Systemic Corticosteroids Should be Used for Pre-School
Children with Virus-Induced Wheezing
Miles Weinberger MD
Professor of Pediatrics
University of Iowa Children’s Hospital
Iowa City IA
www.uihealthcare.com/allerpulm
Reprint requests to:
Miles Weinberger MD
Pediatric Dept., UIHC
200 Hawkins Drive
Iowa City IA 52242
e-mail: lmiles-weinberger@uiowa.edu
Phone: 319 356-3485
Fax: 319 353-6217
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Corticosteroids for the Pre-school Age Child with acute Viral Wheeze (a.k.a. intermittent
viral respiratory infection induced asthma)1
A recent publication in the New England Journal of Medicine reported that pre-school aged
children with wheezing from viral respiratory infections benefitted no more from 10 mg of
prednisolone daily than from placebo.2 That led Dr. Andrew Bush, in an accompanying
editorial, to conclude that “Prednisolone should be administered to preschoolers (with viralinduced wheezing) only when they are severely ill in the hospital.”3
Pre-schoolers are, in fact, frequently in the hospital with wheezing. Asthma most typically
begins in the pre-school age group with the first year of life the most common time for onset of
symptoms (Figure 1).4 There is approximately one hospitalization for asthma in a preschooler for
every 200 pre-school age children annually in the U.S. (Figure 2).5 The implications of the New
England Journal of Medicine publication and Dr. Bush’s recommendation based on that
publication is that we have no solution to the endemic problem of pre-school age hospitalizations
for asthma.
Is that nihilistic view justified? First, we must consider that viral respiratory infections are a
major cause of asthma exacerbations at all ages6,7,8,9,10 and appear to be the major risk factor for
the large increase in hospital admissions for asthma that occurs every autumn.11 Pre-school age
children have a particularly high frequency of viral respiratory infections, with most getting 3-8
infections per year and 10-15% getting 12 or more per year.12 This is the likely explanation for
the frequency of asthma hospitalization in the pre-school age group that far exceeds that of older
children and adults.5 There is no active debate regarding the lack of value of inhaled
corticosteroids for either the treatment or prevention of viral induced wheeze. The use of inhaled
3
corticosteroids for intervention of acute symptoms has been examined in the emergency
department and at the onset of an exacerbation at home. Such attempts have been at best
marginally successful with some amelioration of symptoms at very high doses but no significant
effect on the need for subsequent emergency care, hospitalization, or decisions to use an oral
corticosteroid.13 These agents also do not prevent exacerbations of asthma from viral respiratory
infections.14,15,16 Nor are there any other currently available therapeutic measure that can, as safe
maintenance therapy, prevent viral respiratory infection induced asthma.17 Since viral
respiratory infections are the major contributors to acute care requirements for asthma, especially
in young children who have an especially high frequency of these common cold viruses,
providing effective intervention measures to treat viral respiratory infection induced asthma is
critically important in current efforts to stem the endemic tide of asthma morbidity.
So let’s examine the effect of systemic corticosteroids administered prior to the hospitalized
severely ill patients for whom Dr. Bush feels such treatment should be limited. Several studies
over the past 15 years have demonstrated that earlier aggressive use of systemic steroids in
children, including pre-school age children, having an acute exacerbation of asthma decreases
the likelihood of requiring urgent care and hospitalization.18
Storr et al examined the effect of oral prednisolone in children administered immediately
after being hospitalized with acute asthma.19 In a randomized double-blind placebo controlled
trial, 67 children received prednisolone and 73 received placebo shortly after admission. Mean
age of the children was 5 years. Those less than 5 years old received 30 mg of prednisolone and
those 5 or older received 60 mg. At a 5 hour decision time, about 20% of those who received
prednisolone could be discharged compared with only about 2% of those who received placebo.
4
Among those not discharged at 5 hours, more rapid improvement and earlier discharge occurred
in the prednisolone treated patients than in those in who received placebo.
