Intermittent Inhaled Corticosteroids Research Articles

A network meta-analysis of the association between patient traits and response to regular dosing with ICS plus short-acting β2-agonist reliever or ICS/formoterol reliever only in mild asthma

Introduction/backgroundMild asthma treatment recommendations include intermittent inhaled corticosteroid (ICS)/formoterol dosing or regular ICS dosing with short-acting β2-agonist reliever. Due to the heterogeneity of asthma, identification of traits associated with improved outcomes to specific treatments would be clinically beneficial. Aims/objectivesTo assess the impact of patient traits on treatment outcomes of regular ICS dosing compared with intermittent ICS/formoterol dosing, a systematic literature review (SLR) and network meta-analysis (NMA) was conducted. Searches identified randomised controlled trials (RCTs) of patients with asthma aged ≥12 years, containing ≥1 regular ICS dosing or intermittent ICS/formoterol dosing treatment arm, reporting traits and outcomes of interest. ResultsThe SLR identified 11 RCTs of mild asthma, of 14,516 patients. A total of 11 traits and 11 outcomes of interest were identified. Of these, a feasibility assessment indicated possible assessment of three traits (age, baseline lung function, smoking history) and two outcomes (exacerbation rate, change in lung function). The NMA found no significant association of any trait with any outcome with regular ICS dosing relative to intermittent ICS/formoterol dosing. Inconsistent reporting of traits and outcomes between RCTs limited analysis. ConclusionsThis is the first systematic analysis of associations between patient traits and differential treatment outcomes in mild asthma. Although the traits analysed were not found to significantly interact with relative treatment response, inconsistent reporting from the RCTs prevented assessment of some of the most clinically relevant traits and outcomes, such as adherence. More consistent reporting of respiratory RCTs would provide more comparable data and aid future analyses.

Cost Utility of Intermittent Inhaled Corticosteroids in Preschoolers with Viral-Triggered Wheeze.

Background: Evidence has demonstrated that adding intermittent inhaled corticosteroids (ICS) to treatment with short-acting b2-agonists (SABAs) in children 5 years of age and younger who experience intermittent viral-induced wheezing (VIW) reduces the risk of severe exacerbations. However, there is concern about whether the extra benefit offered by this drug outweighs the additional cost. This study aimed to evaluate the cost-effectiveness of intermittent ICS in children 5 years of age and younger who experience intermittent VIW. Methods: We constructed a probabilistic Markov model to estimate the cost and quality-adjusted life-years (QALYs) of intermittent ICS compared with SABA reliever therapy in preschoolers with viral-triggered wheezing in Colombia. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $5,180. Results: In an analysis of the Markov cohort model, we estimated a gain of 0.2 QALYs per patient per year on intermittent ICS compared with SABA and a reduction of cost per patient of USD $37 per year. This position of dominance negated the need to calculate an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses, our base case results were robust to variations of all assumptions and parameters. Conclusion: Adding intermittent ICS to treatment with SABAs in children 5 years of age and younger who experience intermittent VIW was found to be cost effective. These results could improve the use of health care resources, especially in settings with limited economic resources.

Asthma Phenotypes and COVID-19 Risk: A Population-based Observational Study.

