Correspondence

Safety of small-particle inhaled corticosteroidsin infants

To the Editor:Amirav et al1 provided an excellent review of the delivery of

inhaled corticosteroids (ICSs) in infants and young children.They provided some compelling arguments for considering theuse of devices that generate small particles, such as hydrofluoroal-kane (HFA)–propelled beclomethasone dipropionate (BDP) andciclesonide metered-dose inhalers (MDIs) with a spacer andappropriate facemasks. However, the potential for risks fromthis increased delivery of ICSs to infants was given short shrift,primarily because there are few data on which to draw. It wouldbe a mistake not to take this into greater consideration becausestudies of larger-particle MDIs and nebulized ICSs have clearlydemonstrated efficacy and safety in children 1 to 4 years ofage.2-4 The authors cited 2 studies on growth in older childrenas suggesting that small-particle MDIs were safe in this group.5,6

However, neither of these studies demonstrate improved safety.Pedersen et al5 reported similar growth over a year in an

open-label randomized comparison of chlorofluorocarbon-propelled BDP and HFA-BDP at one half the dose. The doses ofchlorofluorocarbon-propelled BDP (200-400 mg/d) used in thestudy have previously been demonstrated to produce growth retar-dation.7 Thus this study only demonstrated that the systemic effectswere no worse in the HFA-BDP group.

The second trial was a 1-year comparison of ciclesonide HFA-MDI, 40 and 160 mg once daily, with placebo.6 Although it dem-onstrated no effect of ciclesonide on linear growth, the 2 pivotaltrials submitted to the US Food and Drug Administration usingthese same doses failed to unequivocally demonstrate efficacyand neither did the efficacy end points for this study.8 Thus it isunclear that these data actually demonstrate improved safety. Ifin the future ciclesonide does unequivocally demonstrate greatersafety at therapeutic doses in children, it is more likely to be at-tributed to its very low oral bioavailability and increasedsystemic clearance (2-fold or greater than the other ICSs).9

Clearly, the issues of both efficacy and safety need to be morethoroughly addressed before suggesting that small particle–generating devices are preferred in infants.

H. William Kelly, PharmD

From the Department of Pediatrics and Pharmacy, University of New Mexico Health

Sciences Center, Albuquerque, NM. E-mail: hwkelly@salud.unm.edu.

Disclosure of potential conflict of interest: H. W. Kelly is on the advisory boards for

GlaxoSmithKline and MAP and receives research support from the National Heart,

Lung, and Blood Institute.

REFERENCES

1. Amirav I, Newhouse MT, Minocchieri S, Castro-Rodriguez JA, Sch€uepp KG. Fac-

tors that affect the efficacy of inhaled corticosteroids for infants and young children.

J Allergy Clin Immunol 2010 [Epub ahead of print].

2. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al.

Long-term inhaled corticosteroids in preschool children at high risk for asthma.

N Engl J Med 2006;354:1985-97.

3. Skoner DP, Szefler SJ, Welch M, Walton-Bowen K, Cruz-Rivera M, Smith JA. Lon-

gitudinal growth in infants and young children treated with budesonide inhalation

suspension for persistent asthma. J Allergy Clin Immunol 2000;105:259-68.

4. Bisgaard H, Allen D, Milanowski J, Kalev I, Willits L, Davies P. Twelve-month

safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years

with recurrent wheezing. Pediatrics 2004;113:e87-94.

676

5. Pedersen S, Warner J, Wahn U, Staab D, Le Bourgeois M, Van Essen-Zandvliet E,

et al. Growth, systemic safety, and efficacy during 1 year of asthma treatment with

different beclomethasone dipropionate formulations: an open-label, randomized

comparison of extrafine and conventional aerosols in children. Pediatrics 2002;

109:e92.

6. Skoner DP, Maspero J, Banerji D. Ciclesonide Pediatric Growth Study Group.

Assessment of the long-term safety of inhaled ciclesonide on growth in children

with asthma. Pediatrics 2008;121:e1-14.

7. Sharek PJ, Bergman DA. The effect of inhaled steroids on the linear growth of chil-

dren with asthma: a meta-analysis. Pediatrics 2000;106:e8.

8. Alvesco, Full prescribing information. Alvesco (ciclesonide) inhalation aerosol

80 mcg, 160 mcg for oral inhalation only. Available at: http://www.fda.cder/foi/

label/2008/021658lbl.pdf. Accessed March 20, 2010.

9. Kelly HW. Comparison of inhaled corticosteroids: an update. Ann Pharmacother

2009;43:519-27.

Available online June 25, 2010.

doi:10.1016/j.jaci.2010.04.033

Reply

To the Editor:We thank Dr Kelly1 for his comments and agree that more data

arising from appropriately designed studies are certainly needed,as we stated in our article.

However, as we indicated, the main purpose of the review wasto stress that the issue of efficacy needs to be resolved rather thandismissing the potential value of inhaled corticosteroid therapy inthis age group, as was suggested by a small number of publishedstudies2-4 and a New England Journal of Medicine editorial5 refer-ring, for the most part, to considerably older children and aerosoltherapy with much larger particles. Future efficacy studies should,of course, also be adequately powered for evaluation of a varietyof safety issues (eg, growth impairment, adrenal suppression,facial rashes, corneal injury, and pneumonia). From previousstudies, especially those of Agertoft and Pedersen6 with budeso-nide, it seems reasonable to conclude that growth impairment ismodest, occurs only during the first year, diminishes with time,7

and does not appear to affect final height.The other safety issues have not, to our knowledge, been

adequately resolved, and we agree that additional well-designedstudies are badly needed.

Israel Amirav, MDa

Michael Newhouse, MD, MSc, FRCP(C)b

From aPediatric Department, Ziv Medical Center, Safed, Faculty of Medicine, Technion,

Haifa, Israel, and bFirestone Institute of Respiratory Health, St. Joseph’s Hospital,

McMaster University, Hamilton, Ontario, Canada. E-mail: amirav@012.net.il.

Disclosure of potential conflict of interest: The authors have declared that they have no

conflict of interest.

REFERENCES

1. Kelly HW. Safety of small-particle inhaled corticosteroids in infants. J Allergy Clin

Immunol 2010;126:676.

2. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent in-

haled corticosteroids in infants with episodic wheezing. N Engl J Med 2006;354:

1998-2005.

3. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al.

Long-term inhaled corticosteroids in preschool children at high risk for asthma.

N Engl J Med 2006;354:1985-97.

4. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A. IFWIN study team. Sec-

ondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy

INfants (IFWIN): double-blind, randomised, controlled study. Lancet 2006;368:754-62.

5. Gold DR, Fuhlbrigge AL. Inhaled corticosteroids for young children with wheezing.

N Engl J Med 2006;354:2058-60.