Tal et al examined the value of systemic corticosteroids in children ranging from 0.5 to 5
years of age seen in an emergency room for acute asthma.20 Using 4 mg/kg of IM
methylprednisolone or normal saline in a double-blind placebo controlled trial, decision to admit
to hospital at 3 hours after medication administration was reduced from over 40% of the 35 given
the placebo to about 20% of the 39 given the methylprednisolone.
Scarfone et al examined the effect of oral prednisone in children with a mean age of 5 years
seen in an emergency room.21 In a randomized double-blind trial, 36 received 2 mg/kg of
prednisone and 39 received placebo. At 4 hours, about 50% of the placebo treated children were
admitted compared with only about 30% of the prednisone treated children. The differences
were substantially larger for a subgroup judged most sick where over 70% of the placebo treated
children were admitted compared with less than half of the prednisone treated children.
Brunette and colleagues showed that early administration of oral corticosteroids prevented
hospitalization in children at high risk for severe acute asthma from viral respiratory infectioninduced asthma.16 He identified a group of 32 children less than 6 years of age, who had an
average of 7 hospitalizations in one year for acute viral respiratory infection-induced asthma.
During the subsequent year, half were given prednisone, 1 mg/kg/day, at the onset of a viral
respiratory infection. This was associated with a 90% reduction in hospitalizations among the
treated group, whereas no reduction in hospitalization rate occurred in those who were untreated.
Although not a controlled clinical trial, the differences were sufficiently striking that they should
not be ignored.
5
Similarly, an outcomes study of 72 pre-school age children (mean age 2.9 years) referred to
the Pediatric Allergy and Pulmonary Clinic at the University of Iowa who experienced an
intermittent viral respiratory infection induced pattern of asthma had an impressive reduction of
urgent care visits and hospitalizations in association with care that involved early use of oral
prednisolone at the onset of symptoms requiring more than an occasional need for an albuterol
aerosol.22
Our strategy in that study was to provide the families of these young children with an ageappropriate means of giving an inhaled 2 agonist and a supply of oral prednisolone for use when
more than an occasional bronchodilator was needed. Specific instructions regarding
bronchodilator subresponsiveness were provided. Doses were based on age--10 mg twice daily
for infants under one year of age, 20 mg twice daily for toddlers from 1 to 3 years of age, 30 mg
twice daily from age 3. Compared with the year prior to referral, our program was associated
with a greater than 4-fold reduction, from 90% to only 21%, in the number of patients who
required urgent medical care. The total number of urgent care visits decreased from 415 the year
prior to entering our program to 29 during the year under our care. Similarly, hospitalizations,
which had occurred in 42% of those patients the year before, decreased to less than 6% the
subsequent year, with the total number of hospitalizations decreasing from 60 among the 72
patients to only 6. Again, while not a controlled trial, these impressive outcome data support the
controlled clinical trials demonstrating the effect of corticosteroids administered prior to
hospitalization for severe illness.20,21
How do these data mesh with the controlled clinical trial that impressed Dr. Bush.2,3 The
study reported by Panicker, et al, found no difference from placebo when 10 mg of prednisolone
6
were given once daily to preschool age children with viral respiratory infection induced asthma.2
However, their study population improved so rapidly on placebo that any treatment effect would
have been obscured, even if doses had been consistent with those that had been effective
previously in controlled trials.19,20,21 The same criticism applies to a previous study.23,24
While there is concern that the high frequency of viral respiratory infection-induced asthma
in the pre-school child will, at least for periods of time, result in an excessive frequency of oral
corticosteroid use, the risks of this effective strategy appears minimal.25
Corticosteroids for the Infant with an Initial Episode of Acute Viral Wheeze (a.k.a.
