Systemic steroids in preschool children with recurrent wheezing exacerbations

1. Systemic Steroids in Preschool Children
with Recurrent Wheezing Exacerbations
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
 Introduction
 Important studies
 Recent meta-analysis
 Conclusions & Biological
explanations

2. The Dilemma of Systemic Steroids in Preschool Children
with Recurrent Wheezing Exacerbations
Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7
•The use of systemic steroids in preschool children with recurrent wheezing
asthma exacerbations has been widely debated and remains a vital question.
•National guidelines recommend systemic steroids to reduce
inflammation during acute asthma exacerbations.
National Asthma Education Prevention Program. Expert panel report 3 (EPR-3): guidelines for
the diagnosis and management of asthma summary report 2007.
J Allergy Clin Immunol 2007;120:S94–138.
•Updated international (GINA) guidelines, mention the lack of benefit
of oral corticosteroids (OCS) in the outpatient setting but recommend them
during hospital care for preschool children with wheezing exacerbations.
Global Strategy for Asthma Management and Prevention. Available
at http://ginasthma.org/: Global Initiative for Asthma (GINA); 2015.

3. The Dilemma of Systemic Steroids in Preschool Children
with Recurrent Wheezing Exacerbations
Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7
Systemic steroids during asthma exacerbations
are efficacious in school age and older children
in reducing short acting bronchodilator use,
reducing relapses, and decreasing hospitalizations.
•Rowe BH, Corticosteroids for preventing relapse following acute exacerbations of asthma.
Cochrane Database Syst Rev 2007;18:CD000195.
•Rowe BH, Corticosteroid therapy for acute asthma. Respir Med 2004;98:275–284.
These results are often directly extrapolated
to young preschool children with recurrent wheezing
exacerbations, leading to frequent use of systemic steroids in this age group.
Collins AD, An update on the efficacy of oral corticosteroids in the treatment of wheezing
episodes in preschool children. Ther Adv Respir Dis 2014;8:182–190.

4. The Dilemma of Systemic Steroids in Preschool Children
with Recurrent Wheezing Exacerbations
Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7
A recent study evaluating the effect of OCS in preschool children
with recurrent episodic wheezing was declared infeasible and halted
prematurely due to 39% of the study children being prescribed
open-label OCS, reflecting the frequent use of OCS.
Bacharier LB, Guilbert TW, Mauger DT, Boehmer S, Beigelman A, Fitzpatrick AM, Jackson DJ,
Baxi SN, Benson M, Burnham CA, Cabana M, Castro M, Chmiel JF, Covar R, Daines M, Gaffin
JM, Gentile DA, Holguin F, Israel E, Kelly HW, Lazarus SC, Lemanske RF, Jr., Ly N, Meade K,
Morgan W, Moy J, Olin T, Peters SP, Phipatanakul W, Pongracic JA, Raissy HH, Ross K,
Sheehan WJ, Sorkness C, Szefler SJ, Teague WG, Thyne S, Martinez FD, National Heart L,
Blood Institute’s A. Early administration of azithromycin and prevention of severe lower
respiratory tract illnesses in preschool children with a history of such illnesses: a randomized
clinical trial. JAMA 2015;314: 2034–2044.

5. The Dilemma of Systemic Steroids in Preschool Children
with Recurrent Wheezing Exacerbations
Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7
In general, studies on the effect of OCS grouped
wheezing disorders in preschool children as a
single disease entity; however, there is increasing
evidence of endotypes and phenotypes heterogeneity
likely representing pathophysiologically distinct
entities, which appear to be established
in the preschool years.
Preschool children with wheezing commonly have recurrent
intermittent episodic wheezing typically triggered by a viral illness or
may have multi-trigger wheeze with symptoms in between episodes,
but these categories likely represent a disease spectrum
and may not be mutually exclusive subgroups.

6. Systemic Steroids in Preschool Children
with Recurrent Wheezing Exacerbations
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
 Introduction
 Important studies
 Recent meta-analysis
 Conclusions & Biological
explanations

7.  Children (1-5 yrs) admitted to
hospital with viral wheeze
 Stratified by high or low serum
ECP, EPX
 Randomized to 5 days of
prednisolone (n= 51)
(20 mg OD) or
placebo (n=69) for the next
episode
Mean day-time symptoms
score for 7 days during
wheezing episodes
0.95 0.96
PREDNISOLONE PLACEBO
1
ns
Efficacy of a short course of parent-initiated oral
prednisolone for viral wheeze in children aged 1-5 years:
randomised controlled trial. Oommen A, Lancet. 2003;362:1433.

