Jacip jan 1

1. Pro/Con Review
Should a Preschool Child with Acute Episodic
Wheeze be Treated with Oral Corticosteroids?
A Pro/Con Debate
Avraham Beigelman, MD, MSCIa
, Sandy Durrani, MDb
, and Theresa W. Guilbert, MD, MSb
St Louis, Mo; Cincinnati, Ohio
Traditionally, preschool-aged children with an acute wheezing
episode have been treated with oral corticosteroids (OCSs) based
on the efficacy of OCSs in older children and adolescents.
However, this practice has been recently challenged based on the
results of recent studies. The argument supporting the use of
OCSs underscores the observation that many children with
recurrent preschool wheezing develop atopic disease in early life
which predicts both an increased risk to develop asthma in later
life and response to OCS therapy. Further, review of the
literature demonstrates heterogeneity of study designs, OCS
dosage, interventions, study medication adherence, and settings
and overall lack of predefined preschool wheezing phenotypes.
The heterogeneity of these studies does not allow a definitive
recommendation discouraging OCS use. Advocates against the
use of OCSs in this population argue that most of studies
investigating the efficacy of OCSs in acute episodic wheeze in
preschool-aged children have not demonstrated beneficial
effects. Moreover, repeated OCS bursts may be associated with
adverse effects. Finally, both sides can agree that 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. This article presents a summary of recent literature
regarding the use of OCSs for acute episodic wheezing in
preschool-aged children and a “pro” and “con” debate for
such use Ó 2015 American Academy of Allergy, Asthma &
Immunology (J Allergy Clin Immunol Pract 2016;4:27-35)
CASE PRESENTATION
A 3-year-old girl with a maternal history of asthma and eczema
and a history of 3 wheezing episodes treated as an outpatient
presents to the emergency department (ED) with an acute
wheezing episode after 3 days of viral upper respiratory tract
infection symptoms. Her respirations are 30/min, and her oxy-
gen saturation is 93% on room air. She has decreased breath
sounds in the bases and expiratory wheezing bilaterally with mild
intercostal retractions. The rest of her physical examination is
normal. She is treated with 3 albuterol nebulizer therapies as is
done in many large EDs with some improvement in the aeration
of her lungs and less wheezing on auscultation. Her respiratory
rate remains unchanged, but she is not retracting anymore and
her oxygen saturation is 95%. Discharge home is considered.
Her parents ask whether she should be treated with a course of
oral corticosteroids (OCSs) that have been used in the past.
INTRODUCTION
The above clinical vignette highlights a common clinical sce-
nario encountered by practitioners caring for wheezing preschool-
aged children in various settings: home, clinic, ED, or hospital.
Approximately 50% of children experience at least 1 wheezing
episode before the age of 6 years,1
mostly within the context of
viral respiratory infections.1
Overall, early childhood wheezing is a
complex and heterogeneous group of phenotypes, which are
different in their pathophysiologies and natural histories,2,3
and
perhaps in their response to common asthma therapies.4-6
Traditionally, this child has been treated with OCSs on the
basis of the premise that airway inflammation can be attenuated
and this would result in decreased symptoms severity, faster re-
turn to baseline health, and decreased acute care utilization
(outpatient primary care office, urgent care/EDs, or hospitaliza-
tion). In addition, the efficacy of OCSs is well established during
acute asthma exacerbations among school-age children and ad-
olescents in the acute care setting, in which OCSs have been
associated with a lower risk of relapse, fewer hospitalizations, and
a
Department of Pediatrics, Washington University and St Louis Children’s Hospital,
St Louis, Mo
b
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincin-
nati, Ohio
Disclosure: The authors disclose that their position for this pro/con debate manu-
script was assigned to them. This position assignment does not necessarily reflect
their personal opinion regarding the utility of OCS treatment for acute episodic
wheeze among pre-school children.
Conflicts of interest: A. Beigelman has received research support from the National
Heart, Lung, and Blood Institute/the National Institute of Allergy and Infectious
Diseases/the National Institutes of Health (NIH) AsthmaNet/Inner City Asthma
Consortium (ICAC). T. W. Guilbert has received personal fees for the development
of Pediatric Pulmonary board exam questions from the American Board of Pedi-
atrics, Pediatric Pulmonary Subboard; has received research support and personal
fees as an advisory board member from Teva and GlaxoSmithKline; has received
personal fees as an advisory board member from the Centers for Disease Control
and Prevention and Merck; has received research support from the Department of
Health and Human Services, the NIH, UW Madison Medical and Education
Research Committee, Abbott Laboratories, Array Biopharma, Mylan, Forest
Research Institute, F. Hoffman-LaRoche, MedImmune, KaloBios Pharmaceuticals,
Vertex Pharmaceuticals, Roxane Laboratories and CompleWare Corporation, CF
Foundation Therapeutics, and Roche/Genentech; and receives royalties from
UpToDate. S. Durrani declares no relevant conflicts of interest. The authors disclose
that their position for this pro/con debate article was assigned to them. This position
assignment does not necessarily reflect their personal opinion regarding the utility of
oral corticosteroid treatment for acute episodic wheeze among preschool children.