RationaleStudies have suggested some patients with asthma are at risk of severe coronavirus disease (COVID-19), but they have had limited data on asthma phenotype and have not considered if risks are specific to COVID-19.ObjectivesTo determine the effect of asthma phenotype on three levels of COVID-19 outcomes. Compare hospitalization rates with influenza and pneumonia.MethodsElectronic medical records were used to identify patients with asthma and match them to the general population. Patient-level data were linked to Public Health England severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test data, hospital, and mortality data. Asthma was phenotyped by medication, exacerbation history, and type 2 inflammation. The risk of each outcome, adjusted for major risk factors, was measured using Cox regression.Measurements and Main ResultsA total of 434,348 patients with asthma and 748,327 matched patients were included. All patients with asthma had a significantly increased risk of a General Practice diagnosis of COVID-19. Asthma with regular inhaled corticosteroid (ICS) use (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01–1.61), intermittent ICS plus add-on asthma medication use (HR, 2.00; 95% CI, 1.43–2.79), regular ICS plus add-on use (HR, 1.63; 95% CI, 1.37–1.94), or with frequent exacerbations (HR, 1.82; 95% CI, 1.34–2.47) was significantly associated with hospitalization. These phenotypes were significantly associated with influenza and pneumonia hospitalizations. Only patients with regular ICS plus add-on asthma therapy (HR, 1.70; 95% CI, 1.27–2.26) or frequent exacerbations (HR, 1.66; 95% CI, 1.03–2.68) had a significantly higher risk of ICU admission or death. Atopy and blood eosinophil count were not associated with severe COVID-19 outcomes.ConclusionsMore severe asthma was associated with more severe COVID-19 outcomes, but type 2 inflammation was not. The risk of COVID-19 hospitalization appeared to be similar to the risk with influenza or pneumonia.

Summary of the 2020 focused updates to U.S. asthma management guidelines: What has changed and what hasn't?

Despite the availability of effective medications, the majority of pediatric and adult patients with persistent asthma have uncontrolled symptoms. This has been attributed to patient nonadherence and poor self-management, but clinicians also contribute through inaccurate assessment of asthma and lack of familiarity with best practice guidelines for medication management. Thus, improving patient outcomes will require improving clinical management by health care providers, including utilization of evidence-based practice guidelines. In this report, we briefly summarize key points of the national guidelines for asthma management and delineate important changes enacted by 2020 Expert Panel Report-4 updates. These include revised recommendations on the use of fractional exhaled nitric oxide testing, indoor allergen mitigation, bronchial thermoplasty, adjunctive immunotherapy, and important modifications to medication management that are likely to have widespread impact on prescribing throughout the United States. In particular, for all patients aged five years and older taking stepwise therapy levels 3-4, it is now recommended to use Single Maintenance and Reliever Therapy, whereas the use of intermittent inhaled corticosteroids (ICSs) administered at the same time as short-acting beta agonist is recommended for step 2 to reduce symptom burden, improve control, and minimize total ICS dose.

The 2020 Focused Updates to the NIH Asthma Management Guidelines: Key Points for Pediatricians.

* Abbreviations: FeNO — : fractional exhaled nitric oxide ICS — : inhaled corticosteroid LABA — : long-acting β2-agonist LAMA — : long-acting muscarinic antagonist SABA — : short-acting β2-agonist SCIT — : subcutaneous immunotherapy SLIT — : sublingual immunotherapy SMART — : single maintenance and reliever therapy The National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group (hereinafter “panel”) of the National Heart, Lung, and Blood Institute recently published its 2020 Focused Updates to the Asthma Management Guidelines (https://www.nhlbi.nih.gov/asthmaguidelines).1 These are the first updates from the panel since 2007, a remarkably long interval given the advances in care of the last decade. Using the Grading Recommendations, Assessment, Development, and Evaluation platform,2 the panel made 19 recommendations across six topic areas: intermittent inhaled corticosteroid (ICS) therapy, long-acting muscarinic antagonist (LAMA) therapy, indoor allergen-mitigation strategies, immunotherapy, fractional exhaled nitric oxide (FeNO) testing, and bronchial thermoplasty.3 Of these, 18 are relevant to children and adolescents (Table 1). The panel made strong recommendations (to be implemented by clinicians for almost all their patients as standard of care) and conditional recommendations (intended for many individuals as part of a shared decision-making process involving the clinician, family, and patient). For pediatric clinicians, the most exciting updates are those affirming several treatment options for using ICS with long-acting β2-agonists (LABAs) and LAMAs. Those for allergen mitigation, immunotherapy, and FeNO testing provide useful clarifications but not transformative alternatives for care. Of note, the updates did not address biological therapies because at the time that a decision regarding which topics to update was made (2014), only one biologic (omalizumab) was available. View this table: TABLE 1 New Recommendations of the 2020 Focused Updates by Age Group The updates’ most highly pediatric-relevant recommendations involve three treatment options: (1) intermittent ICS dosing with as-needed short-acting β2-agonist (SABA) for quick-relief therapy, (2) single maintenance and reliever … Address correspondence to Stephen J. Teach, MD, MPH, Children’s National Hospital, 111 Michigan Ave NW, Washington, DC 20010. E-mail: steach{at}childrensnational.org

Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

Overweight/obesity status in preschool children associates with worse asthma but robust improvement on inhaled corticosteroids

Overweight/obesity (OW) is linked to worse asthma and poorer inhaled corticosteroid (ICS) response in older children and adults. We sought to describe the relationships between OW and asthma severity and response to ICS in preschool children. This post hoc study of 3 large multicenter trials involving 2- to 5-year-old children compared annualized asthma symptom days and exacerbations among normal weight (NW) (body mass index: 10th-84th percentiles) versus OW (body mass index: ≥85th percentile) participants. Participants had been randomized to daily ICS, intermittent ICS, or daily placebo. Simple and multivariable linear regression was used to compare body mass index groups. Within the group not treated with a daily controller, OW children had more asthma symptom days (90.7 vs 53.2, P=.020) and exacerbations (1.4 vs 0.8, P=.009) thanNW children did. Within the ICS-treated groups, OW and NW children had similar asthma symptom days (daily ICS: 47.2 vs 44.0days, P=.44; short-term ICS: 61.8 vs 52.9days, P=.46; as-needed ICS: 53.3 vs 47.3days, P=.53), and similar exacerbations (daily ICS: 0.6 vs 0.8, P=.10; short-term ICS: 1.1 vs 0.8days, P=.25; as-needed ICS: 1.0 vs 1.1, P=.72). Compared with placebo, daily ICS in OW led to fewer annualized asthma symptom days (90.7 vs 41.2, P=.004) and exacerbations (1.4 vs 0.6, P=.006), while similar protective ICS effects were less apparent among NW. In preschool children off controller therapy, OW is associated with greater asthma impairment and exacerbations. However, unlike older asthmatic patients, OW preschool children do not demonstrate reduced responsiveness to ICS therapy.

Intermittent inhaled corticosteroid therapy versus placebo for persistent asthma in children and adults.

