistent asthma: Strategies and unresolved issues. Front Pharmacol 2: 35.

29.

Montuschi

Barnes

(2011) New perspectives in pharmacological treatment of mild persistent asthma. Drug Discov Today 16: 1084–1091.

30.

Montuschi

Mondino

Koch

Ciabattoni

Barnes

Baviera

(2007) Effects of montelukast treatment and withdrawal on fractional exhaled nitric oxide and lung function in children with asthma. Chest 132: 1876–1881.

31.

Montuschi

Peters-Golden

(2010) Leukotriene modifiers for asthma treatment. Clin Experiment Allergy 40: 1732–1741.

32.

Nayak

Lanier

Weinstein

Stanpone

Welch

(2002) Efficacy and safety of beclomethasone dipropionate extrafine aerosol in childhood asthma: A 12-week, randomized, double-blind, placebo-controlled study. Chest 122: 1956–1965. [Published correction appears in Chest 123: 2164.]

33.

Nelson

Weiss

Bleecker

Yancey

Dorinsky

and SMART Study Group (2006) The salmeterol multicenter asthma research trial: A comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 129: 15–26. [Published correction appears in Chest 129: 1393.]

34.

Papadopoulos

Arakawa

Carlsen

Custovic

Gern

Lemanske

. (2012) International consensus on (ICON) pediatric asthma. Allergy 67: 976–997.

35.

Pauwels

Pedersen

Busse

Tan

Chen

Ohlsson

. (2003) Early intervention with budesonide in mild persistent asthma: A randomised, double-blind trial. Lancet 361: 1071–1076.

36.

Pearce

Ait-Khaled

Beasley

Mallol

Keil

Mitchell

. (2007) Worldwide trends in the prevalence of asthma symptoms: Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 62: 758–766.

37.

Rodrigo

Moral

Marcos

Castro-Rodriguez

(2009) Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma: A systematic review. Pulmon Pharmcol Therapeut 22: 9–19.

38.

Simons

and the Canadian Beclomethasone Dipropionate–Salmeterol Xinafoate Study Group (1997) A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N Engl J Med 337: 1659–1665.

39.

Straub

Moeller

Minocchieri

Hamacher

Wildhaber

(2005) The effect of montelukast on lung function and exhaled nitric oxide in infants with early childhood asthma. Eur Respir J 25: 289–294.

40.

Tal

Simon

Vermeulen

Petru

Cobos

Everard

. (2002) Budesonide/formoterol in a single inhaler vs. inhaled corticosteroids alone in the treatment of asthma. Pediatr Pulmonol 34: 342–350.

41.

U.S. Department of Health and Human Services (2007) National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf (accessed July 2013).

42.

von Berg

de Blic

la Rosa

Kaad

Moorat

(1998) A comparison of regular salmeterol vs ‘as required’ salbutamol therapy in asthmatic children. Respir Med 92: 292–299.

43.

Wang

Zhong

Wheeler

(2005) Direct and indirect costs of asthma in school-age children. Prev Chronic Dis [serial online]. Available at: http://www.cdc.gov/pcd/issues/2005/jan/pdf/04_0053.pdf (accessed May 2013).

44.

Weiss

Sullivan

Lyttle

(2000) Trends in the cost of illness for asthma in the United States, 1985–1994. J Allergy Clin Immunol 106: 493–499.

45.

Zimmerman

D’Urzo

Bérubé

(2004) Efficacy and safety of formoterol turbuhaler when added to inhaled corticosteroid treatment in children with asthma. Pediatr Pulmonol 37: 122–127.

Safety of long-acting beta agonists and inhaled corticosteroids in children and adolescents with asthma

Abstract

Keywords

Introduction

LABA studies

ICS studies

LABA/ICS combination studies

Discussion

Footnotes

Funding

Conflict of interest statement

References