Correspondence

Inhaled Corticosteroids and Children

N Engl J Med 2006; 355:624-626August 10, 2006

Article

To the Editor:

Guilbert and colleagues and Bisgaard and colleagues (May 11 issue)1,2 investigated the effect of inhaled corticosteroids in infants and preschool children with wheezing or an increased risk of asthma. The two studies, at best, found a marginal benefit in the inhaled-corticosteroid group, as compared with the placebo group. The treatment effect appeared to be somewhat stronger in the preschool cohort studied by Guilbert et al.

Guilbert et al. used propellant-driven metered-dose inhalers with fluticasone, and Bisgaard et al. used the same type of inhalers with budesonide, both delivered by means of a valved spacer. The particle size (mass median aerodynamic diameter) of either agent at the exit site of the spacer is approximately 3 to 4 μm.3,4 Because of the small size of the airways in children under the age of five years and especially in infants, less than 5 percent of such particles would be deposited in the lung.5 The use of a smaller particle size (e.g., mass median aerodynamic diameter, 1 μm) would have increased lung deposition by a factor of 4 to 5,6 and might have resulted in a different outcome.

Dieter Köhler, M.D.
Peter Haidl, M.D.
Dominic Dellweg, M.D.
Kloster Grafschaft, D-57392 Schmallenberg, Germany
d.koehler@fkkg.de

6 References

1
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;354:1985-1997
Full Text | Web of Science | Medline

2
Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006;354:1998-2005
Full Text | Web of Science | Medline

3
Ross DL, Schultz RK. Effect of inhalation flow rate on the dosing characteristics of dry powder inhaler (DPI) and metered dose inhaler (MDI) products. J Aerosol Med 1996;9:215-226
CrossRef | Web of Science | Medline

4
Terzano C, Mannino F. Aerosol characterization of three corticosteroid metered dose inhalers with volumatic holding chambers and metered dose inhalers alone at two inspiratory flow rates. J Aerosol Med 1999;12:249-254
CrossRef | Web of Science | Medline

5
Janssens HM, Krijgsman A, Verbraak TF, Hop WC, de Jongste JC, Tiddens HA. Determining factors of aerosol deposition for four pMDI-spacer combinations in an infant upper airway model. J Aerosol Med 2004;17:51-61
CrossRef | Web of Science | Medline

6
Devadason SG, Huang T, Walker S, Troedson R, Le Souef PN. Distribution of technetium-99m-labelled QVAR delivered using an Autohaler device in children. Eur Respir J 2003;21:1007-1011
CrossRef | Web of Science | Medline

To the Editor:

The results of the study by Bisgaard et al. emphasize that inhaled corticosteroids are no panacea for all airway diseases with wheezing. However, wheezing in infants comprises a heterogeneous group of disorders. Respiratory syncytial virus (RSV) bronchiolitis is one of these disorders and is clinically well recognized. About half the children hospitalized for RSV bronchiolitis go on to have recurrent episodes of wheezing.1 The pathogenesis of this disease is thought to be distinct from that of other wheezing disorders of infancy. Therefore, the role of inhaled corticosteroids in the prevention of recurrent wheezing after RSV bronchiolitis is of specific interest. Previous studies investigating whether inhaled corticosteroids can reduce the occurrence of postbronchiolitis wheezing have yielded conflicting data,2,3 although no large, randomized trials have been conducted. Bisgaard et al. performed viral evaluation on nasal samples during wheezing episodes. Do they have data on the effect of inhaled corticosteroids when the first episode of wheezing was caused by RSV bronchiolitis?

Louis Bont, M.D., Ph.D.
Jan L.L. Kimpen, M.D., Ph.D.
Marieke J.J. Ermers, M.D.
University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands
l.bont@umcutrecht.nl

3 References

1
Bont L, Aalderen WMC, Kimpen JLL. Long-term consequences of respiratory syncytial virus (RSV) bronchiolitis. Paediatr Respir Rev 2000;1:221-227
CrossRef | Medline

2
Wong JY, Moon S, Beardsmore C, O'Callaghan C, Simpson H. No objective benefit from steroids inhaled via a spacer in infants recovering from bronchiolitis. Eur Respir J 2000;15:388-394
CrossRef | Web of Science | Medline

3
Reijonen T, Korppi M, Kuikka L, et al. Anti-inflammatory therapy reduces wheezing after bronchiolitis. Arch Pediatr Adolesc Med 1996;150:512-517
Web of Science | Medline

