Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age.

Abstract

Recent studies have documented the efficacy and safety of sublingual immunotherapy (SLIT) in patients with rhinitis, but the value of this treatment in those with asthma is still debated. We evaluated the efficacy of SLIT in the treatment of allergic asthma in children by a metaanalysis of randomized, double-blind, and placebo-controlled (DBPC) clinical trials.
Electronic databases were searched up to May 31, 2006, for randomized DBPC trials assessing SLIT in pediatric cases of asthma. Effects on primary outcomes (ie, symptom scores and concomitant use of rescue medication) were calculated with standardized mean differences (SMDs) using the random-effects model. We performed the metaanalysis using a statistical software package (RevMan, 4.2.8; The Cochrane Collaboration; Oxford, UK), and we followed the recommendations of the Cochrane Collaboration and the Quality of Reporting of Metaanalyses guidelines.
Seventy-three articles were identified and reviewed. Nine studies, all published after 1990, fulfilled the selection criteria. A total of 441 patients had a final assessment and were included in the analysis. Two hundred thirty-two patients received SLIT, and 209 patients received placebo. The results of the present analysis demonstrated a relevant heterogeneity due to widely differing scoring systems. Overall, there was a significant reduction in both symptoms (SMD - 1.14; 95% confidence interval [CI], - 2.10 to - 0.18; p = 0.02) and medication use (SMD, - 1.63; 95% CI, - 2.83 to - 0.44; p = 0.007) following SLIT.
SLIT with standardized extracts reduces both symptom scores and rescue medication use in children with allergic asthma compared with placebo.

Full text

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DOI 10.1378/chest.06-1425

2008;133;599-609; Prepublished online October 20, 2007;Chest

Canonica
Baena-Cagnani, Socorro Orozco, Alvaro Pedroza and Giorgio Walter
Martin Penagos, Giovanni Passalacqua, Enrico Compalati, Carlos E.

*Age
Asthma in Pediatric Patients, 3 to 18 Years of
Immunotherapy in the Treatment of Allergic
Metaanalysis of the Efficacy of Sublingual