International guidelines advocate using daily inhaled corticosteroids (ICS) in the management of children and adults with persistent asthma. However, in real world clinical settings, these medicines are often used at irregular intervals by patients. Recent evidence suggests that the use of intermittent ICS, with treatment initiated at the time of early symptoms, may still have benefits for reducing the severity of an asthma exacerbation. To compare the efficacy and safety of intermittent ICS versus placebo in the management of children and adults diagnosed with, or suspected to have, symptoms of mild persistent asthma. We searched the Cochrane Airways Group Specialised Register of trials (CAGR), the ClinicalTrials.gov website and the World Health Organization (WHO) trials portal in March 2015. We included randomised controlled trials (RCTs) that compared intermittent ICS versus placebo in children and adults with symptoms of persistent asthma. No co-interventions were permitted other than rescue relievers and oral corticosteroids used during exacerbations. Two review authors independently assessed trials for inclusion, methodological quality and extracted data. The primary efficacy outcome was the risk of asthma exacerbations requiring oral corticosteroids and the primary safety outcome was serious adverse health events. Secondary outcomes included exacerbations, lung function tests, asthma control, adverse effects, and withdrawal rates. Quality of the evidence was assessed using the GRADE criteria. Six trials (representing 490 preschool children, 145 school-aged children and 240 adults) met the inclusion criteria. Study durations were 12 to 52 weeks. Results for preschool children were presented in a separate analysis as this represents a distinct clinical condition, not necessarily related to the development of long term asthma.There was a reduction in the risk of patients experiencing one or more exacerbations requiring oral corticosteroids in older children (145 participants, odds ratio (OR) 0.57; 95% confidence interval (CI) 0.29 to 1.12, low quality evidence) and adults with asthma (240 participants, OR 0.10; 95% CI 0.01 to 1.95, low quality evidence). These analyses were each based on the findings of a single study. No group difference was observed in the risk of serious adverse health events (385 participants; OR 1.00; 95% CI 0.14 to 7.25, moderate quality evidence). Compared to the placebo group, there was an insufficient number of participants to make firm conclusions whether the intermittent ICS group displayed any reduction in the rate of hospitalisations, day time and night time symptoms scores, or adverse events. Lung function tests reported by a single study favoured the use of ICS. There was no significant group difference in growth rate of children, or overall withdrawals.In preschool children with frequent wheezing episodes, the use of intermittent ICS at the onset of early symptoms reduced the likelihood of requiring rescue oral corticosteroids by half (490 participants; OR: 0.48; 95% CI 0.31 to 0.73, moderate quality evidence with minimal heterogeneity). Intermittent therapy was associated with fewer serious adverse events (439 participants; OR 0.42; 95% CI 0.17 to 1.02, low quality evidence). There was no significant difference in hospitalisations or in a single study measuring parent perceived quality of life. However, intermittent therapy was associated with improvements in both day time and night time symptoms. There was no increase in the rates of withdrawals, and overall and treatment-specific adverse events. In children and adults with mild persistent asthma, two studies have shown that the use of intermittent ICS at the time of exacerbation reduced the chances of needing oral corticosteroids by half. This result is statistically significant if we assume that the effect size is the same for each study population (fixed effects model), but is not statistically significant when using a random effects model. However, the paucity of published evidence limits our conclusions towards the 'as-needed' use of this medication. The small number of studies and participants were the major reasons for downgrading the overall quality of the findings. A corresponding result was found in preschool children with wheeze. In this age group, an improvement in day time and night time asthma symptoms score and parental perceived quality of life of children similarly favoured the ICS group. However, there was no statistical difference in hospitalisation rates in any group. This treatment was not associated with any significant increase in adverse events. There was no growth suppression noted with the use of intermittent ICS in either preschool or school-aged children. Considering the limited number of available studies, we emphasise the need for more randomised controlled studies in order to confirm these findings.

Cost-utility analysis of daily versus intermittent inhaled corticosteroids in mild-persistent asthma.

Despite the many benefits that have been demonstrated by the continuous administration of inhaled corticosteroids (ICS) in persistent asthma, a new strategy for mild-asthma is emerging, consisting of using intermittent or as-needed ICS treatment in conjunction with short-acting beta2 agonists in response to symptoms. However, no previous studies have reported an economic evaluation comparing these two therapeutic strategies. A Markov-type model was developed in order to estimate costs and health outcomes of a simulated cohort of pediatric patients with persistent asthma treated over a 12-month period. Effectiveness parameters were obtained from a systematic review of the literature. Cost data were obtained from official databases provided by the Colombian Ministry of Health. The main outcome was the variable "quality-adjusted life-years" (QALYs). For the base-case analysis, the model showed that compared to intermittent ICS, daily therapy with ICS had lower costs (US$437.02 vs. 585.03 and US$704.62 vs. 749.81 average cost per patient over 12 months for school children and preschoolers, respectively), and the greatest gain in QALYs (0.9629 vs. 0.9392 QALYs and 0.9238 vs. 0.9130 QALYS for school children and preschoolers, respectively), resulting in daily therapy being considered dominant. The present analysis shows that compared to intermittent therapy, daily therapy with ICS for treating pediatric patients with recurrent wheezing and mild persistent asthma is a dominant strategy (more cost effective), because it showed a greater gain in QALYs with lower total treatment costs.

Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing?