To the Editor:

In Figure 1 of their editorial (May 11 issue),1 Gold and Fuhlbrigge list the airway inflammation of bronchopulmonary dysplasia among the conditions with a better clinical response to inhaled corticosteroids. We think that this concept might lead to mistaken therapeutic practices. The assumption of a corticosteroid-sensitive inflammation in bronchopulmonary dysplasia suggests a pathophysiological analogy to allergic airway inflammation, which is the main condition mentioned as responsive to inhaled corticosteroids. However, evidence of persistent airway inflammation in bronchopulmonary dysplasia in toddlers with recurrent wheezing is scant, and the nature of the inflammation probably differs from that in asthma. Eosinophilic inflammation (a typical corticosteroid-responsive feature of asthma) is not present in survivors of bronchopulmonary dysplasia, and such patients have low levels of exhaled nitric oxide2 and different mechanisms of airway hyperresponsiveness, as compared with children with asthma.3 A response to inhaled corticosteroids therefore cannot be taken for granted in bronchopulmonary dysplasia; interestingly, two randomized studies showed no beneficial effect of treatment with inhaled corticosteroids in infants with bronchopulmonary dysplasia.4,5 Moreover, the corticosteroid-associated risk of limitation of lung growth1 should be particularly emphasized in infants with bronchopulmonary dysplasia, in whom alveolar development is already restricted.

Eugenio Baraldi, M.D.
Marco Filippone, M.D.
University of Padua, 35128 Padua, Italy
baraldi@pediatria.unipd.it

5 References

1
Gold DR, Fuhlbrigge AL. Inhaled corticosteroids for young children with wheezing. N Engl J Med 2006;354:2058-2060
Full Text | Web of Science | Medline

2
Baraldi E, Bonetto G, Zacchello F, Filippone M. Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation. Am J Respir Crit Care Med 2005;171:68-72
CrossRef | Web of Science | Medline

3
Kim do K, Choi SH, Yu J, Yoo Y, Kim BI, Koh YY. Bronchial responsiveness to methacholine and adenosine 5′-monophosphate in preschool children with bronchopulmonary dysplasia. Pediatr Pulmonol 2006;41:538-543
CrossRef | Web of Science | Medline

4
Beresford MW, Primhak R, Subhedar NV, Shaw NJ. Randomised double blind placebo controlled trial of inhaled fluticasone propionate in infants with chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2002;87:F62-F63
CrossRef | Web of Science | Medline

5
Dugas MA, Nguyen D, Frenette L, et al. Fluticasone inhalation in moderate cases of bronchopulmonary dysplasia. Pediatrics 2005;115:e566-e572
CrossRef | Web of Science | Medline

Author/Editor Response

We would like to stress that during the treatment period, the use of inhaled corticosteroids resulted in a significant decrease in the symptom burden. However, we agree with Köhler et al. that our data do not provide evidence of a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. The fact that we saw effects on growth and symptom burden indicated that drug delivery was achieved; however, the relative deposition within the small airways in children of preschool age is not known for any of the drugs mentioned, since the two studies cited were conducted in an infant anatomical model1 and in children 5 to 14 years of age.2 Without available data on the effect of spacer use on the delivery of the hydrofluoroalkane (propellant) formulation3 when we were designing the study, we chose fluticasone because of its high potency, relatively small particle size, and long use (although not approved) in preschool children.

Theresa Guilbert, M.D.
Fernando D. Martinez, M.D.
Arizona Respiratory Center, Tucson, AZ 85724
guilbert@arc.arizona.edu

Stanley J. Szefler, M.D., Ph.D.
National Jewish Medical and Research Center, Denver, CO 80206

for the Childhood Asthma Research and Education (CARE) Network Steering Committee

3 References

1
Janssens HM, Krijgsman A, Verbraak TF, Hop WC, de Jongste JC, Tiddens HA. Determining factors of aerosol deposition for four pMDI-spacer combinations in an infant upper airway model. J Aerosol Med 2004;17:51-61
CrossRef | Web of Science | Medline

2
Devadason SG, Huang T, Walker S, Troedson R, Le Souef PN. Distribution of technetium-99m-labelled QVAR delivered using an Autohaler device in children. Eur Respir J 2003;21:1007-1011
CrossRef | Web of Science | Medline

3
Martin RJ, Szefler SJ, Chinchilli VM, et al. Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med 2002;165:1377-1383
CrossRef | Web of Science | Medline