Received for publication July 23, 2015; revised October 13, 2015; accepted for
publication October 15, 2015.
Corresponding author: Theresa W. Guilbert, MD, MS, Division of Pulmonary
Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical
Center, 3333 Burnet Ave, MLC 2021, Cincinnati, OH 45229. E-mail: theresa.
guilbert@cchmc.org.
2213-2198
Ó 2015 American Academy of Allergy, Asthma & Immunology
http://dx.doi.org/10.1016/j.jaip.2015.10.017
27
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2. Abbreviations used
AIMS- Acute Intervention Management Strategies
API- Asthma predictability index
ED- Emergency department
ICS- Inhaled corticosteroid
mAPI- Modified asthma predictability index
MIST- Maintenance and Intermittent Inhaled Corticosteroids in
Wheezing Toddlers
OCS- Oral corticosteroid
PRAM- Preschool Respiratory Assessment Measure
less need for b2-agonist treatments.7
However, this dogma has
been recently challenged on the basis of studies that have been
published in the last decade. Table I presents a summary of
randomized trials and post hoc analyses that investigated the
efficacy of OCSs for acute episodic wheeze in preschool children.
The authors will present both the “pro” and “con” sides for the
use of OCSs in the setting of preschool wheezing.
PRO: DRS SANDY DURRANI AND THERESA W.
GUILBERT
The advocates for not using systemic steroids in children with
recurrent preschool wheezing often presume that these children
do not have atopic disease and thus will not respond to this
therapy. However, many preschool-aged children with recurrent
wheezing develop atopic disease in early life17-20
and this is one
of the strongest and most consistent risk factors for the devel-
opment of asthma in later life. Moreover, up to 60% of children
with recurrent wheeze at high risk to develop asthma on the basis
of positive modified asthma predictive index (mAPI) were found
to have aero- or food-allergen sensitization at age 2 to 3 years.21
Early atopic sensitization also was associated with subsequent
increased risk of viral wheezing illnesses, particularly rhino-
virus.22
Some studies have found that younger preschool-aged
children have a predominance of neutrophilic airway inflam-
mation,23,24
whereas others have demonstrated eosinophilic
airway inflammation in those with confirmed recurrent
wheezing.25-27
It is not clear at which age the presumed transi-
tion from neutrophilic to eosinophilic airway inflammation seen
in school-aged children28-30
occurs due to the paucity of airways
studies in this vulnerable population. Furthermore, multiple
studies have demonstrated that the use of inhaled corticosteroids
(ICSs) in preschool-aged children with recurrent wheezing has
resulted in reducing wheezing exacerbations compared with
placebo31-34
and ICSs have been recommended by asthma
guidelines, particularly in those with a history of severe wheezing
exacerbations or those with a positive mAPI.35,36
Because many
preschool children respond to ICSs, it would be unreasonable to
expect these children to respond to ICSs but not OCSs.
When taken together, most of the evidence (Table I) seems to
suggest that the use of OCSs may not be effective in this vulnerable
population. However, the response of a preschool-aged child to
OCSs is complex and can be confounded by many factors. To that
end, reviewing the evidence more granularly reveals important
points. For example, an important study by Panickar et al15
(for
details, see Table I as well as Dr Beigelman’s discussion), often cited
by advocates against OCSs, demonstrated no differences between
the OCS and the placebo groups of hospitalized children in the
median time to discharge, 30-day wheezing readmissions, as well as
short-term symptom scores and albuterol use. From our perspective,
it is important to point out that a lower range of the recommended
OCS dose35
was used in these children (10-20 mg daily) and that
most of these children had milder exacerbations given their average
length of stay (11-13.9 hours) and their low severity (based on the
Preschool Respiratory Assessment Measure [PRAM] scoring system)
scores. Furthermore, 30% were very young children presenting with
their first wheezing episode, which we would label as bronchiolitis,
an important distinction because many of these children with
bronchiolitis will outgrow their wheezing symptoms19,37
and sys-
temic steroids have not been demonstrated to be effective.38
Furthermore, only 18% (n ¼ 124) of these patients were identi-
fied as having a positive mAPI, ostensibly the group at the highest
risk for school-age asthma.
