Daily or Intermittent Budesonide in Preschool Children with Recurrent Wheezing

Background: Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy.
Methods: We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy.
Results: The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen.
Conclusion: A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; MIST number, NCT00675584.)

Daily or Intermittent Budesonide in Preschool Children with Recurrent Wheezing
Robert S. Zeiger, M.D., Ph.D., David Mauger, Ph.D., Leonard B. Bacharier, M.D., Theresa W. Guilbert, M.D., Fernando D. Martinez, M.D., Robert F. Lemanske, Jr., M.D., Robert C. Strunk, M.D., Ronina Covar, M.D., Stanley J. Szefler, M.D., Susan Boehmer, M.A., Daniel J. Jackson, M.D., Christine A. Sorkness, Pharm.D., James E. Gern, M.D., H. William Kelly, Pharm.D., Noah J. Friedman, M.D., Michael H. Mellon, M.D., Michael Schatz, M.D., Wayne J. Morgan, M.D., Vernon M. Chinchilli, Ph.D., Hengameh H. Raissy, Pharm.D., Elizabeth Bade, M.D., Jonathan Malka-Rais, M.D., Avraham Beigelman, M.D., and Lynn M.

N Engl J Med 2011; 365:1990-2001, November 24, 2011

Paracetamol use in early life and asthma: prospective birth cohort study

Objective: To determine if use of paracetamol in early life is an independent risk factor for childhood asthma.
Design: Prospective birth cohort study.
Setting: Melbourne Atopy Cohort Study.
Participants: 620 children with a family history of allergic disease, with paracetamol use prospectively documented on 18 occasions from birth to 2 years of age, followed until age 7 years.
Main outcome measures: The primary outcome was childhood asthma, ascertained by questionnaire at 6 and 7 years. Secondary outcomes were infantile wheeze, allergic rhinitis, eczema, and skin prick test positivity.
Results: Paracetamol had been used in 51% (295/575) of children by 12 weeks of age and in 97% (556/575) by 2 years. Between 6 and 7 years, 80% (495/620) were followed up; 30% (148) had current asthma. Increasing frequency of paracetamol use was weakly associated with increased risk of childhood asthma (crude odds ratio 1.18, 95% confidence interval 1.00 to 1.39, per doubling of days of use). However, after adjustment for frequency of respiratory infections, this association essentially disappeared (odds ratio 1.08, 0.91 to 1.29). Paracetamol use for non-respiratory causes was not associated with asthma (crude odds ratio 0.95, 0.81 to 1.12).
Conclusion: In children with a family history of allergic diseases, no association was found between early paracetamol use and risk of subsequent allergic disease after adjustment for respiratory infections or when paracetamol use was restricted to non-respiratory tract infections. These findings suggest that early paracetamol use does not increase the risk of asthma.

Paracetamol use in early life and asthma: prospective birth cohort study
Adrian J Lowe, research fellow,corresponding author, John B Carlin, director of Clinical Epidemiology and Biostatistics Unit, Catherine M Bennett, associate professor, Clifford S Hosking, paediatric allergist, Katrina J Allen, paediatric gastroenterologist/allergist, Colin F Robertson, respiratory physician, Christine Axelrad, research nurse,Michael J Abramson, deputy head of department, David J Hill, senior consultant allergist, and Shyamali C Dharmage, principal research fellow

BMJ. 2010; 341: c4616, accepted July 16, 2010

Health experiences of adolescents with uncontrolled severe asthma

Background and aims: Many adolescents with asthma experience continued symptoms and impaired quality of life despite modern therapy. This study sought to understand their experience and to use this understanding to improve their clinical management.
Design and subjects: Qualitative study based on in-depth semi-structured interviews conducted with adolescents with uncontrolled severe asthma.
Results: 22 adolescents (1118 years) with uncontrolled severe asthma were interviewed. Two of the overarching themes that emerged were: (A) medication and adherence; and (B) interaction with healthcare professionals and adherence with their advice. Despite frequent visits to clinic, some did not understand why they were using medications. Many felt that only some medications worked and were concerned about adverse effects. Factors related to intentional non-adherence were not being bothered and conflicts with other activities. In particular, most were not using their spacer. Some though perceived a positive benefit to using their preventer treatment. Half the participants lived with a pet that they were sensitised to and two-thirds lived with a smoker. Adolescents felt involved in the clinic consultation and felt it was helpful but many did not take responsibility for interacting with health professionals. Parents were relied on to report symptoms, translate medical terms and remember the management plan.
Conclusion: Adherence was often poor particularly with the use of spacers. Adolescents had a poor understanding of their medication and using it often conflicted with other activities. Adolescents are very reliant on their parents. Healthcare professionals need to work to empower them to gradually take on the responsibility for their asthma.

