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\begin{document}

\title{Adding nebulized to systemic corticosteroids for acute asthma in
children: a meta-analysis}



\author[1]{Jose Castro-Rodriguez}%
\author[1]{Mauricio Pincheira}%
\author[2]{Diana Escobar-Serna}%
\author[2]{Monica Sossa-Briceño}%
\author[3]{Carlos Rodriguez-Martinez}%
\affil[1]{Pontificia Universidad Catolica de Chile}%
\affil[2]{Universidad Nacional de Colombia}%
\affil[3]{School of Medicine, Universidad El Bosque}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
International guidelines have recommended the use of inhaled beta-2
agonists and systemic corticosteroids (SC) as the first-line treatment
for acute asthma. Objective: To evaluate the evidence for the efficacy
of inhaled corticosteroids (ICS) in addition to SC compared to SC alone
in children with acute asthma in the ED or during hospitalization. Data
sources: Five electronic databases were searched. Study Selection: All
RCTs that compared ICS (via nebulizer or metered dose inhaler) plus SC
(oral or parenteral) with placebo (or standard care) plus SC were
included without language restriction. Data extraction: Two reviewers
independently reviewed all studies. The primary outcomes were hospital
admission or hospital length of stay {[}LOS{]}, and secondary outcomes
were readmissions during follow-up, ED-LOS, lung function, asthma
clinical score, oxygen saturation, and heart and respiratory rates.
Results: Nine studies (n=1473) met the inclusion criteria. In all the
studies, the ICS was budesonide. Compared to SC alone, adding budesonide
to SC did not affect hospitalization rate, but decreased hospital LOS by
more than one day (MD= -29.08 hours {[}-39.9 to -18.3{]}; I2=0\%,
p=\textless{}0.00001). Moreover, adding budesonide (especially with [?]2mg
doses) significantly improved the acute asthma severity score among
patients at ED. Conclusions: Compared to SC alone, adding budesonide to
SC did not affect hospitalization rate, but decreases the LOS and
improves the acute asthma score in children at ED setting.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Childhood asthma is the most common chronic disease in childhood and a
significant public health problem in the U.S. as well as in many other
countries\textsuperscript{1}. Despite relatively recent advances in our
understanding of the inflammatory nature of the disease and the
availability of highly effective medications to control their symptoms,
many pediatric patients continue to experience poor asthma control with
recurrent disease exacerbations\textsuperscript{2}.

Acute asthma has a significant impact not only on the utilization of
health care and the quality of life of children and their families but
also on a large percentage of disease costs\textsuperscript{3}. Recent
international evidence-based asthma clinical practice guidelines
recommend the use of inhaled beta-2 agonists (SABA) and systemic
corticosteroids (SC) as the first-line agents for acute
asthma\textsuperscript{4,5}. The efficacy of SC in acute asthma is well
established, with a positive impact on several clinically meaningful
outcomes, such as hospital admission rate, symptom scores, and the
number of relapses after discharge from the emergency department
(ED)\textsuperscript{6}. However, the fact that despite SC use many
children still require admission to hospital and that SCs have a slow
onset of action (3--4 h after their administration) is a cause of
concern among ED teams\textsuperscript{7}.

For this reason, the use of other anti-inflammatory therapies such as
inhaled corticosteroids (ICS) for the treatment of acute asthma has been
explored\textsuperscript{6}. Potential benefits of ICS in acute asthma
therapy might include a rapid onset of action and a significant efficacy
in diminishing airway reactivity and edema because of their direct
delivery to the airways\textsuperscript{8}. This is mainly because ICS,
but not SC, cause immediate local bronchial mucosal vasoconstriction and
inhibition of edema formation mediated by non-genomic
mechanisms\textsuperscript{9}. The main non-genomic mechanisms involve
the activation of endothelial nitric oxide (NO) synthase and NO
synthesis, which produce an increase in noradrenergic neurotransmission
in the airway vasculature, with a consequent reduction in airway blood
flow\textsuperscript{10}. The decrease in airway blood flow is a
desirable effect in asthmatic patients, given that they have
significantly increased blood flow in the airway
mucosa\textsuperscript{11}.