Oral corticosteroids (OCSs) are recommended for severe wheezing episodes in children. However, limited evidence supports this intervention in preschool children with outpatient wheezing illnesses. We sought to investigate whether OCSs reduce symptom scores during acute lower respiratory tract illnesses (LRTIs) in preschool children with recurrent wheeze. We performed post hoc and replication analyses in 2 outpatient cohorts of children aged 1 to 5 years with episodic wheezing participating in clinical trials. We compared symptom scores during LRTIs that were or were not treated with OCSs, adjusting for differences in disease and episode severity covariates. We stratified episodes by severity by using a propensity model. The primary outcome was the area under the curve (AUC) of total symptom scores among the more severe episodes. Two hundred fifteen participants from the Acute Intervention Management Strategies trial experienced 798 acute LRTIs, 112 of which were defined as severe based on propensity scores. The AUCs of total symptom scores did not differ between the episodes that were (n = 70) and were not (n = 42) treated with OCSs (P = .46) nor was there an OCS treatment effect on individual symptom scores. Similar analyses of the Maintenance Versus Intermittent Inhaled Corticosteroids in Wheezing Toddlers trial, involving 278 participants with 133 severe LRTIs, confirmed the above findings (P = .46 for AUC of total symptoms score comparison). In 2 separate cohorts of preschool children with episodic wheezing, OCS treatment during clinically significant LRTIs did not reduce symptom severity during acute LRTIs, despite asthma controller medication use during most episodes. These findings need to be confirmed in a prospective randomized controlled trial.

Breathe easy: Updates on asthma management

Several asthma trials have been published in recent months evaluating key treatments such as long-acting beta-2 agonists (LABAs), inhaled corticosteroids (ICSs), and tiotropium (Spiriva— oehringer Ingelheim, Pfizer). Studies have questioned the recommendation to discontinue LABAs; compared the efficacy of intermittent, symptom-based ICS use with scheduled inhalations in adults with mild to moderate persistent asthma; evaluated the effects of ICS use in children on their adult height; and evaluated the role of tiotropium in the management of uncontrolled asthma.