Advocates of minimizing the use of OCSs in acute preschool
wheezing cite studies that have demonstrated little to no benefit
particularly those in the home or hospital settings8-10,13,15
(Table I). Highlighting how complex and nuanced this discus-
sion is, even settings in which the intervention was studied can
confound results. Children who are seen in the ED are less likely
to have received regular medical care or basic asthma education or
have private insurance.39-41
These children are also more likely to
have a history of recurrent wheezing and present with more severe
exacerbations. Indeed, one study has shown benefit in the ED
setting in children with a history of recurrent wheezing (Table I).
Tal et al12
performed a randomized double-blind placebo-
controlled trial of 74 children aged 7 to 54 months with a history
at least 3 wheezing episodes who presented to the ED with acute
wheezing. Those who received intravenous methylprednisolone
were less likely to be hospitalized than those who received placebo
(20% vs 43%).
Another major study endorsed by those opposed to the use of
oral steroids in preschool wheezing was a post hoc analysis of 2
preschool wheezing clinical trials11
(Acute Intervention Man-
agement Strategies [AIMS]42
and Maintenance and Intermittent
Inhaled Cortico Steroids in Wheezing Toddlers [MIST]43
trials)
led by our coauthor on behalf of the National Institutes of
Healthesponsored multicenter Childhood Asthma and Research
Education network. These analyses did not demonstrate a dif-
ference in symptoms scores in 2 study populations. These were
well-conducted studies involving multiple centers with excellent
methodology. However, the issue remains that this study was a
post hoc analysis, a fact that cannot be taken lightly in spite of
remonstrations that these analyses were done diligently.44
Finally, there are several additional points that need to be
illustrated before making a recommendation to the medical
community to abandon OCS therapy for preschool wheezing.
First, there is heterogeneity of study designs such as relatively low
OCS dosage and delayed initiation of OCS therapy, in-
terventions, study medication adherence, and settings (see above)
and lack of predefined preschool wheezing phenotypes studied.16
Illustrative of this point, the Oommen et al10
and Webb et al8
studies gave a 5-day OCS treatment whereas Grant et al9
used
a single OCS dose. Primary outcomes studied ranged from
decreased symptoms8,10
to decreased health care utilization.9
More importantly, many of these studies are relatively small in
numbers and involved only single centers and all interventions
were parent-initiated. Furthermore, these studies were designed
only to detect large differences while insufficiently powered to
detect differences in subgroups with more severe exacerbations.
In many studies, the children were excluded if they had a history
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3. TABLE I. Summary of studies investigating the efficacy of OCSs in the treatment of acute episodic wheeze in preschool children
Study Characteristics of study population Intervention/timing of intervention
Power to detect a difference in the
primary outcome Results
Outpatient studies
Webb et al,8
1986
Double- blind partial-crossover
trial
-<18-mo-olds (n ¼ 38) with !2
previous wheezing episodes
-Neither the atopic status of the study
population nor the daily ICS
status was reported
-Parent-initiated prednisolone
1 mg/kg twice a day for 5 d,
or placebo
-Study medication was initiated for
episodes that were still clinically
significant after at least 48 h
-Not reported (likely to be
underpowered based on the
small study population)
-No significant improvement in
symptom scores, measured daily
over 8 d*
Grant et al,9
1995
RDBPCT, crossover design
-2-14-y-olds (n ¼ 86) with history of
2 acute care visits for asthma in
the past 12 mo
-Atopic status of the study population
was not reported
-5% were treated with daily ICS
-Specific subgroup analysis was
reported for the 2-5-y-old
participants
-Early parent-initiated prednisone
2 mg/kg  1 (max 60 mg), or
placebo
-“Study medication was initiated for
asthma attack that had not
improved within 3 hours of a
dose of the child’s regular
asthma medicine(s)”
- Cross over design: 6 months in each
block
-A total sample size of 80 participants
provided 80% power to detect
33% reduction in the number of
unscheduled outpatient visits
-Results for the 2-5-y-old subgroup:
Higher number and a greater
proportion of episodes that
resulted in unscheduled
outpatient visits or in ED visits
once the children were treated
with prednisone*
-Children were followed 6 mo after
each study medication was
given in a crossover design
Oommen et al,10
2003
RDBPCT
-1-5-y-olds (n ¼ 120) with a history
of hospitalization for wheeze,
stratified by eosinophilic
priming status as a marker for
atopic tendency
-Approximately a third of the
participants were treated with
daily ICS
-Half the study population had an
atopic tendency as defined by
high- eosinophilic priming
status
-Early parent-initiated prednisolone
20 mg/d  5 d, or placebo
-Study medication was initiated “at
the start of viral wheeze
episode”
-50 children in each treatment group
provided 80% power to detect a
difference of 0.34 in symptom
score (on a scale of 0-6)
-No significant difference in
symptom scores*, measured
over 7 d (independent of
eosinophilic priming status)
-No significant difference in
hospitalization or ED visits rate
Beigelman et al,11
2013
Post hoc analyses of 2
RDBPCTs
-1-5-y-olds with episodic wheeze (at
least 2 previous episodes)
participating in 2 clinical trials
(>700 episodes in each cohort)
-Almost all (91%) the participants
were treated with asthma
controller medications (daily or
intermittent ICS, or daily
montelukast)
-55% of the participants had
aeroallergen sensitivity
-Prednisolone 2 mg/kg/d  2 d, then
1 mg/kg/d  2 d
-Prednisolone was prescribed as a
rescue treatment based on
predefined protocol criteria
-The median time from the beginning
of the illness to starting
prednisolone was 2 d
-The number of episodes defined as
“more severe” (n ¼ 112)
provided 91% power to detect
35% reduction in the total
symptom score
-Prednisolone treatment was not
associated with a reduction in
symptoms severity* or in a
shorter time until symptom
resolution
-Symptom scores were recorded daily
for 14 d from the beginning of
the illness
(continued)
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4. TABLE I. (Continued)
Study Characteristics of study population Intervention/timing of intervention
Power to detect a difference in the
primary outcome Results
ED studies
Tal et al,12
1990
Age-matched RDBPCT
-7-54-mo-olds (n ¼ 76) with !3
previous wheezing episodes.