Health experiences of adolescents with uncontrolled severe asthma
K. Edgecombe,S. Latter, S. Peters, G. Roberts

Arch Dis Child doi:10.1136/adc.2009.171579, published 30 July 2010

Parent initiated prednisolone for acute asthma in children of school age: randomised controlled crossover trial

Objective: To evaluate the efficacy of a short course of parent initiated oral prednisolone for acute asthma in children of school age.
Design: Double blind, randomised, placebo controlled, crossover trial in which episodes of asthma, rather than participants, were randomised to treatment. Setting: The Barwon region of Victoria, Australia.
Participants: Children aged 5-12 years with a history of recurrent episodes of acute asthma.
Intervention: A short course of parent initiated treatment with prednisolone (1 mg/kg a day) or placebo.
Main outcome measures: The primary outcome measure was the mean daytime symptom score over seven days. Secondary outcome measures were mean night time symptom score over seven days, use of health resources, and school absenteeism.
Results: 230 children were enrolled in the study. Over a three year period, 131 (57%) of the participants contributed a total of 308 episodes of asthma that required parent initiated treatment: 155 episodes were treated with parent initiated prednisolone and 153 with placebo. The mean daytime symptom score was 15% lower in episodes treated with prednisolone than in those treated with placebo (geometric mean ratio 0.85, 95% CI 0.74 to 0.98; P=0.023). Treatment with prednisolone was also associated with a 16% reduction in the night time symptom score (geometric mean ratio 0.84, 95% CI 0.70 to 1.00; P=0.050), a reduced risk of health resource use (odds ratio 0.54, 95% CI 0.34 to 0.86; P=0.010), and reduced school absenteeism (mean difference 0.4 days, 95% CI 0.8 to 0.0 days; P=0.045).
Conclusion: A short course of oral prednisolone initiated by parents when their child experiences an episode of acute asthma may reduce asthma symptoms, health resource use, and school absenteeism. However, the modest benefits of this strategy must be balanced against potential side effects of repeated short courses of an oral corticosteroid.

Parent initiated prednisolone for acute asthma in children of school age: randomised controlled crossover trial
P J Vuillermin, C F Robertson, J B Carlin, S L Brennan, M I Biscan, M South

Published 1 March 2010, doi:10.1136/bmj.c843

Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids

Background: For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.
Methods: We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 g of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 g of fluticasone twice daily (ICS step-up), 100 g of fluticasone plus 50 g of a long-acting beta-agonist twice daily (LABA step-up), or 100 g of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.
Results: A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005).
Conclusions: Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy.

Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids
Robert F. Lemanske, Jr., M.D., David T. Mauger, Ph.D., Christine A. Sorkness, Pharm.D., Daniel J. Jackson, M.D., Susan J. Boehmer, M.S., Fernando D. Martinez, M.D., Robert C. Strunk, M.D., Stanley J. Szefler, M.D., Robert S. Zeiger, M.D., Ph.D., Leonard B. Bacharier, M.D., Ronina A. Covar, M.D., Theresa W. Guilbert, M.D., Gary Larsen, M.D., Wayne J. Morgan, M.D., Mark H. Moss, M.D., Joseph D. Spahn, M.D., Lynn M. Taussig, M.D., for the Childhood Asthma Research and Education (CARE) Network of the National Heart, Lung, and Blood Institute

Published at March 2, 2010 (10.1056/NEJMoa1001278)