Inhaled Corticosteroid Dose Adjustment in Mild Persistent Asthma

REGULAR USE OF CONTROLLER MEDICATIONS, SUCH AS INhaledcorticosteroids(ICS), improvesoutcomesinpatientswithasthma.Theimportanceofdailyuseof ICS is emphasized in asthma management guidelines. However, ensuring that patients with asthma adhere to daily useof ICS,evenwhenasymptomatic, is achallenge.Therefore, cliniciansspendsubstantial timeandenergyeducatingpatients with asthma about the importance of daily use of ICS. The latter medications, however, do not lead to the immediate relief of asthmasymptomsassociatedwithshort-actingrescuebronchodilators, such as albuterol, so patients often neglect to take ICS due to the incorrect perception that they do not help. This frequently observed pattern of poor adherence to daily use of ICShasledtothehypothesisthattyinguseofICStotheas-needed use of a short-acting bronchodilator may lead to better asthma control forpatientswithrelativelymildasthma.Combininguse of ICS with as-needed short-acting bronchodilators may improve asthma control by increasing the patient’s motivation to take ICS and by focusing ICS therapy on periods when symptoms of asthma (which vary over time due to environmental factors) are more prounounced. This as-needed ICS strategy could also potentially reduce costs and patient inconvenience by avoiding use of ICS when asthma is not bothersome. In this issue of JAMA, Calhoun et al report the results of the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial comparing as-needed, symptom-based use of ICS, as well as a biomarker-based dosing strategy, with traditional everyday use of ICS with dosing determined by a physician. In this randomized controlled trial, conducted by the National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network (ACRN), the investigators randomly assigned adults with mild to moderate persistent asthma (defined as acceptable symptom control and lung function while receiving low-dose ICS therapy) to 1 of 3 strategies for dose adjustment of ICS: physician assessment–based adjustment (n=114 patients), in which the physician prescribes a regular twice-daily ICS dose, which is guided by the National Asthma Education and Prevention Program (NAEPP) guidelines, at clinic visits approximately every 6 weeks; symptombased adjustment (n=113 patients), in which patients are instructed to take 2 puffs of beclomethasone HFA (40 μg/puff) whenever taking 2 puffs of albuterol to relieve asthma symptoms; or biomarker-based adjustment (n=115 patients) in which ICS dosing is adjusted according to the concentration of exhaled nitric oxide, which was measured every 6 weeks. During the 36-week follow-up, the time to clinical worsening of asthma (the primary outcome measure of the trial) did not differ in the primary comparisons of symptombased adjustment vs physician assessment–based adjustment or of biomarker-based adjustment vs physician assessment–based adjustment. Nine-month rates of clinical failure estimated by Kaplan-Meier analysis were 22% for the physician assessment–based adjustment group, 15% for the symptom-based adjustment group, and 20% for the biomarker-based adjustment group. Participants in the symptom-based adjustment group took significantly less ICS per month than the other groups. This outcome was 1 of 18 secondary outcome measures, and most of these did not differ significantly among the treatment groups; thus, this finding should be interpreted with caution. This report adds to prior randomized trials that have compared the typical physician-prescribed dosing of ICS with intermittent dosing guided by symptoms for patients with relatively mild asthma. A prior ACRN study of adults with mild persistent asthma indicated that a strategy of initiating a course of inhaled or oral corticosteroid only when asthma symptoms became bothersome (according to a written action plan), led to a similar peak expiratory flow rate and asthma exacerbation rate as the everyday physician-prescribed dosing of controller medications (ICS or leukotriene antagonist), although some outcomes such as bronchial reactivity and symptom-free days were improved by regular twice-daily use of ICS. Like the BASALT trial, the prior ACRN study was designed to show superiority of one strategy over another, rather than to test equivalence, and the lack of superiority of any strategy over the others must be interpreted accordingly. Taking a different approach to intermittent ICS treatment, European investigators conducted an equivalence study comparing asneeded use of an inhaler containing both the short-acting bronchodilator albuterol and beclomethasone (a combination inhaler not available in the United States) with the traditional approach of regular twice daily beclomethasone and as-

Six‐year follow‐up of an intervention to improve the management of preschool children with asthma

In a randomized controlled study involving 60 preschool children with asthma, an intervention with extra information and support to parents in the form of group discussions was performed. An earlier follow-up after 18 months revealed an improved adherence and a reduction of exacerbation days. This is a 6-year follow-up. Fifty-four children performed clinical examinations, blood tests, measurements of exhaled nitric oxide, spirometry, bronchial provocation with dry air and skin prick tests. Data from the patients' records and questionnaires were obtained. Twenty-nine per cent had no current signs of asthma, whereas 43% exhibited persistent and 28% intermittent asthma. The burden on the healthcare system was minimal. Intermittent inhaled corticosteroid (ICS) therapy was used by 81%. The intervention group (IG) had fewer contacts with nurses. Their parents had a better quality of life. Interviewing children separately contributed in identification of children needing treatment. More children in the IG had to restart ICS as they had signs of worse asthma control. Straightforward and timely support to parents of children with asthma can have long-term positive effects by strengthening the ability of parents to treat their children at home, although parents may also develop an underestimation of mild symptoms. It is important to directly ask children about their disease and to maintain regular follow-up visits.

Guidelines versus practice: UK asthma nurses often recommend intermittent, symptom-driven use of inhaled corticosteroids

Recent clinical trials suggest that intermittent use of inhaled corticosteroids (ICS) is safe for mild persistent asthma. Intermittent ICS use is inconsistent with current guidelines but is a common form of non-compliance. The aim of this study was to investigate how asthma nurses advise patients to use ICS. Practice managers of 241 GP surgeries in the southwest of England were sent questionnaires to distribute to practice nurses. Questionnaires were returned by 105 nurses (104 had asthma-specific training). There was a wide variation in attitudes to guideline-based care and advice given to patients. 97% indicated that they sometimes advised patients to decrease their ICS use, 85% sometimes advised patients to stop their ICS when their asthma was well controlled, and 70% reported sometimes advising intermittent use. Asthma nurse recommendations are often inconsistent with guidelines. There is considerable variation between different asthma nurses in the advice given to patients.