Included a subgroup analysis of
the 7-24-mo-olds and 25-54-
mo-olds
-Participants were excluded if treated
with ICS or OCS 1 mo before
enrollment
-22% had a history of allergic
disorders
-Single dose of IM
methylprednisolone 4 mg/kg, or
placebo within 30 min of ED
arrival
-The ED visit occurred on average
22.4 h after the onset of
symptoms
-95% power to detect a difference in
success rates of !65% for
combined group vs 35% for
salbutamol alone
-Significant reduction in admission
rate* in the methylprednisolone
group measured at 3-h period
(significant in 7-24- mo-olds,
but not in the 25-54-mo-olds)
-Significant improvement in
symptom score measured at 3-h
period
Csonka et al,13
2003
RDBPCT
-6-35-mo-olds (n ¼ 123) with 1
previous wheezing episode
(35%-45% in each group with
no history of previous wheezing
episodes)
-Children were excluded if they had a
diagnosis of asthma, !2
previous wheezing episodes, or
anti-inflammatory medication
for 14 d before the study
-34% had a history of any allergy
-Prednisolone 2 mg/kg once then 2
mg/kg/d  3 d, or placebo
-It is unclear when the prednisolone
was given in relation to
symptoms onset
-80% power to detect a !75%
decrease in the need for
additional asthma medication
among the prednisone- treated
hospitalized children
-No significant difference in
admission rate* after 4 h of ED
observation
-Significant reduction in symptom
duration in the prednisolone
group measured over 14 d
-No significant difference in length of
hospital stay, revisits after initial
ED visit, or revisits after the
hospitalization measured over
14 d
Inpatient studies
Jartti et al,14
2015
RDBPCT
-3-23-mo-olds (n ¼ 79) with first
wheezing episode and
rhinovirus detected in a
nasopharyngeal aspirate sample
by using PCR. Children with
recurrent wheeze or previous
ICS or OCS use were excluded
-None of the participants was treated
with daily ICS
-28% had allergic sensitization
-Prednisolone 2 mg/kg once then
2 mg/kg/d divided thrice a
day  3 d, or placebo
-The study medication was started “as
soon as possible for rhinovirus-
positive children by a study
physician”
-80% power to detect a 34% absolute
difference in relapse rate
between prednisolone (22%)
and placebo (56%) within 2 mo
after a rhinovirus-induced first
wheezing episode
-No significant difference in the
occurrence of a new physician-
confirmed wheezing episode
within 2 mo,* the number of
physician-confirmed wheezing
episodes within 12 mo,* and
initiation of regular controller
medication for asthma
symptoms within 12 mo*
-The prednisolone group had less
cough, rhinitis, noisy breathing,
severe breathing difficulties, and
nocturnal respiratory symptoms
at home within 2 wk
-25 children with >7000 rhinovirus
copies/mL and treated with
prednisolone had significantly
less physician-confirmed
recurrence within 2 and 12 mo
compared with placebo
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5. of recurrent wheezing, diagnosis of asthma, or had received ICSs.
In several studies, a medical practitioner did not directly assess the
severity of the exacerbation and the length of follow-up varied.
Furthermore, Oommen et al10
evaluated subjects with an
increased risk of asthma using levels of serum eosinophil cationic
protein and eosinophil protein X (“eosinophilic priming”).