Anti-asthmatic drug prescriptions to an Italian paedriatic population

To estimate the prevalence and evaluate the appropriateness of anti-asthmatic drug prescriptions in an Italian paediatric population, drug prescriptions involving 24,407 children <18 years old, dispensed during 2003 by the retail pharmacies of the local health unit in Lecco, Italy, were analysed. Children > or = 6 years old receiving anti-asthmatics were categorized into three subgroups based on the number of boxes prescribed: occasional (one box), low (two and three boxes) and high (> or = four boxes) users. A logistic regression analysis was performed to estimate the relationship between the drug use patterns and formulations, antibiotic co-prescriptions, systemic steroid prescriptions and rate of hospitalization. Anti-asthmatic drugs were prescribed to 6594 (12%) children and adolescents; 58% of whom received only one box of the drug. Prevalence varied according to age, with the highest values at 1 and 4 years (24% and 21% respectively), and decreased to 6% in 17-year-old adolescents. Inhaled steroids were the most prescribed drugs (83%). The most common of these was beclomethasone. Occasional, low and high users represented 58%, 29%, and 13%, respectively, of the treated population > or = 6 years old. High users were found to be at increased risk of systemic steroid prescriptions (OR 8.6) and hospital admission for asthma (OR 6.8). This study confirms that in Italy the prevalence of anti-asthmatic prescription is much higher than prevalence of disease, indicating that anti-asthmatics are over-prescribed. Moreover, steroids, especially nebulized, are mainly prescribed only once in a year, supporting the idea that are prescribed not for asthma, which as chronic disease requires a chronic therapy. The approach to create subgroups on the basis of number of boxes prescribed seems to be effective in estimating asthma severity and appropriateness of the therapies.

Anti-asthmatic drug prescriptions to an Italian paedriatic population
Bianchi M, Clavenna A, Labate L, Bortolotti A, Fortino I, Merlino L, Locatelli GW, Giuliani G, Bonati M.
Laboratory for Mother and Child Health, Mario Negri Pharmacological Research Institute, 20156, Milan, Italy.

Pediatr Allergy Immunol. 2009 Sep;20(6):585-91. Epub 2008 Sep 3.

British Guideline on the Management of Asthma
A national clinical guideline

In 1999 the British Thoracic Society (BTS) and the Scottish Intercollegiate Guidelines Network (SIGN) agreed to jointly produce a comprehensive new asthma guideline, both having previously published guidance on asthma. The original BTS guideline dated back to 1990 and the SIGN guidelines to 1996. Both organisations recognised the need to develop the new guideline using explicitly evidence based methodology. The joint process was further strengthened by collaboration with Asthma UK, the Royal College of Physicians of London, the Royal College of Paediatrics and Child Health, the General Practice Airways Group, and the British Association of Accident and Emergency Medicine (now the College of Emergency Medicine). The outcome of these efforts was the British Guideline on the Management of Asthma published in 2003.1 The 2003 guideline was developed using SIGN methodology,2 adapted for UK-wide use. Electronic literature searches extended to 1995, although some sections required searches back as far as 1966. The pharmacological management section utilised the North of England Asthma guideline to address some of the key questions on adult management.3 The North of England guideline literature search covered a period from 1984 to December 1997, and SIGN augmented this with a search from 1997 onwards. Since 2003 sections within the guideline have been updated annually and posted on both the BTS ( and SIGN ( websites. In 2004 the sections on pharmacological management, acute asthma and patient self management and compliance were revised. In 2005 sections on pharmacological management, inhaler devices, outcomes and audit and asthma in pregnancy were updated, and occupational asthma was rewritten with help from the British Occupational Health Research Foundation. In 2006 the pharmacological management section was again updated. While the web-based alterations appeared successful, it was felt an appropriate time to consider producing a new paper-based version in which to consolidate the various yearly updates. In addition, since 2006, the guideline has had input from colleagues from Australia and New Zealand. The new 2008 guideline has considered literature published up to March 2007. It contains a completely rewritten section on diagnosis for both adults and children; a section on special situations which includes occupational asthma, asthma in pregnancy and the new topic of diffi cult asthma; updated sections on pharmacological and non-pharmacological management; and amalgamated sections on patient education and compliance, and on organisation of care and audit. The timescale of the literature search for each section is given in Annex 1. It is hoped that this 2008 asthma guideline continues to serve as a basis for high quality management of both acute and chronic asthma and a stimulus for research into areas of management for which there is little evidence. Sections of the guideline will continue to be updated on the BTS and SIGN websites on an annual basis.