Bronchiolitis)
This remains a controversial topic. The use of corticosteroids for bronchiolitis is driven by
the similar clinical presentations of bronchiolitis and asthma. A double-blind study of 5 mg/kg
methylprednisolone on the first day of hospitalization with half that dose on the second day was
published in 1965. Among the 44 patients randomized to the corticosteroid or placebo, no
significant differences in outcome were observed.26 Subsequent studies in hospitalized children
similarly also concluded there was no effect of systemic corticosteroids on the outcome of
bronchiolitis.27,28,29,30,31 However, a meta-analysis that included many of these studies concluded
that there was a modest but statistically significant improvement in clinical symptoms, length of
stay, and duration of symptoms.32 The mean difference in length of stay or duration of
symptoms from the pooled analysis was 0.43 days (CI 0.81-0.05) less among those who received
corticosteroids. A subsequent study of 174 children with bronchiolitis who received either a
single intramuscular dose of 1 mg/kg of dexamethasone reported significant reductions in mean
7
duration of respiratory distress and length of hospital stay.33 While children up to 2 years old
were included in the study, the results were similar in a subgroup analysis of those under 12
months of age.
Studies in outpatients who did not require hospitalization when initially seen in the
emergency department have suggested that treatment with corticosteroids in that population may
be more likely to provide clinical benefit than has been seen in studies limited to inpatients.
Significantly lower symptom scores on day 2 were seen following a 2 mg/kg/day of prednisolone
given for 5 days who could be discharged from the emergency department.34 A randomized,
double-blind placebo-controlled trial among 230 children who received 2 mg/kg/day of
prednisolone or placebo for 3 days found the mean duration of respiratory distress to be 2 days in
the placebo treated group and only 1 day in the placebo treated group for both the 123 who had
to be initially admitted to the hospital and the others who remained as outpatients.35 While that
study included patients who had previous wheezing episodes in addition to those for whom their
wheezing was a first time event, the authors described similar results for the first time wheezers
as for the 2nd time wheezers.
A study by Schuh et al demonstrated a 57% reduction (from 44% to 19%) in blinded
decisions to hospitalize infants with bronchiolitis seen in the emergency department by 4 hours
after administration of 1 mg/kg of dexamethasone or placebo (p=0.039).36 In an attempt to
examine the implications of the Schuh study, a large multi-center study by Corneli et al
demonstrated no benefit from treating bronchiolitis with the same dose regimen used by Schuh.37
In an editorial related to another positive study,38 I speculated that the conflicting results of
studies examining the effect of corticosteroids for bronchiolitis related to timing.39 Early
8
treatment with a high dose of corticosteroid may be effective during an early inflammatory phase
of bronchiolitis but is ineffective once that inflammation results in the characteristic dense plugs
of cellular debris and strands of fibrin that characterizes the eventual course of bronchiolitis.40
Interestingly, the duration of respiratory distress in the study by Schuh et al was 1.7 + 1.4
days (mean + SD)36 while that of the multi-center study was 3.7 + 2.5 days,37 more than a 2-fold
difference. Thus, although the use of systemic corticosteroids for first time wheezing infants
remains controversial at best, my previous speculations regarding the timing of corticosteroid
administration continues to be worth consideration.
Summary
While much viral wheezing is mild and self-limited, requiring no intervention, recurrent viral
wheezing (i.e., acute exacerbations of viral respiratory infection induced intermittent asthma) is
the major cause of hospitalizations in pre-school age children with a prevalence of approximately
one hospitalization per 200 U.S. children annually. The value of systemic corticosteroids in
decreasing the frequency of hospitalization has been demonstrated in controlled clinical trials,
and outcome studies have demonstrated that urgent care and hospitalizations can be prevented by
the early use of systemic corticosteroids. For first time wheezing in an infant (i.e., bronchiolitis),
the use of systemic corticosteroids is more controversial with conflicting data that may relate to
the timing of the corticosteroids. Early use for bronchiolitis may be associated with benefit
whereas use later in the course appears to be associated with no benefit.
9
Legends for Figures
Figure 1.
Annual age- and sex-adjusted incidence of asthma onset in a population-based
epidemiologic study in Rochester, Minnesota.4
Figure 2.
Hospital discharge rates for asthma as the first-listed, by age group and year –
United States, 1980-1999 (data from the National Center for Health Statistics,
Center for Disease Control). (Adapted from Akinbami et al)5
10
Figure 1.
N u m b e rp e r 1 0 ,0 0 0c h ild re n
7000
6000
5000
4000
3000
2000
1000
0
<1
1-4
Age of onset (years)
Girls
Boys
5 - 14
11
12
Figure 2.
13
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