However, eosinophil biomarkers are often not used alone in
asthma risk indices,45
perhaps missing the subjects who truly
would benefit from OCSs. Taken as a whole, these studies are
underpowered to examine the effect of OCSs on wheezing epi-
sodes in children with a history of recurrent wheezing and atopic
disease or those at risk for more severe exacerbations (Table I).
Importantly, very few of these studies have involved children
who were clearly at risk for school-age asthma as defined by the
mAPI. This point is important because it emphasizes a larger
concept, the evolution of asthma care to phenotype-driven ap-
proaches. Biomarker- or phenotype-targeted care has clearly been
found to have benefit as observed with the use of biologic therapy
in adults with asthma.46
In preschool-aged children, the use of
ICS appears to be most effective in children with positive mAPI,
particularly those with a history of severe exacerbation or aero-
allergen sensitization.33,43,47
In cohort studies of preschool
wheezers, 2 major risk factors have been consistently identified in
the inception of childhood asthma: rhinovirus-induced wheezing
and allergic sensitization. None of the aforementioned studies
incorporated these risk factors a priori in their study design.
Indeed, there is a paucity of data regarding rhinovirus-induced
wheezing episodes and OCS efficacy. This is striking given
some have argued that rhinovirus may be causative in childhood
asthma and is known to be the most common cause of virus-
induced wheezing, particularly among those with atopic sensiti-
zation.17,20,48-51
Highlighting the need for phenotype-driven
approaches (especially involving rhinovirus), Jartti et al14
per-
formed a randomized double-blind placebo-controlled trial of 79
children aged 3 to 23 months with first acute rhinovirus-induced
wheezing episode and found that children treated with 2 mg/kg
of OCSs for 3 days had less respiratory symptoms 2 weeks after
the episode but no differences in the frequency of wheezing
episodes at 12 months. More importantly, the investigators
found that children with high rhinoviral loads (>7000 copies/
mL) had decreased episodes of physician-confirmed wheezing
and controller medication at 2 and 12 months compared with
placebo group children. In a post hoc analysis, Lukkarinen et al52
found that 111 children with a median age of 12 months hos-
pitalized with wheezing episodes were less likely to have subse-
quent wheezing episodes during a 7-year follow-up if treated
with OCSs than with placebo if they wheeze with rhinovirus or
had eczema at the time of their hospitalization. In summary,
these studies highlight the need for more phenotypic studies to
be performed in this population.
CON: DR AVRAHAM BEIGELMAN
Treatment recommendations for any medical condition
should be determined on the basis of applicable evidence.
Therefore, and because most of the studies that have investigated
the efficacy of OCSs in acute episodic wheeze among pre-
schoolers have not demonstrated beneficial effects (Table I), we
should seriously consider minimizing their use.
OCSs are recommended by asthma guidelines for acute asthma
exacerbations that are not responsive to bronchodilators.53
Panickaretal,15
2009
RDBPCT
-10-60-mo-olds(n¼687)withacute
wheezeprecededbyURI
symptoms
-Two-thirdoftheparticipantshada
historyofpreviouswheezeand
24%hadahistoryofhayfever
-18%oftheparticipantsweretreated
withdailyICSand0.4%with
montelukast
-SubgroupanalysesbasedonAPI
status,andbasedoninitial
symptomsseverity
-Prednisolone10mg/dÂ5d
(24-mo-olds),Prednisolone
20mg/dÂ5d(!24-mo-olds);
orplacebo
-80%powertodetectadifferenceof
5hinthegeometricmeanofthe
durationofhospitalstay
-Nosignificantdifferenceinthe
durationofhospitalization,*
24-hsymptomscore,mean7-d
symptomscore,or7-d
albuteroluse
-Nodifferencesinoutcomesinthe
subgroupanalysisbasedonAPI
status,initialsymptomsseverity
IM,Intramuscular;LRTI,lowerrespiratorytractillnesses;RDBPCT,randomizeddouble-blindplacebo-controlledtrial;URI,upperrespiratorytractinfection.
*Theprimaryoutcomeofthestudy.Thetablewasadoptedandrevised(withpermission)fromCollinsandBeigelman.16
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6. However, the asthma guidelines do not include age-specific (or
wheezing phenotype-specific) recommendations regarding the
use of OCSs. The main reason that OCSs have been the
mainstay of acute episodic wheeze management in young pre-
school children is their proven efficacy in older children and
adults with established asthma. However, episodic wheeze in
toddlers and asthma in older children are distinct disease phe-
notypes that are different in their clinical manifestations and
probably in their pathophysiology, which are likely to result in
different patterns of underlining airway inflammation. Thus, it
has been questioned whether differential OCS treatment
response should be expected in these 2 clinical conditions.54-56
Indeed, and as will be reviewed in the following subsection,
there is very little evidence to support the utility of OCSs in
young children with acute episodic wheeze (Table I).