Therefore, the use of ICS for treating patients with acute asthma has
become a subject of interest in recent years. There are reports showing
the clear efficacy of ICS in the management of acute asthma when
compared with a placebo\textsuperscript{8,12}. In a recent systematic
review with a meta-analysis that compared the efficacy of ICS with SC
for acute asthma in children consulting in the ED or the equivalent, we
found no significant differences between ICS and SC in terms of hospital
admission rates, unscheduled visits for asthma symptoms, or need for an
additional course of SC\textsuperscript{12}. However, only a few studies
have investigated the possibility of a beneficial effect of ICS added to
SC, and the results have been conflicting, as was stated in a systematic
review published in 2012, where only two RCTs carried out exclusively in
a pediatric population were included\textsuperscript{8}.

Thus the present systematic review aims at updating and evaluating the
available evidence for the efficacy of ICS (via nebulizer or metered
dose inhaler {[}MDI{]}) in addition to SC compared to the standard
therapy with SC for treating pediatric patients with acute asthma in the
ED or during hospitalization.

\textbf{METHODS}

\textbf{Search and selection criteria}

This study was registered with the International Prospective Register of
Systematic Reviews (PROSPERO, http://www.crd.york.ac.uk/PROSPERO) as
CRD42019133045. We followed the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines to perform this
review\textsuperscript{13}. The authors identified studies published in
MEDLINE, EMBASE, LILACS, CENTRAL and CINAHL databases, up to August
2019, using the terms ``(((budesonide OR ciclesonide OR mometasone OR
beclomethasone OR flunisolide OR fluticasone OR triamcinolone) AND
(prednisone OR prednisolone OR hydrocortisone OR methylprednisolone OR
dexamethasone OR betamethasone) AND (asthma exacerbations OR acute
asthma OR acute wheezing OR wheezing exacerbations)))'', filtered for
children birth--18 yrs and clinical trials; language restrictions were
not applied.

To be included, studies had to meet all of the following criteria: 1)
children (preschoolers to adolescents) with asthma presenting with an
acute asthma in the ED or hospitalized 2) randomized clinical trials
(RCTs; parallel group or cross-over design) of any duration; 3)
comparison of ICS (by nebulizer or MDI) \emph{plus} SC (oral or
parenteral) vs. placebo (or standard care)\emph{plus} SC; and 4) a
report of at least one of the following outcomes: primary outcomes:
hospital admission (for ED studies) or hospital length of stay {[}LOS{]}
(for hospitalized studies); and secondary outcomes: asthma clinical
score, readmissions during the follow-up, ED-LOS, lung function, oxygen
saturation (SpO\textsubscript{2}), heart and respiratory rates,
additional SABA requirements, and drug-related adverse effects {[}AEs{]}
or severe adverse events {[}SAEs{]}. An SAE was defined as any untoward
medical occurrence that results in death, is life-threatening, requires
inpatient hospitalization, or results in persistent or significant
disability or incapacity\textsuperscript{14}.

We excluded studies that only involved patients experiencing their first
wheezing episode or bronchiolitis and patients with other chronic
respiratory conditions (e.g. bronchopulmonary dysplasia, cystic
fibrosis, primary ciliary dyskinesia, and post-infectious bronchiolitis
obliterans) or congenital cardiopulmonary conditions.

\textbf{Data Extraction and Assessment of Risk of Bias}

Titles, abstracts, and citations were independently analyzed by the
authors (JC-R, CR-M). From the full text, all studies were independently
assessed for inclusion. The authors were independently involved in all
stages of study selection, data extraction, and risk of bias assessment.
The latter was assessed according to recommendations outlined in the
Cochrane Handbook\textsuperscript{15} for the following items: 1)
adequacy of sequence generation; 2) allocation concealment; 3) blinding
of participants and investigators; 4) blinding of outcome assessment; 5)
incomplete outcome data; 6) selective outcome reporting, and other bias.
Disagreements were discussed and resolved by consensus.

