Elsevier

The Lancet

Volume 368, Issue 9537, 26 August–1 September 2006, Pages 754-762
The Lancet

Articles
Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study

The authors dedicate this paper in fond memory of our friend and colleague, Stephen Langley.
https://doi.org/10.1016/S0140-6736(06)69285-4Get rights and content

Summary

Background

Wheezing and asthma often begins in early childhood, but it is difficult to predict whether or not a wheezy infant will develop asthma. Some researchers suggest that treatment with inhaled corticosteroids at the first signs of wheezing in childhood could prevent the development of asthma later in life. However, other investigators have reported that although such treatment could help control symptoms, the benefits can disappear within months of stopping treatment. We tested our hypothesis that to prevent loss of lung function and worsening asthma later in childhood, anti-inflammatory treatment needs to be started early in life.

Methods

We did a randomised, double-blind, controlled study of inhaled fluticasone propionate 100 μg twice daily in young children who were followed prospectively and randomised 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. Children were followed-up to 5 years of age, at which point we gave their parents or guardians questionnaires, and measured the children's lung function (specific airways resistance [sRaw], forced expiratory volume in 1s [FEV1]) and airway reactivity (eucapnic voluntary hyperventilation [EVH] challenge). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN86717853.

Findings

We followed 1073 children prospectively, of whom 333 were eligible, and 200 of these began treatment (130 male, median age 1·2 years [range 0·5–4·9]; 101 placebo, 99 treatment); 173 (85 treatment, 88 placebo) completed the follow-up at age five years. 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 to 13·4]) vs for treatment 5·0% [−2·2 to 12·2], p=0·87). 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=0·60), or the proportion needing the open-label drug (43 [42·57%] placebo, 41 [41·41%] treatment).

Interpretation

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 did not prevent lung function decline or reduce airway reactivity.

Introduction

Most cases of persistent wheezing and asthma begin in early childhood,1 and these can determine respiratory health throughout life.2, 3 Although wheeze is common in pre-school children, it can result from several different conditions,4 and it is difficult to predict whether or not a wheezy infant will develop asthma. Cohort studies suggest that around half of children who wheeze early in life become asymptomatic by school age.1 Lung function in these children tends to be diminished in infancy, and improved (but still lower than normal) by age 6 years.1 By contrast, lung function in children with persistent wheeze is normal in infancy, but reduced by age 6 years.1 Asthmatics with significant airway obstruction in mid-adult life (aged 30–40) already have reduced lung function by the age of 10 years.5 This evidence suggests that most asthmatic children have normal lung function at birth, but that an ongoing chronic inflammatory process could be associated with airway changes resulting in loss of lung function by early childhood, which then extends into adulthood.

Some researchers have suggested that treatment with inhaled corticosteroids (ICS) early in childhood asthma could improve long-term outcomes.6 However, others have reported that although such treatment of school-aged children with asthma improves symptom control, the benefits can disappear within months of stopping treatment.7 We postulated that to stop the progression of childhood wheezing and prevent loss of lung function, anti-inflammatory treatment needs to be started early in life. Thus, in the IFWIN study (Inhaled Fluticasone in Wheezy INnfants), we investigated whether the use of ICS early in the natural history of wheezing at the minimum dose required to control symptoms alters the progression of disease, prevents lung function decline, or reduces the incidence of asthma in later childhood.

Section snippets

Participants

Potential participants at risk of asthma (one parent atopic) were identified prenatally during recruitment for a birth cohort study in South Manchester, UK8 and followed prospectively from birth. A further group of young children with one atopic parent was referred by local doctors after the first confirmed episode of wheeze. All participants were followed-up through monthly telephone calls. In addition, parents were asked to contact the study team immediately if the child developed wheeze.

Results

The study profile is shown in figure 2. 1073 children were followed (820 from birth and 253 from their first wheezy episode). Of the 333 eligible for randomisation, 206 were randomised and 200 commenced treatment (median age 1·2 yrs, 130 male; 101 placebo, 99 study drug). By their fifth birthday, 13 children had been withdrawn, 55 moved into the observational group, and 43 children in the placebo group and 41 in the treatment group had received open-label fluticasone propionate. 173 (86·5%)

Discussion

Our results suggest that in very young children at risk of asthma, the use of ICS when they first start to wheeze has no significant effect on the natural history of wheezing, at least until age 5 years. In addition, there was no effect of this early intervention on lung function or airway reactivity by this age. We saw a small, but significant improvement in symptom scores and the number of unscheduled physician visits for wheeze in children in the treatment group, but only during the third

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