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REVIEW ARTICLES: Jose A. Castro-Rodriguez and Gustavo J. Rodrigo Efficacy of Inhaled Corticosteroids in Infants and Preschoolers With Recurrent Wheezing and Asthma: A Systematic Review With Meta-analysis Pediatrics 2009; 123: e519-e525 [Abstract] [Full text] [PDF]

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Inhaled corticosteroids in infants and preschoolers with persistent wheeze/asthma: an open issue

Giorgio L. Piacentini, Diego g. Peroni and Attilio L. Boner   (27 March 2009)

A more cautious conclusion is needed

Uwe Hasenbein, Martin Gerken, Michaela Eikermann, Ulrich Grouven, and Monika Lelgemann.   (27 April 2009)

Inhaled corticosteroids in infants and preschoolers with persistent wheeze/asthma: an open issue 27 March 2009
Giorgio L. Piacentini, Pediatric Department University of Verona - Italy, Diego g. Peroni and Attilio L. Boner Send letter to journal: Re: Inhaled corticosteroids in infants and preschoolers with persistent wheeze/asthma: an open issue giorgio.piacentini{at}univr.it Giorgio L. Piacentini, et al.	We have read with interest the systemic review with meta-analysis by Castro-Rodriguez and Rodrigo (1) regarding the controversial issue of the use of inhaled corticosteroid (ICS) in infants and preschool children with recurrent wheezing and asthma. They conclude that ICS are useful in such paediatric population in term of reduction of exacerbations, symptom and lung function improvement. Nevertheless, though the conclusions of this analysis are presented for the pooled group of wheezing and asthmatic children, they are mostly driven by studies including patients with pronounced asthmatic features as previously described by Castro-Rodriguez et al. (2), for whom the effectiveness of ICS treatment is widely accepted. In particular, the study by Guilbert et al (3), which weight 22,8% for the RR of wheeze/asthma exacerbation (WAE) was designed to select and treat children with a positive asthma predictive index. Also in the study by Baker et al. (4), which weighted for 15.1% in the meta-analysis by Castro Rodriguez and Rodrigo (1), were considered only children with a specific diagnosis of persistent asthma. In the study by Roorda et al (5), accounting for 13.7% in the meta-analysis, it is clearly indicated that a significant response to ICS treatment was observed in the children with frequent symptoms, a family history of asthma, or both, but not in those without a family history. Similar consideration can be extended to a number of further studies with lighter weight in the analysis. Therefore, the conclusion that ICSs are useful in infants and preschoolers with wheeze/asthma can represent a misleading message to the reader regarding the potential usefulness of a maintenance treatment with ICSs in the group of transient wheezers. To the best of our knowledge, for this group, at the present, there is no indication that a maintenance treatment with ICCs can be effective in reducing the number or the severity of wheezing episodes (6). References: 1) Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. Pediatrics. 2009;123:e519- 25 2) Castro-Rodriguez JA, Wright AL, Taussig LM, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162(4 pt 1):1403–1406 3) Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354(19):1985–1997 4) Baker JW, Mellon M, Wald J, Welch M, Cruz-Rivera M, Walton-Bowen K. A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics. 1999;103(2):414–421 5) Roorda RJ, Mezei G, Bisgaard H, Maden C. Response of preschool children with asthma symptoms to fluticasone propionate. J Allergy Clin Immunol. 2001;108(4):540–546 6) Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, de Blic J, de Jongste JC, Eber E, Everard ML, Frey U, Gappa M, Garcia-Marcos L, Grigg J, Lenney W, Le Souëf P, McKenzie S, Merkus PJ, Midulla F, Paton JY, Piacentini G, Pohunek P, Rossi GA, Seddon P, Silverman M, Sly PD, Stick S, Valiulis A, van Aalderen WM, Wildhaber JH, Wennergren G, Wilson N, Zivkovic Z, Bush A. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008;32:1096-110. Conflict of Interest: None declared
A more cautious conclusion is needed 27 April 2009
Uwe Hasenbein, social scientist Institute for Quality and Efficiency in Health Care (IQWiG), Martin Gerken, Michaela Eikermann, Ulrich Grouven, and Monika Lelgemann. Send letter to journal: Re: A more cautious conclusion is needed uwe.hasenbein{at}iqwig.de Uwe Hasenbein, et al.	In their systematic review (SR) Castro-Rodriguez and Rodrigo conclude that inhaled corticosteroids (ICS) are useful in infants and preschoolers with persistent wheeze/asthma, independent of age and further characteristics. In a recently completed health technology assessment (HTA) report on therapeutic interventions in preschoolers (2 to <5 years of age) with bronchial obstruction (IQWiG V06-02B), commissioned by the Federal Joint Committee (Gemeinsamer Bundesausschuss) in Germany, we actually came to a far more cautious conclusion. Taking the uncertainty of diagnosis in young children into account, we restricted the age range as mentioned above. Only studies in which at least 80% of the children were between 2 and <5 years of age at study entry were included. The lower age limit seems justified by the fact that many children presenting with asthma-like symptoms before the age of 2 are actually suffering from bronchiolitis (Emmers et al. BMJ. 2009;338:b897), which is considered a different clinical entity. The upper limit was set by the existing German disease management programme and follows the guideline of the European Medicines Agency (EMEA) (CPMP/EWP/2992/01). It is also endorsed by other experts (Bisgaard. J Allergy Clin Immunol. 2008;121(4):1066). Castro-Rodriguez and Rodrigo included studies with a wider age range (between 1 month and 5 years of age). However, they also considered studies where the age of many children lay outside the predefined age range (most notably the study by Shapiro et al. J Allergy Clin Immunol. 1998;102(5):789). Furthermore, the above SR included wheezers and asthmatics, but the authors did not mention how the diagnosis of asthma and the symptom “wheezing” were defined and ascertained in the primary studies. The minimum treatment period in the included studies also differed: it was 12 weeks in our HTA report compared with 4 weeks in the SR by Castro-Rodriguez and Rodrigo, where patients were treated for less than 12 weeks in 11 of the 29 studies. As the study results will most likely be used as a basis for long-term treatment recommendations, we feel that the limitations of shorter studies should be stressed, especially concerning adverse effects of ICS such as growth retardation. One study with a negative result (Schokker et al., Pulm Pharmacol Ther. 2008;21(1):88) was not included in the above SR, even though it would have met the inclusion criteria. As our inclusion criteria were stricter, we were only able to include 2 studies (Wasserman et al.. Ann Allergy Asthma Immunol. 2006;96(6):808 and Guilbert et al. N Engl J Med. 2006;354(19):1985), in contrast to the 29 studies included by Castro-Rodriguez and Rodrigo. The primary outcome in the SR by Castro-Rodriguez and Rodrigo was wheezing/asthma exacerbations (WAEs). In the included studies, WAEs were defined and assessed differently (e.g. different symptom scores, parental versus physician-reported exacerbations), which might limit the validity of a pooled effect estimate. With regard to the secondary outcomes selected in the above SR, we do not consider pulmonary function parameters to be appropriate outcomes for children under 5 years of age. Measurement of PEV and FEV1 requires the patient’s cooperation; results can be misleading if not available for all included patients. In addition, adverse effects of ICS therapy were unfortunately not considered as an outcome, even though they are well known and are mentioned by the authors in the introduction section. From our point of view, the risk-benefit balance for the long-term use of ICS in preschoolers seems far more uncertain than is suggested by Castro-Rodriguez and Rodrigo. Conflict of Interest: None declared