\textbf{Data Analysis}

The analysis was performed on the basis of intention to treat and
included all participants. Outcomes were pooled using mean differences
(MD) (inverse variance method), standardized mean differences (SMD) for
similar outcomes measured in different scales, and Mantel-Haenszel risk
ratios (RR). When significant data was reported only in median and IQR,
mean and SD were estimated according to the
literature\textsuperscript{16}, and the estimation was pooled in the
meta-analysis; all estimated data will be properly identified. Estimate
precision was quantified by 95\% confidence intervals (CI).
Heterogeneity was measured by the I\textsuperscript{2} test ([?]25\%
absence of bias; 26 to 39\% unimportant; 40\% to 60\% moderate; and 60\%
to 100\% substantial bias)\textsuperscript{17}. A fixed-effects model
was used when there was no evidence of significant heterogeneity in the
analysis (I\textsuperscript{2} \textless{}40\%); if significant
heterogeneity was found, a random-effects model was
used\textsuperscript{18,19}. \emph{A priori} subgroup analyses included:
setting (ED vs. hospitalized), age (preschooler vs. school-age), acute
asthma severity score, doses of ICS, type of SC, and sponsored
(pharmaceutical industry vs. independent). The meta-analysis was
performed with Review Manager 5.3.5 software (Cochrane IMS, 2014).

\textbf{RESULTS}

A total of 41 studies were identified after duplicates were removed, and
32 studies were excluded based on the title and the abstract (11 were
not performed for acute asthma, 13 did not use systemic corticosteroids
in both groups, 5 did not specify the data for children, and 2 RCTs did
not include intervention drugs). We performed a full text review of nine
articles, \textsuperscript{20-28} all of which met our inclusion
criteria and were counted in the quantitative and qualitative analyses
(Figure 1).

\textbf{Included Studies}

These nine studies\textsuperscript{20-28} were published between 1998
and 2017. A summary of the characteristics of the included studies is
shown in Table 1. Three were done in Turkey\textsuperscript{22,26,28}and
one in each of the following countries: Canada\textsuperscript{20},
US\textsuperscript{23}, Saudi Arabia\textsuperscript{25},
Venezuela\textsuperscript{27}, Brazil\textsuperscript{21}, and
Bangladesh\textsuperscript{24}. All of the studies were of
parallel-group design, eight trials\textsuperscript{20-26,28} were
double-blinded, and one was a simple blinded trial\textsuperscript{27}.
Six studies were performed in the
ED\textsuperscript{20,22,23,25,27,28}and three in hospitalized
children\textsuperscript{21,24,26}. Two studies\textsuperscript{20,27}
were performed in the ED but also had some information for admitted
patients, and one\textsuperscript{27} of those studies had a
three-intervention-group design, but we included only information for
our comparison criteria (ICS + SC vs. SC). One study\textsuperscript{25}
allowed the inclusion of patients previously included in the
study\emph{.} All the studies included an asthma clinical severity
score, but the score varied between studies (Table 1). Four
studies\textsuperscript{20,23,25,28} reported funding information, and
all of them were independently sponsored (not by the pharmaceutical
industry). All except two studies\textsuperscript{21,22} had high
methodological quality (Figure 2).

\textbf{Participants}

Selected studies included 1473 patients, who presented 1656 episodes of
acute asthma. A higher percentage of males than females were enrolled in
all the studies (Table 1). The age range of the enrolled patients was
between 0.58 yrs. to 13 yrs. Two studies\textsuperscript{21,26} reported
younger patients (mean age 12.4 months\textsuperscript{21} and 19
months\textsuperscript{26}); however, none of them enrolled patients
with bronchiolitis or first wheezing episode.

Four studies\textsuperscript{20,25,26,27} reported the family history of
asthma (12\% to 75\% of the patients included had a positive family
history). Only two studies\textsuperscript{26,28} reported the positive
asthma predictive index (API) status (30--38\% had positive API). Six
studies\textsuperscript{20,22,23,25,26,28} reported the use of ICS in
the past (range from 20\% to 100\%). Sung et al.\textsuperscript{20} and
Upham et al.\textsuperscript{23} stratified patients according to the
use of ICS, while Nuhoglu et al.\textsuperscript{22} and Alangari et
al.\textsuperscript{25} only reported the prevalence of ICS used. In the
Razi et al.\textsuperscript{26} trial, the use of ICS was a mandatory
inclusion criterion, but in the Razi et al.\textsuperscript{28} trial,
patients with budesonide more than 400 mcg/day or those who change their
doses in the last 2 months were excluded. The acute asthma severity
scores at randomization were moderate to severe in four
studies\textsuperscript{23-26}, but using different clinical scores
(Table 1).