8. Mean salbutamol
actuation per day
Prednisolone Placebo
1.59
1.66
ns
2.0 -
1.5 -
1.0 -
0
Efficacy of a short course of parent-initiated oral
prednisolone for viral wheeze in children aged 1-5 years:
randomised controlled trial. Oommen A, Lancet. 2003;362:1433.
 Children (1-5 yrs) admitted to
hospital with viral wheeze
 Stratified by high or low serum
ECP, EPX
 Randomized to 5 days of
prednisolone (n= 51)
(20 mg OD) or
placebo (n=69) for the next
episode

9. % children admitted
Prednisolone Placebo
12%
3%
p=0.058
15 –
10 –
5 –
0
Efficacy of a short course of parent-initiated oral
prednisolone for viral wheeze in children aged 1-5 years:
randomised controlled trial. Oommen A, Lancet. 2003;362:1433.
 Children (1-5 yrs) admitted to
hospital with viral wheeze
 Stratified by high or low serum
ECP, EPX
 Randomized to 5 days of
prednisolone (n= 51)
(20 mg OD) or
placebo (n=69) for the next
episode

10. Median duration of
hospitalization (hrs)
15 –
10 –
5 –
0
placebo prednisolone
13.9
11.0
ns
Oral Prednisolone for Preschool Children with Acute
Virus-Induced Wheezing Panickar J, NEJM 2009;360:329
700 children
(10-60 months) with an
attack of wheezing
associated with a viral
infection
5-day course of oral
prednisolone
(10 mg once a day for
children 10 to 24
months of age and
20 mg once a day for
older children)
compared with placebo

11. 3.0 -
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0
PRAM score
*Placebo
* Prednisolone
4hr 12hr 24hr
Hours post-admission
*
*
* *
**
Oral Prednisolone for Preschool Children with Acute
Virus-Induced Wheezing Panickar J, NEJM 2009;360:329

12. Comparison of total symptom scores in the Acute Intervention
Management Strategies (AIMS) cohort between episodes that
were or were not treated with OCSs
Bacharier LB. JACI 2008;122:1127-35
Do oral corticosteroids reduce the severity of acute
lower respiratory tract illnesses in preschool children
with recurrent wheezing? Beigelman A. JACI 2013;131:1518-25

13. Comparison of total symptom scores in the Manteinance and Intermittent
Inhaled Corticosteroids in Wheezing Toddlers (MIST) cohort
between episodes that were or were not treated with OCSs
Zeiger RS. N Engl J Med 2011;365:1990-2001
Do oral corticosteroids reduce the severity of acute
lower respiratory tract illnesses in preschool children
with recurrent wheezing? Beigelman A. JACI 2013;131:1518-25

14. Systemic Steroids in Preschool Children
with Recurrent Wheezing Exacerbations
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
 Introduction
 Important studies
 Recent meta-analysis
 Conclusions & Biological
explanations

15. 11 clinical trials of OCS in
children <6 years of age (n = 1,733);
presenting with recurrent
wheezing/asthma exacerbations
of any severity.
hospitalizations,
need of additional OCS courses
unscheduled emergency
department (ED) visits
in following month,
length of stay (ED or hospital)
4 were conducted
on an outpatient basis,
5 in inpatients, and
2 in the ED
Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.

16. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
outpatient
ED
inpatient

17. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
Five studies reported hospital admission rates
There was no significant difference between OCS and placebo
(RR: 1.00; 95%CI: 0.49–2.05),
All studies

18. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
Five studies reported hospital admission rates
Analyzing only outpatient studies, OCS treatment was associated with
a higher hospital admission rate (RR: 2.15; 95%CI:1.08–4.29)
Only outpatient studies

19. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
Five studies reported hospital admission rates
Considering only the two studies conducted in the ED, OCS treatment
had a lower risk of hospital admissions (RR: 0.58; 95%CI: 0.37–0.92)
Only ED studies

20. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
Three studies reported Additional Course of Systemic Corticosteroids
One outpatient study 20 and two inpatient studies 24,28
There was no significant difference between OCS and placebo
(RR: 0.74; 95%CI: 0.40–1.34).

21. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
Only the two inpatient studies, 24,28
Three studies reported Additional Course of Systemic Corticosteroids
the difference became significant favoring the OCS group
(RR: 0.57; 95%CI: 0.40–0.81;),

22. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
Three inpatient studies reported unscheduled visits for asthma
symptoms in the month following.
There was no significant statistical difference between OCS and
placebo (RR: 0.73; 95%CI: 0.35–1.52)

23. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
Hospital Length of Stay
Finally, four studies (25–28) reported no differences in hospital length
of stay were found between OCS and placebo, while one study
reported the OCS group had a shorter stay 24.
However, length of stay was reported differently (means vs. medians)
and thus we were not able to perform a pooled analysis.
25. Gleeson JG, Placebo controlled trial of systemic corticosteroids in acute childhood asthma.
Acta Paediatr Scand 1990;79:1052–1058.
26. Fox GF, Treatment of recurrent acute wheezing episodes in infancy with oral salbutamol and prednisolone.
Eur J Pediatr 1996;155:512–516.
27. Jartti T, Efficacy of prednisolone in children hospitalized for recurrent wheezing.
Pediatr Allergy Immunol 2007;18:326–334.
28. Panickar J, Oral prednisolone for preschool children with acute virus-induced wheezing.
N Engl J Med 2009;360:329–338.

24. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
When analyzing studies performed in the ED, OCS
treatment was associated with a lower hospitalization rate.
Similarly, when analyzing studies performed in the
inpatient setting, OCS treatment was associated with
a lower need for additional courses of SCS.
In the outpatient studies, on the other hand, OCS
administration was associated with more hospital admissions
(behavioral changes), suggesting that OCS may not be
beneficial in all clinical settings for this age group.

25. Systemic Steroids in Preschool Children
with Recurrent Wheezing Exacerbations
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
 Introduction
 Important studies
 Recent meta-analysis
 Conclusions & Biological
explanations

26. Efficacy of oral corticosteroids in the treatment of acute
wheezing episodes in asthmatic preschoolers:
Systematic review with meta-analysis.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.
OCS may be more effective in certain
subgroups depending on exacerbation
severity or timing of administration:
in this age group, OCS may be more
beneficial among children who present
with more severe exacerbations that
require urgent care or hospitalization.
However, asthma in young children is a heterogeneous condition with
different underlying pathophysiological pathways, which could explain why
some patients may benefit from OCS prescription while others show no
response.

27. preschoolers with severe recurrent wheeze, biopsies of
children up to 36 months were found to contain more inflammatory
cells with fewer eosinophils than those on older preschoolers.
Airway Remodeling in Preschool Children with Severe
Recurrent Wheeze.
Lezmi G. Am J Respir Crit Care Med. 2015;192(2):164-71.
(36-59 months)(≤36 months)(Age months)

28. The Dilemma of Systemic Steroids in Preschool Children
with Recurrent Wheezing Exacerbations
Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7
Airway pathology in preschool children with episodic wheezing due to
viral illnesses resembles a neutrophil-predominant, low eosinophilic
picture as compared to an eosinophilic predominance in children with
classic atopic asthma making it less likely for steroids to be effective.
•Stevenson EC, Bronchoalveolar lavage findings suggest two different forms of childhood
asthma. Clin Exp Allergy 1997;27:1027–1035.
•Le Bourgeois M, Bronchoalveolar cells in children <3 years old with severe recurrent wheezing.
Chest 2002;122:791–797.

29. Other factors that may affect OCS response include:
the timing of administration,
•Davis SR, Corticosteroid timing and length of stay for children with asthma in the emergency
department. J Asthma 2012;49:862–867.
•Zemek R, Triage nurse initiation of corticosteroids in pediatric asthma is associated with
improved emergency department efficiency. Pediatrics 2012;129:671–680.
vitamin D deficiency,
Beigelman A, The association between vitamin D status and the rate of exacerbations
requiring oral corticosteroids in preschool children with recurrent wheezing.
J Allergy Clin Immunol 2014;133:1489–1492.
genetic predisposition.
Ducharme FM, Determinants of oral corticosteroid responsiveness in wheezing asthmatic
youth (DOORWAY): protocol for a prospective multicentre cohort study of children with
acute moderate-to-severe asthma exacerbations. BMJ Open 2014;4:e004699.
Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.

30. HOW CAN WE END THIS DEBATE?
Beigelman A, J Allergy Clin Immunol Pract 2016;4:27-35
•Most of the available data do not support the role of OCSs as a treatment
for acute mild episodic wheeze.
•However, on the basis of uncertainties, we cannot recommend to completely
abandon this traditional therapy.
•Previous editorials on this important clinical question have suggested that
OCSs should be given only to a subgroup of severely ill children in the
inpatient setting.
•National Asthma Education and Prevention Program. Expert Panel Report III:
guidelines for the diagnosis and management of asthma. Bethesda, MD: US
Department of Health and Human Services; 2007.
•Bush A. Practice imperfect-treatment for wheezing in preschoolers.
N Engl J Med 2009;360:409-10.

31. Beigelman A, J Allergy Clin Immunol Pract 2016;4:27-35
•Moreover, because it was never shown that OCSs are not effective in
preschool children hospitalized in the intensive care unit or in children
who have other chronic medical conditions, these children should be
treated with OCSs.
•Ultimately, there is a significant need to conduct efficacy trials evaluating
OCS treatment in preschool-aged children with recurrent wheezing targeted
at phenotypes that would be expected to respond to OCSs.
•Specifically, studies must examine a larger number of subjects with a
positive API and/or mAPI eosinophilic airway inflammation or airway
pathologic consistent with asthma as well as older preschool-aged children
with more persistent asthma symptoms, and children presenting with severe
exacerbations.
HOW CAN WE END THIS DEBATE?

32. Thank you for
your attention
to the story
my grandpa told you.
Mia Charlize Powell