It has been suggested that OCSs given early during the course
of the exacerbation would provide beneficial effects.57
Although
the timing of OCS initiation may affect treatment response, the
negative results of the 2 clinical trials9,10
in which the OCSs were
initiated early during the course of the exacerbation by the
parents at home do not support this hypothesis. Participants of
these 2 studies had histories of at least 1 prior wheeze that
required hospitalization10
or 2 wheezing episodes that required
urgent-care visits to the ED.9
Oommen et al10
randomized
preschool children to prednisolone or placebo treatments,
whereas in a crossover trial Grant et al9
randomized children to
treatment blocks of prednisone or placebo; the latter trial
included preschool-aged and school-aged children, but reported
the results of a subgroup analysis that included only children
aged 2 to 5 years. In both studies, the parents were instructed to
start the study intervention at home, early during the course of
the next episode of viral wheeze. The results of the study by
Oommen et al10
have shown no difference between the groups in
the primary outcome: the 7-day mean daytime and nighttime
respiratory symptom scores. The results of the other trial per-
formed by Grant at al9
are even more provocative: a greater
proportion of medicated episodes, among the 2- to 5-year-old
children, resulted in ED or urgent clinic visits once children were
in the prednisone treatment block (35% vs 14%; P ¼ .04.) The
investigators could not identify the cause of the worse clinical
outcomes that were related to the use of OCSs.
Drs Durrani and Guilbert have suggested that atopic charac-
teristics of the children may affect the OCS response. Although
this by itself is a very sound argument, the results of the study by
Oommen et al10
do not support this hypothesis because strati-
fication of the study population by the risk for future persistent
atopic asthma, measured by levels of eosinophil metabolites, did
not change the negative results of this study.10
To balance my
argument, I would note that interpretation of this study results is
complicated because of suboptimal parents’ compliance with the
study protocol.
Parents’ suboptimal adherence to study medications in the
biggest outpatient trial10
is probably a result of parents’ hesitation
to use OCSs: a therapy that is associated with short-term and
long-term adverse effects. Therefore, and to overcome this
obstacle, we explored a different approach of investigating the
efficacy of OCSs in the outpatient setting. We recently reported
the results of post hoc and replication analyses11
in 2 outpatient
cohorts of preschool children with episodic wheeze participating
in 2 clinical trials. Overall, we evaluated the OCS treatment
response in more than 1500 outpatient episodes of significant
lower respiratory tract illnesses.11
To minimize the effect of
potential indication bias, all outcome analyses were adjusted for
differences in disease and baseline episode severity covariates
while using a propensity modeling methodology. The results
obtained in the initial cohort (the AIMS clinical trial42
) have
shown that the addition of OCSs did not reduce symptoms
severity measured by symptoms scores, and it did not hasten
clinical recovery measured by the time to resolution of symp-
toms.11
The results were then confirmed in the validation cohort
(the MIST clinical trial43
), which included only those preschool
children who had a higher risk for future asthma based on a
positive mAPI status58
including personal history of eczema and/
or family history of asthma. Lack of OCS response among these
children, who might have been more likely to respond to OCSs
on the basis of their asthma tendency, is another piece of evi-
dence to suggest that many of the preschool children with
episodic wheeze may not respond to this traditional intervention.
Studies performed in the outpatient setting are likely to
include episodes characterized by a relatively mild severity of
symptoms. This has been one of the main criticisms of these
outpatient studies because mild episodes that are usually self-
resolving are unlikely to benefit from any additional interven-
tion. Therefore, it is essential to evaluate OCS treatment
response among the most severe patients, the hospitalized
patients.
In the largest clinical trial investigating the efficacy of OCSs,
Panickar et al15
randomized 687 preschool children, hospitalized
because of acute viral wheeze, to receive oral prednisolone or
placebo. The duration of hospitalization, which was the primary
outcome, did not significantly differ between children treated
with prednisolone or placebo (median 11.0 vs 13.9 hours,
respectively; P ¼ .18). Neither the clinical symptom scores
measured over the following week nor the number of hospital
readmissions for wheezing within the following month were
different between the groups. Because the OCS response could
be potentially related to patients’ atopic characteristics, the in-
vestigators repeated the primary analysis in a subgroup of 124
children who were at an increased risk for atopic asthma. This
subgroup of children fulfilled the major criteria of the API44
: All
had a history of at least 4 previous wheezing episodes and had a
parent with asthma and/or physician-diagnosed eczema. Even
within this subgroup of children who might be more likely to
respond to OCSs, prednisolone treatment did not shorten the
duration of hospitalization. Finally, initial severity of the exac-
erbation measured by a symptoms score did not affect prednisone
treatment response.15
In summary, based on the current literature, there is very little
high-quality data to support OCS therapy for preschool children
with acute episodic wheeze. However, multiple OCS bursts may
be associated with adverse effects. It was reported that repeated
OCS bursts, among school-age children with asthma, resulted in
a dose-dependent reduction in bone mineral accretion and were
associated with increased risk of osteopenia.58
Another study
reported that 4 of 16 patients receiving 4 or more OCS courses
in a previous year evidenced an abnormal cortisol response to
either hypoglycemia or adrenocorticotropic hormone (ACTH)
stimulation.59
Because the use of OCSs is probably not necessary
for many preschool children with episodic wheeze, and because
OCS therapy could be associated with short-term and long-term
adverse effects, we should seriously consider minimizing their
use.