\textbf{Intervention}

In seven studies\textsuperscript{20,22,23-26,28}, a comparison was made
between ICS+SC and SABA vs. saline solution (as a placebo)+SC and SABA.
Only two studies\textsuperscript{21,27} included different interventions
for comparison: Kassisse et al.\textsuperscript{27} included no placebo
and Sano et al.\textsuperscript{21} compared ICS+SC and SABA vs.
ipratropium bromide+SC and SABA. All the studies performed in the ED
used nebulized budesonide as the ICS in the intervention group at
various total doses from 1 mg to 3 mg (administrated in two or three
nebulizations). Two\textsuperscript{21,26} out of three of the
hospitalized studies described the use of nebulized budesonide during
hospitalization (2mg/day up to 5 days in Razi et
al.\textsuperscript{26}and ``0.25 mg of inhaled budesonide suspension 4
times daily to a total dose of 1 mg/d throughout the hospitalization
period'' in Sano et al.\textsuperscript{21}). All the studies included
SC as the standard care for both intervention and control groups (Table
1).

\textbf{Primary Outcomes}

\textbf{a. Hospital admission in ED studies:} Five
studies\textsuperscript{20,23,25,27,28} reported information for this
outcome. In the pooled data of the four
studies\textsuperscript{20,23,25,27} that reported absolute admission
data, there was a tendency to favor budesonide for reducing the risk of
hospital admission, but it did not reach a significant difference (RR=
0.89 {[}95\% CI: 0.74 to 1.07{]}, I\textsuperscript{2}=0\%, p=0.21)
(Figure 3). This result was similar using random effect model (RR=0.92
{[}0.77-1.09), p=0.34). Razi et al.\textsuperscript{28} reported a
significantly higher discharge rate in the budesonide than in the
placebo group (survival analyses: log-rank=12.407, p\textless{}0.001).

In the subanalysis of studies that included only moderate to severe
acute asthma episodes\textsuperscript{23,25}, there was no significant
difference in hospital admission between the budesonide and placebo
groups (RR= 0.88 {[}0.68 to 1.14{]}, I\textsuperscript{2}=47\%, p=
0.34). In the subanalysis of ICS doses (budesonide [?] 2 mg vs.
\textless{} 2mg), there was no significant difference in hospital
admission between groups (RR=0.89 {[}0.71 to 1.11{]},
I\textsuperscript{2}=26\%, p=0.29 vs. RR=0.89 {[}0.67 to 1.19{]},
p=0.44).

\textbf{b. Hospital LOS:} Four
studies\textsuperscript{20,21,26,27}reported data for this outcome.
Pooled data from two studies\textsuperscript{21,26} that reported
hospital LOS in hours showed a significant reduction in LOS for those
who received budesonide rather than controls (MD = -29.08 hours {[}-39.9
to -18.3{]}; I\textsuperscript{2}=0\%, p=\textless{}0.00001) (Figure 4).
This result was similar using random effect model (data not shown). The
other study\textsuperscript{20}reported a survival analysis where
children who received budesonide were released from the ED or discharged
from the hospital significantly more rapidly than were those who
received placebo (log rank test, p = 0.02); but Kassisse et
al.\textsuperscript{27} reported no significant difference.

\textbf{Secondary Outcomes}

\textbf{a. Acute asthma severity score in ED and hospitalized
studies:}Although all the studies included information for this outcome,
they were analyzed separately according to the setting, type of score,
and how it was reported. The two big trials\textsuperscript{23,25} done
in the ED included difference in score, without giving the basal or
post-intervention score, precluding the possibility to include their
data in the overall score meta-analysis of ED studies. There was no
significant difference in the asthma score between the budesonide and
the control group in these two trials (Figure 5a). This result was
similar using random effect model (RR=-0.13 {[}-0.38 to 0.12), p=0.30).
The other four studies done in ED\textsuperscript{20,22,27,28} reported
post-intervention data; when the data was reported in median and IQR, we
estimated mean and SD according to the literature\textsuperscript{16}.
We found that children from the budesonide group significantly improved
their asthma score compared with the placebo group in the ED
studies\textsuperscript{20,22,27,28} (SMD: -0.30 {[}-0.53 to -0.06{]},
p=0.01, I\textsuperscript{2}=27\%), Figure 5b. This result was similar
using random effect model (SMD: -0.31 {[}-0.60 to -0.02), p=0.04). In
the subanalysis comparing doses of budesonide ([?]2mg vs. \textless{}2
mg), the pool data of ED studies showed a significant improvement in
acute asthma severity score in the budesonide vs. placebo group, but
clearly this effect was driven by the studies using [?]2 mg (Figure 5c).