Inhaled corticosteroids do not prevent the development of asthma

Question In children with early wheezing, does the use of inhaled corticosteroids (ICS) prevent loss of lung function or reduce the incidence of asthma later in childhood? Design Randomized, double-blind, controlled study. Setting South Manchester, United Kingdom. Participants 1073 children were followed prospectively, of whom 333 were eligible, and 200 began treatment. One hundred and seventy-three completed follow-up at 5 years of age. Intervention Fluticasone propionate 100 μg twice daily in young children who were randomized after either one prolonged (>1 month) or two medically confirmed wheezy episodes. The dose of study drug was reduced every 3 months to the minimum needed. If the symptoms were not under control by 3 months, open-label fluticasone propionate 100 μg twice daily was added to the treatment. Outcomes Children’s lung function (specific airways resistance [sRaw], forced expiratory volume in 1 second [FEV1]) and airway reactivity (eucapnic voluntary hyperventilation [EVH] challenge). Main Results The groups did not differ significantly in the proportion of children with current wheeze, physician-diagnosed asthma or use of asthma medication, lung function, or airway reactivity (percentage change in FEV1, adjusted mean for placebo 5.5% [95% CI −2.5-13.4]) vs for treatment 5.0% [−2.2-12.2], P = .87). There were no differences in the results after adjustment for open-label fluticasone propionate, nor between the two groups in the time before the open-label drug was added (estimated hazard ratio 1.12 [95% CI 0.73–1.73], P = .60) or the proportion needing the open-label drug. Conclusions The early use of inhaled fluticasone propionate for wheezing in preschool children had no effect on the natural history of asthma or wheeze later in childhood, and it did not prevent lung function decline or reduce airway reactivity. Commentary Asthma is characterized by chronic airway inflammation and obstructive lung physiology that frequently cause symptoms in early childhood. Studies in school-aged children with mild to moderate asthma demonstrated that inhaled corticosteroid (ICS) therapy improves asthma symptoms and airway hyperreactivity, but it does not improve lung function.1The Childhood Asthma Management Program Research GroupLong-term effects of budesonide or nedocromil in children with asthma.N Engl J Med. 2000; 343: 1054-1063Crossref PubMed Scopus (1297) Google Scholar Therefore, it has been hypothesized that an earlier intervention with anti-inflammatory therapy may be able to alter the natural course of asthma and prevent the decline in lung function over time. The IFWIN study instituted ICS therapy in preschool children after their second wheezing episode and failed to show any difference in lung function or asthma diagnosis at 5 years of age compared with placebo. This agrees with two recent studies (PEAK2Guilbert T.W. Morgan W.J. Zeiger R.S. Mauger D.T. Boehmer S.J. Szefler S.J. et al.Long-term inhaled corticosteroids in preschool children at high risk for asthma.N Engl J Med. 2006; 354: 1985-1997Crossref PubMed Scopus (884) Google Scholar and PAC3Bisgaard H. Hermansen M.N. Loland L. Halkjaer L.B. Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing.N Engl J Med. 2006; 354: 1998-2005Crossref PubMed Scopus (477) Google Scholar) that also did not demonstrate improvement in pulmonary function with chronic or intermittent ICS therapy in children with early wheezing. These studies suggest that the predisposition to asthma may be set very early in life and/or that development of asthma is insensitive to the effects of corticosteroids. These early treatment approaches are complicated by the high incidence of wheezing in preschool children, and the fact that these “early wheezers” are a heterogeneous population from which only a subgroup will progress to chronic asthma. Despite these findings, it is important to point out that the evidence remains strong that ICS therapy improves control of asthma symptoms in preschool children. Therefore, judicious use of ICS in early childhood is still warranted in those with chronic wheezing in accordance with established guidelines for the treatment of childhood asthma.