British Guideline on the Management of Asthma
Scottish Intercollegiate Guidelines Network - British Thoracic Society
First published 2003 - Revised edition published 2008

Preemptive Use of High-Dose Fluticasone for Virus-Induced Wheezing in Young Children


Background: Although virus-induced wheezing is common in preschool-age children, optimal management remains elusive. We examined the efficacy and safety of preemptive treatment with high-dose fluticasone in reducing the severity of recurrent virus-induced wheezing in children.

Methods: We randomly assigned 129 children who were 1 to 6 years of age to receive 750 g of fluticasone propionate (ex-valve [manufacturer-measured] dose) or placebo twice daily, beginning at the onset of an upper respiratory tract infection and continuing for a maximum of 10 days, over a period of 6 to 12 months. The primary outcome was rescue oral corticosteroid use. Secondary outcomes included symptoms, use of β2-agonists, acute care visits, hospitalizations, discontinuation of the study drug, change in growth and bone mineral density, basal cortisol level, and adverse events.

Results: Over a median period of 40 weeks, 8% of upper respiratory tract infections in the fluticasone group led to treatment with rescue systemic corticosteroids, as compared with 18% in the placebo group (odds ratio, 0.49; 95% confidence interval [CI], 0.30 to 0.83). Children who were treated with fluticasone, as compared with those who were given placebo, had smaller mean (SD) gains from baseline in height (6.232.62 cm [unadjusted value]; z score, 0.19 0.42 vs. 6.562.90 cm [unadjusted value]; z score, 0.000.48; difference between groups in z score from baseline to end point, 0.24 [95% CI, 0.40 to 0.08]) and in weight (1.531.17 kg [unadjusted value]; z score, 0.150.48 vs. 2.171.79 kg [unadjusted value]; z score, 0.110.43; difference between groups in z score from baseline to end point, 0.26 [95% CI, 0.41 to 0.09]). There were no significant differences between the groups in basal cortisol level, bone mineral density, or adverse events.

Conclusions: In preschool-age children with moderate-to-severe virus-induced wheezing, preemptive treatment with high-dose fluticasone as compared with placebo reduced the use of rescue oral corticosteroids. Treatment with fluticasone was associated with a smaller gain in height and weight. Given the potential for overuse, this preventive approach should not be adopted in clinical practice until long-term adverse effects are clarified. ( number, NCT00238927 [] .)

Preemptive Use of High-Dose Fluticasone for Virus-Induced Wheezing in Young Children
Francine M. Ducharme, M.D., Chantal Lemire, M.D., Francisco J.D. Noya, M.D., G. Michael Davis, M.D., Nathalie Alos, M.D., Hlne Leblond, M.D., Cheryl Savdie, M.Sc., Jean-Paul Collet, M.D., Ph.D., Lyudmyla Khomenko, Ph.D., Georges Rivard, M.D., and Robert W. Platt, Ph.D.
NEJM Volume 360:339-353 January 22, 2009 Number 4

Managing childhood asthma: challenge of preventing exacerbations

Acute episodes of airway obstruction followed by periods of apparent wellness are the main clinical manifestations of the disease for many children with persistent asthma. Although currently available asthma controllers decrease the risk for acute asthma exacerbations, 30% of children taking these medicines still have >or=1 episode requiring oral corticosteroid treatment per year. There is increasing evidence that neutrophilic inflammation, against which inhaled corticosteroids are not very effective, plays a major role in the pathogenesis of asthma exacerbations. New therapeutic approaches are needed for this frequent cause of consultation in pediatric practice. One approach could be the development of drugs that target neutrophilic inflammation specifically. Studies in adults have shown that use of inhaled corticosteroids every time a bronchodilator is needed may decrease the frequency of asthma exacerbations. This strategy is currently being tested in a large clinical trial involving children with mild persistent asthma.

Managing childhood asthma: challenge of preventing exacerbations.
Martinez FD.
Department of Pediatrics and Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA.

Pediatrics. 2009 Mar;123 Suppl 3:S146-50.

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