Among studies performed in trials with hospitalized children, one
study\textsuperscript{24} showed a significant differences in the asthma
score at 1 hour, 2 hours and 3 hours from intervention favor to
budesonide vs placebo group (7.36\selectlanguage{ngerman}±1.03 vs 9.18±1.01 p\textless{}0.01 at
1h, 5.91±0.52 vs 7.30±1.05 p\textless{}0.01 at 2 h, 5.42±0.50 6.36±0.70
p\textless{}0.01 at 3 h, respectively). The other
trials\textsuperscript{21,26} only gave graphics but not data on asthma
score. One study\textsuperscript{21} reported a significantly reduction
in the clinical score for the budesonide, but the
other\textsuperscript{26} did not.

\textbf{b. LOS in ED studies:} Three studies\textsuperscript{20,25,28}
reported data for this outcome. There was not significantly difference
in LOS between the budesonide and control groups MD= -0.26 {[}-0.88 to
0.35{]}; I\textsuperscript{2}= 91\%, p=0.40).

\textbf{c. Readmissions during follow-up:} Four
studies\textsuperscript{20,21,23,25} included data for this outcome.
There was no significant difference in readmission during the follow-up
(overall OR=0.89 {[}0.36 to 2.25{]}; I2 = 0\%, p=0.81).

\textbf{d. Lung function:} Only two
studies\textsuperscript{22,24}reported this outcome and both measured
the peak expiratory flow rate (PEFR). Nuhoglu et al.\textsuperscript{22}
reported an increased mean of PEFR in the budesonide vs. placebo group
(72.50 ± 23.8 vs. 47.86 ± 18.9, p=0.02). Similarly, Akhtaruzzaman et
al.\textsuperscript{24} reported significantly more improvement in the
\% of predicted PEFR value in the budesonide vs. placebo group at 1,2
and 3 hour after treatment (76.63 ± 1.4 vs. 69.30 ± 1.1,
p=\textless{}0.01; 77.42 ± 1.2 vs. 71.42 ± 1.1, p=\textless{}0.01; and
78.58 ± 1.1 vs. 72.36 ± 1.0, p=\textless{}0.01, respectively).

\textbf{e. SpO\textsubscript{2}:} Four studies done in
ED\textsuperscript{20, 23,27,28} reported data for this outcome. The
pooled data of two studies\textsuperscript{23,27} showed no difference
in the mean change from baseline among budesonide vs. control group
(data not shown). Similarly, Sung et al.\textsuperscript{20} reported no
difference. However, Razi et al.\textsuperscript{28} showed significant
higher SpO\textsubscript{2} at 120 min post-intervention in the
budesonide vs. placebo group (95\% {[}93--98{]} vs. 91.5\% {[}90--96{]},
p=0.012).

Among studies performed in trials with hospitalized children,
Akhtaruzzaman et al.\textsuperscript{24} found a significant difference
at 1, 2, and 3 hrs. after intervention favorable for the budesonide vs.
placebo group (95.15\% ± 0.71 vs. 94.12\% ± 0.89, p \textless{}0.01;
95.55\% ± 0.71vs. 94.45\% ± 0.83, p\textless{}0.01; and 95.94\% ± 0.35
vs. 94.76\% ± 0.66, p\textless{}0.01, respectively).

\textbf{f. Heart and respiratory rates:} Three
studies\textsuperscript{20,23,28} done at ED and one in hospitalized
children\textsuperscript{24}reported data for heart rate. The pooled
data of two ED studies\textsuperscript{23,28} showed no significant
difference in overall heart rate change between the budesonide and
control groups (MD = -1.08 {[}-6.48 to 4.32{]}; I\textsuperscript{2} =
0\%, p=0.70). Also, Sung et al.\textsuperscript{20} reported that there
were no differences between groups. The study performed in hospitalized
children\textsuperscript{24} showed a significant lower heart rate at 1,
2, and 3 hrs. after intervention favorable to budesonide vs. placebo
group (102.18±6.58 vs. 109.09±5.48, p \textless{}0.01; 88.42±5.36 vs.
96.85±5.24, p\textless{}0.01; 83.64±3.86 vs. 93.52±4.56,
p\textless{}0.01, respectively).