Author/Editor Response

We found that intermittent use of inhaled corticosteroids had no short- or long-term effect on recurrent wheezing in infants. Köhler et al. raise the possibility of a different outcome had we used an aerosol of smaller particle size. We agree that aerosols of smaller particle size would increase the lung dose, but they would also increase the systemic exposure. It is unknown how this exposure would affect the relative deposition in the airways and alveolar region. Alternatively, we could have chosen a higher nominal dose to obtain greater airway deposition. We used a nonelectrostatic spacer that we developed and previously documented as delivering a high and reproducible dose to the lungs in young children.1-3 This device and formulation were similar to what we previously used to demonstrate an effect on lung function and bronchial reactivity in young children.4 Yet, as discussed in the article, we cannot rule out the possibility that an increased lung dose would lead to a different outcome.

Bont et al. raise the possibility of a different outcome in the subgroup of infants in whom RSV bronchiolitis developed during the first episode. We found RSV bronchiolitis in 39 percent of the first episodes. The effect of budesonide in this subgroup was similar to that in the main analyses — that is, without short- or long-term benefit.

Hans Bisgaard, M.D., D.M.Sci.
Copenhagen University Hospital, Gentofte, DK-2900 Copenhagen, Denmark
bisgaard@copsac.dk

4 References

1
Bisgaard H. A metal aerosol holding chamber devised for young children with asthma. Eur Respir J 1995;8:856-860
CrossRef | Web of Science | Medline

2
Bisgaard H, Anhoj J, Klug B, Berg E. A non-electrostatic spacer for aerosol delivery. Arch Dis Child 1995;73:226-230
CrossRef | Web of Science | Medline

3
Lipworth BJ, Lee DK, Anhoj J, Bisgaard H. Effect of plastic spacer handling on salbutamol lung deposition in asthmatic children. Br J Clin Pharmacol 2002;54:544-547
CrossRef | Web of Science | Medline

4
Nielsen KG, Bisgaard H. The effect of inhaled budesonide on symptoms, lung function, and cold air and methacholine responsiveness in 2- to 5-year-old asthmatic children. Am J Respir Crit Care Med 2000;162:1500-1506
Web of Science | Medline

Author/Editor Response

Most trials of inhaled corticosteroids in bronchopulmonary dysplasia,1 including the trial by Dugas et al.2 cited by Baraldi and Filippone, have focused on the use of postnatal corticosteroids in reducing the risk of bronchopulmonary dysplasia and the need for supplementary oxygen or ventilatory support, not on the use of inhaled corticosteroids for reducing wheeze symptoms. In our editorial, we were careful to point out that “after the neonatal period, clinicians tend to use intermittent therapy with inhaled corticosteroids for wheezing in children with established bronchopulmonary dysplasia, though studies evaluating the efficacy of treatment are few.” In Figure 1 of our editorial, bronchopulmonary dysplasia straddles the two categories “more responsive to steroids” and “less responsive to steroids,” to highlight the uncertainty regarding the efficacy of inhaled corticosteroids for bronchopulmonary dysplasia–associated wheezing. We did not state or imply that the use of corticosteroids in the clinical setting of bronchopulmonary dysplasia suggests a pathophysiological analogy to allergic airway inflammation. Corticosteroids have a broad range of effects on the immune system and are used in the treatment of nonallergic inflammatory disorders; their use in bronchopulmonary dysplasia does not assume that inflammation present in this disorder is eosinophilic in nature. We agree that prolonged use of inhaled corticosteroids in young children needs to be considered carefully, as we state: “Given the potential risks of therapy in early life, prolonged treatment for toddlers under the age of two years should be highly selective.”

Diane R. Gold, M.D., M.P.H.
Anne L. Fuhlbrigge, M.D.
Brigham and Women's Hospital, Boston, MA 02115

2 References

1
Pantalitschka T, Poets CF. Inhaled drugs for the prevention and treatment of bronchopulmonary dysplasia. Pediatr Pulmonol (in press).

2
Dugas MA, Nguyen D, Frenette L, et al. Fluticasone inhalation in moderate cases of bronchopulmonary dysplasia. Pediatrics 2005;115:e566-e572
CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1
Ricardo M Fernandes, Liza M Bialy, Ben Vandermeer, Lisa Tjosvold, Amy C Plint, Hema Patel, David W Johnson, Terry P Klassen, Lisa Hartling, Ricardo M Fernandes. 2010. Glucocorticoids for acute viral bronchiolitis in infants and young children. .
CrossRef