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7. REBUTTAL PRO: DRS DURRANI AND GUILBERT
Early life sensitization still remains the major risk factor for the
development of asthma,17,19,22,50
and multiple studies have
demonstrated that ICSs, a similar therapeutic class to OCSs,
improve respiratory symptoms and reduce exacerbations in pre-
school children with recurrent wheezing compared with pla-
cebo.31-34
Critical points are often overlooked that are important to
highlight in these studies such as many excluded children with a
history of recurrent wheezing, previous use of ICSs, or those
experiencing a severe exacerbation. In response to Dr Beigelman,
we must review the points we previously highlighted. For
example, the Panickar et al15
study, while large and elegantly
designed, has yet to be replicated and has flaws including the
mild severity of the disease and the short duration of hospitali-
zation. Moreover, only a minority (18%) of these patients had a
positive mAPI, a relevant point reviewed in detail above. The
Beigelman et al11
study (combination cohort of the AIMS and
MIST trials) was a post hoc analysis and thus is simply hy-
pothesis generating, as stated even by our coauthor.16,43
In spite
of this fact, this study is now often highlighted in the argument
against OCSs.16,43
Furthermore, the study setting may also make
a difference as a study conducted by Tal et al12
did demonstrate
improvement in respiratory outcomes in the ED setting in
children with a history of recurrent wheezing.
Regarding the concern about the adverse effects of repeated
oral steroid courses, a more recent, larger, and better designed
investigation did not observe effects on bone metabolism, bone
density, and adrenal or hypothalamic-pituitary-adrenal axis
function associated with 2 or more short OCS courses (median 4
OCS courses) for wheezing exacerbations in preschool-aged and
school-aged children.60
Dr Beigelman’s arguments also overlook the importance of
phenotypic differences in preschool wheezing exacerbations and
their subsequent response to asthma medications. For example, Dr
Beigelman does in fact highlight the Oommen et al trial10
as ev-
idence that even atopy is not an important phenotype in deter-
mining OCS responsiveness in preschool wheeze. However, as
stated above, the “eosinophilic metabolites” measured by Oom-
men et al are not typically used as in asthma risk indices. This
brings home our larger point—the identification of more relevant
biomarkers or risk factors that potentially allow a more targeted
treatment approach directed at wheezers who are more likely to be
responsive to OCSs. Indeed, the recent exciting results of the Jartti
et al and Lukkarinen et al studies regarding the short-term and
long-term efficacy of prednisolone in children with rhinovirus-
induced wheezing episodes in children with and without atopic
disease merit further exploration. In fact, based on these data alone
it is unclear whether anyone in the asthma community can be
comfortable making a clear recommendation without more work
as it relates to the phenotype-targeted approach.
REBUTTAL CON: DR BEIGELMAN
Drs Durrani and Guilbert, in their rebuttal section, and
others56
have identified some potential limitations of the clinical
trials that might have contributed to their negative results. These
include relatively low OCS dosage and the inclusion of very
heterogeneous patient populations. Although these are legitimate
arguments, I believe that it is unlikely that these factors alone are
the explanation for lack of efficacy of OCSs.
Prednisolone (or prednisone) used in these studies was pre-
scribed in a dosing range of 1 to 2 mg/kg/d. This is the dosing
regimen recommended by the National Asthma Education and
Prevention Program Guidelines52
for the treatment of asthma
exacerbation in children. There is no solid evidence that higher
OCS dosing in children would provide additional benefits, as
comparison of 3 single doses of prednisolone (0.5, 1, or 2 mg/kg)
given in children hospitalized for asthma exacerbation did not
show any differential effects on clinical outcomes.43
Further-
more, increasing the prednisolone dose from 1 mg/kg/d to 2 mg/
kg/d, prescribed for asthma exacerbation in children, resulted in
twice as many behavioral adverse effects, including anxiety and
aggressive behavior.61
Finally, the cumulative exposure to OCSs
was reported to be directly related to the reduction in bone
mineral accretion and to an increased risk for osteopenia.58
Therefore, and as was recently suggested,55
increasing OCS
dosing in preschool children with intermittent wheeze is very
unlikely to provide any additional benefits, but it is likely to
increase the chance of short-term and long-term adverse effects.