Four studies\textsuperscript{21,23,24,27} reported data for the
respiratory rate. There was no significant change in pooled data for
respiratory rate among studies done in ED\textsuperscript{23,27} (MD =
0.43 {[}-1.43 to 2.29{]}; I\textsuperscript{2} = 0\%, p=0.65). However,
among trials with hospitalized children, Sano et
al.\textsuperscript{21}reported significantly higher respiratory rates
at 24, 36, and 48 hrs. among children in the control group (who received
ipratropium bromide) than those in the budesonide group; and
Akhtaruzzaman et al.\textsuperscript{24} reported a significant lower
respiratory rate at 1, 2, and 3 hrs. after intervention favorable to
budesonide vs. placebo group (24.97±3.25 vs. 27.82±4.10, p
\textless{}0.01; 23.55±2.77 vs. 25.27±3.35,p \textless{}0.01; and
22.42±1.79 vs. 24.48±2.74, p \textless{}0.01, respectively).

\textbf{g. Additional SABA requirement:} Only one
study\textsuperscript{20} reported this outcome, showing no difference
in additional salbutamol use between groups.

\textbf{h. Adverse events:} Six
studies\textsuperscript{20,23-27}reported AE data, and four
studies\textsuperscript{20,24,26,27} reported no occurrence of AEs.
Upham et al.\textsuperscript{23} reported a total of 106 AEs in 62
patients (33 in the budesonide and 29 in the control group). Alangari et
al.\textsuperscript{25} described 28 AE episodes, 17 cases of fine
tremors (7 in the budesonide and 10 in the control group), and 11 cases
of palpitations (6 in the budesonide and 5 in the control group); these
details were described in their protocol document (NCT01524198).

\textbf{DISCUSSION}

To our knowledge, this is the first meta-analysis of trials exclusively
carried out in

children and adolescent populations that explored the efficacy of adding
ICS to SC compared with SC alone for acute asthma when consulting in the
ED or during hospitalization. Our study demonstrates that in children
hospitalized with an acute asthma episode adding budesonide
significantly reduces the LOS by more than one day. Among the trials
done in the ED, adding budesonide significantly improved the acute
asthma severity score, especially when using high doses of budesonide
(\selectlanguage{english}[?]2 mg).

Objective measurements such as SpO\textsubscript{2} and respiratory and
heart rates were significantly different between children treated with
the addition of budesonide versus controls. The
SpO\textsubscript{2}improved, while respiratory and heart rates
decreased in the budesonide group only among trials with hospitalized
children; however, not pooled data analysis was able to performed. It is
important to mention that heart rate could be influenced by the SABA
drugs included in the protocol. In terms of lung function, only two
studies (one in the ED and one in hospitalized children) reported this
outcome, and in both children on ICS+SC significantly improved the PEFR
in comparison with SC. The same result was before described in adults
using PEFR, but not with FEV1\textsuperscript{8}. Similarly, the present
review shows that adding budesonide to SC does not result in more AEs or
SAEs, as was described in the last Cochrane review\textsuperscript{8}.

The most recent GINA guidelines\textsuperscript{4} stated that a high
dose of ICS within the first hours after presentation to ED reduces the
need for hospitalization in patients who did not receive SC, but the
addition of ICS to SC is inconclusive, and the type of ICS, doses, and
duration remain unclear; moreover, the cost is an issue that remains to
be resolved. Likewise, the latest Cochrane review\textsuperscript{8} of
five studies (n=433 patients), but only two
studies\textsuperscript{20,23} in children, showed that ICS plus SC
significantly reduces hospital admission compared with SC, but with high
heterogenicity (OR=0.54 {[}0.36 to 0.81{]}, I\textsuperscript{2}=52\%),
and stated the necessity for further research ``to clarify the most
appropriate drug dosage and delivery device, and to define which
patients are most likely to benefit from ICS therapy''. Our systematic
review of nine studies done exclusively in a population of children with
acute asthma (n=1473) showed that adding budesonide via nebulizer did
not reduce hospital admission, but significantly reduces the LOS, and
improves the asthma severity score in the ED, especially when using high
doses of budesonide. In terms of cost, in a recent cost-effectiveness
analysis done in a middle-high income country, we demonstrated that ICS
in addition to SCs compared with standard therapy with SCs for treating
pediatric asthma model showed that compared to SCs, therapy with ICS+SCs
was associated with lower total costs (US\$ 88.8 vs.US\$97.7 average
cost per patient) and a lower probability of hospital admission (0.9060
vs. 0.9000)\textsuperscript{29}.

The biological explanation of the superiority of adding ICS to SC vs. SC
is the addition of the non-genomic effect, which only ICS exhibit (i.e.
activation of endothelial NO synthase and NO synthesis, increasing the
noradrenergic neurotransmission in the airway vasculature and therefore
reducing the airway blood flow\textsuperscript{10}, a desirable effect
in asthmatic patients, where a significant increased blood flow in the
airway mucosa ocurrs\textsuperscript{11}), to the genomic effect of SC.
Another advantage of adding ICS is their very rapid onset of action (in
minutes) in contrast to the slow onset of action of SCs (3--4 h after
administration). An additional mechanism is that ICS administration
simultaneously with SABA could acutely potentiate its bronchodilation
effect\textsuperscript{30}.

In all the RCTs included in this systematic review, the ICS used was
budesonide. A study in vivo\textsuperscript{31} showed that budesonide
oleate is formed rapidly in human airways after inhalation and is
detectable in lung tissue for almost 2 days after a single inhalation.
Esterification takes place intracellularly within the lungs, and the
sustained action of budesonide is explained by this fatty acid
conjugation. This sustained retention of esterified budesonide in the
lungs supports the prolonged duration of action of budesonide and its
suitability for once-daily administration\textsuperscript{31}.
Budesonide, compared with other ICS, had the highest vasoconstrictive
effect in airway blood flow\textsuperscript{32,33}, and since airway
blood flow is increased in asthmatics, the vasoconstrictive effect of
ICS is beneficial. Also, when budesonide was nebulized up to 26\% of the
drug is systemically bioavailable in children\textsuperscript{34}.

This study has several limitations. First, no studies using ICS delivery
by MDI were found, and therefore the results of budesonide via nebulizer
cannot be extrapolated to ICS delivery via MDI or to other types of ICS.
Also, it was not possible to evaluate the relative efficacy of the
different nebulizer devices used in these trials. Second, only two
studies measured lung function. Third, differences in type of SC was not
analysis in detail. Fourth, the minimal clinically important difference
for each asthma score using in the trials was not reported. Five, since
better results were obtained using 2mg doses of budesonide, more trials
with higher doses need to be performed. The strength of this study is
that it includes nine RCTs exclusively carried out in a population of
children, most of them with high-quality methodology, from seven
different countries around the world involving more than 1400 patients
with asthma.

In conclusion, adding budesonide to SC, compared with SC alone, for
acute asthma in hospitalized children significantly reduces the LOS by
more than one day, and significantly improves the acute asthma severity
score for patients in the ED (especially using \selectlanguage{english}[?]2 mg).

\textbf{List of Abbreviations:} AEs= adverse effects, API= asthma
predictive index, ED= emergency department, ICS= inhaled
corticosteroids, LOS= length of stay, MDI= metered dose inhaler, NO=
nitric oxide, PEFR= peak expiratory flow rate, RCTs= randomized clinical
trials, RR= risk ratios, SAEs= severe adverse effects, SABA= beta-2
agonists, SpO\textsubscript{2}= oxygen saturation, SC= systemic
corticosteroids, SMD= standardized mean differences.

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\textbf{FIGURE LEGENDS:}

Figure 1. Process of study selection.

Figure 2. Risk of bias of the eligible studies.

Figure 3. Pooled RRs and 95\% CIs for overall hospital admissions in ED
studies.

Figure 4. Pooled MDs and 95\% CIs for LOS in hospital studies

Figure 5.a. Pooled MDs and 95\% CI in the difference for acute asthma
severity score in ED studies (mean differences).

Figure 5.b. Pooled SMD and SMD95\% CI for acute asthma severity score in
ED studies (mean after intervention).

Figure 5.c. Pooled SMD and SMD95\% CI for acute asthma severity score in
ED studies according by budesonide doses.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figures-3-and-4/Figures-3-and-4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5/Figure-5}

\end{center}
\end{figure}

\selectlanguage{english}
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