I agree with Drs Durrani and Guilbert that the inclusion of
very heterogeneous patient populations, which are very different
in their atopy status, risk for future asthma (i.e., API status), and
severity of the exacerbation, is definitely a limitation of the
available studies. However, it should be noted that studies that
stratified outcome analyses on the basis of atopy/API sta-
tus10,11,15
or on the basis of the initial severity of the exacerba-
tion11,15
did not detect differential responses to OCS therapy.
Yet, it is unclear whether these studies were well powered for
these additional secondary stratifications.
Finally, we should be willing to acknowledge the growing
amount of evidence suggesting that in contrast to older children
with established asthma, many preschool children with inter-
mittent wheezing are unlikely to respond to OCS therapy. Many
of these young preschool children have a different disease
phenotype: the severe episodic wheeze phenotype characterized
by significant morbidity during acute exacerbations separated by
asymptomatic periods.62
The limited number of bronchoscopies
that were performed among these preschoolers with episodic
wheeze have shown that many, but not all25
of them, have a
distinct pattern of airway inflammation characterized in a more
neutrophilic and less chronic eosinophilic airway inflamma-
tion24
; these findings were even more prominent in the younger
preschool population.23
Because eosinophils are more susceptible
to the effects of OCSs, this might provide a mechanistic rational
to explain why the apparent OCS response noted among older
children with asthma cannot be detected in many preschoolers
with episodic wheeze.
SUMMARY: HOW DO WE END THIS DEBATE?
Most of the available data do not support the role of OCSs as
a treatment for acute mild episodic wheeze (Table I). However,
on the basis of uncertainties presented in this article, 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.53,54
In general, we
agree that clinicians may consider postponing OCS therapy,
while providing supportive care and albuterol inhalations espe-
cially in the outpatient setting in otherwise healthy toddlers. For
example, the child in the case presentation above could be treated
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BEIGELMAN ET AL 33
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8. as an outpatient without the use of systemic steroids assuming
proper follow-up can be guaranteed, and if her clinical course is
not getting worse. However, if the patient had oxygen saturations
of less than 90% and more than minimal retractions that did not
improve after 3 doses of albuterol, the child would likely be
admitted.
The highest quality of data regarding lack of OCS efficacy as a
treatment for acute episodic wheeze originated from the inpatient
setting.15
Because the results of this well-designed and well-
conducted clinical trial revealed that OCS therapy was not
beneficial, it is very likely that many preschool children hospi-
talized with acute episodic wheeze could be managed, at least
initially, with supportive care and albuterol inhalations without
using OCSs. Panickar et al15
also reported the results of addi-
tional subgroup analysis showing that the initial exacerbation
severity, measured by the PRAM symptom score, was not asso-
ciated with a differential response to prednisolone. However,
only a small number of participants who had severe exacerbation
were included in this subgroup analysis, as only 4.5% of the
cohort had a PRAM score above 8 (on a scale of 0-12). Because
the results of any clinical trial are applicable only to its study
population, we cannot conclude that OCSs are not an effective
therapy in this subgroup of hospitalized preschool children pre-
senting with and/or progressing to severe exacerbation; therefore,
these children with severe exacerbation based on clinical signs
included in PRAM such as suprasternal retractions, scalene
muscle contraction, chest air entry, wheezing, and oxygen satu-
ration should be treated with OCSs. 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 ex-
pected 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. A recent study by Lezmi et al27
demonstrated that
both eosinophilic and neutrophilic airway inflammation was
present in bronchial biopsies of preschool-aged children with
recurrent wheeze. Moreover, increased airway smooth muscle
was found in atopic compared with nonatopic preschool
wheezers, suggesting that functional airway changes occur early
in life and vary by atopic history of the child. The role of
rhinovirus in wheezing and differential response to OCSs, based
on the causative virus, must be explored more comprehensively.
Question regarding adherence to study medication may be
addressed by conducting these studies in medical settings such as
the ED in which the severity of the exacerbation can be
confirmed, or by comparing OCSs to another active therapy such
as high-dose inhaled steroids or azithromycin. Finally, large
observational and pragmatic trials may also provide valuable
additional data on the comparative effectiveness and safety of
OCS in the outpatient or ED setting.
Acknowledgments
We thank Dr Leonard Bacharier for many insightful discus-
sions about the role of OCSs as a therapy for acute episodic
wheeze: the conclusions of some of these discussions are reflected
in this article.
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