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Metaanalysis of the Efficacy of
Sublingual Immunotherapy in the
Treatment of Allergic Asthma in
Pediatric Patients, 3 to 18 Years of Age*
Martin Penagos, MD, MSc; Giovanni Passalacqua, MD; Enrico Compalati, MD;
Carlos E. Baena-Cagnani, MD; Socorro Orozco, MD; Alvaro Pedroza, MD; and
Giorgio Walter Canonica, MD
Background: Recent studies have documented the efficacy and safety of sublingual immunother-
apy (SLIT) in patients with rhinitis, but the value of this treatment in those with asthma is still
debated. We evaluated the efficacy of SLIT in the treatment of allergic asthma in children by a
metaanalysis of randomized, double-blind, and placebo-controlled (DBPC) clinical trials.
Methods: Electronic databases were searched up to May 31, 2006, for randomized DBPC trials
assessing SLIT in pediatric cases of asthma. Effects on primary outcomes (ie, symptom scores and
concomitant use of rescue medication) were calculated with standardized mean differences
(SMDs) using the random-effects model. We performed the metaanalysis using a statistical
software package (RevMan, 4.2.8; The Cochrane Collaboration; Oxford, UK), and we followed the
recommendations of the Cochrane Collaboration and the Quality of Reporting of Metaanalyses
guidelines.
Results: Seventy-three articles were identified and reviewed. Nine studies, all published after
1990, fulfilled the selection criteria. A total of 441 patients had a final assessment and were
included in the analysis. Two hundred thirty-two patients received SLIT, and 209 patients
received placebo. The results of the present analysis demonstrated a relevant heterogeneity due
to widely differing scoring systems. Overall, there was a significant reduction in both symptoms
(SMD ? 1.14; 95% confidence interval [CI], ? 2.10 to ? 0.18; p ? 0.02) and medication use
(SMD, ? 1.63; 95% CI, ? 2.83 to ? 0.44; p ? 0.007) following SLIT.
Conclusion: SLIT with standardized extracts reduces both symptom scores and rescue medication
use in children with allergic asthma compared with placebo.
(CHEST 2008; 133:599–609)
Key words: asthma; children; efficacy; metaanalysis; randomized controlled trials; sublingual immunotherapy
Abbreviations: CI ? confidence interval; DBPC ? double-blind, placebo-controlled; QUOROM ? Quality of Report-
ing of Metaanalyses; REM ? random-effects model; SLIT ? sublingual immunotherapy; SMD ? standardized mean
difference
S
as the only allergen-oriented biological response
modifier, and it is regarded as an essential part of the
therapeutic approach for respiratory allergy.1The
relevance of immunotherapy in the treatment of
allergic respiratory diseases is further underlined by
the fact that it can exert a preventive effect on the
progression of respiratory allergy in children,2thus
acting as a secondary prevention. The use of sublin-
gual immunotherapy (SLIT) was proposed about 20
pecific immunotherapy, usually administered by
the subcutaneous route, is presently considered
years ago with the main rationale of minimizing the
risk of severe adverse events, possibly related to the
injection route of administration.3After some years
and many controlled trials performed in adults
For editorial comment see page 589
and children,4SLIT was finally accepted as a viable
alternative to the traditional subcutaneous adminis-
tration route.1,5The satisfactory safety profile of
SLIT was repeatedly confirmed in both clinical trials
CHEST
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ASTHMA
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and postmarketing surveys, even in children ? 5
years of age.6Of note, some double-dummy stud-
ies7,8failed to detect a significant difference between
SLIT and the subcutaneous route of administration
as far as clinical efficacy was concerned. Finally,
stringent experimental evidence9,10of the immuno-
logic effects of the treatment, consistent with the
clinical effects, has also been provided.
The abundant literature on injection immunother-
apy allowed the performance of detailed metaanaly-
ses of its efficacy in asthma patients.11Based on the
available randomized and controlled trials, meta-
analyses have been also performed with SLIT, and
two studies have confirmed its efficacy in adults12
and in pediatric subjects.13Nevertheless, the men-
tioned metaanalyses were essentially limited to aller-
gic rhinitis, due to the paucity of experimental data
available for asthma so that the value of SLIT in
asthma patients is still matter of debate. This is
especially true in children who are expected to be the
idealcandidatesforSLIT.Duringthelastyears,several
new pediatric studies have been published, and further
data have become available; thus, we evaluated the
efficacy of SLIT in cases of allergic asthma among
pediatric patients (3 to 18 years old) by conducting a
metaanalysis of the published randomized, double-
blind, placebo-controlled (DBPC) clinical trials.
Materials and Methods
Search Strategy
This review was conducted following the Cochrane Collabora-
tion and the Quality of Reporting of Metaanalyses (QUOROM)
guidelines standards.14,15The MEDLINE, EMBASE, LILACS,
and CINAHL databases were searched from 1966 to May 31,
2006, for randomized DBPC trials investigating the efficacy of
SLIT in children with allergic asthma using MeSH headings and
text words. We searched also for any additional study mentioned
in the references of the identified publications, including previ-
ous relevant metaanalyses and narrative reviews. Abstracts of
relevant meetings were also searched.
Two authors conducted independent search strategies. The
first MEDLINE search strategy retrieved citations containing
the subject heading “sublingual immunotherapy” (limited to the
publication types clinical trial and metaanalysis) or the text words
“sublingual or swallow desensitization” or oromucosal immuno-
therapy.” The second MEDLINE search strategy retrieved cita-
tions containing the subject heading “sublingual immunotherapy”
combined with exploded subject headings describing allergic
disease (“asthma,” “bronchial,” or “wheezing”) or text words
describing “sublingual immunotherapy efficacy in asthma” ap-
pearing in close proximity to each other (“sublingual,” “immuno-
therapy,” “asthma,” and “efficacy”) or those focused to the target
population (“children” or “adolescent”). We limited citations
from the second search to randomized, controlled trials using a
maximally sensitive strategy.16We modified these searches for
other databases. We screened reference lists from all retrieved
articles and from recent review articles to identify additional
studies. There were no language restrictions.
Study Selection and Characteristics
We included parallel-group randomized, DBPC trials. Patients
had to be ? 18 years of age as accepted by the American
Academy of Pediatrics,17,18with a history of allergic asthma with
or without allergic rhinitis and/or conjunctivitis, in whom the
causal allergen had been identified, and IgE sensitization had
been proven by skin-prick tests and/or specific IgE assays.
Immunotherapy had to be delivered by the sublingual route,
whether or not the allergen was subsequently swallowed. All
appropriate allergens were considered at all doses and for all
durations of treatment. Trials of SLIT for allergic rhinitis were
considered only if the results for subjects with asthma were
separately analyzed. Trial eligibility was determined on full text
format by two authors and checked by the principal investigator.
The observed percentage agreement between the investigators
for the assessment of inclusion was calculated by using the ?
test.15,19The ? statistic (Table 119–22,24,26–32,46,54,64,65,71–74) repre-
sents the rate of agreement remaining between two independent
observers after chance agreement is removed. The ? statistic
values range from 1 (excellent) to 0 (no agreement).
Assessment of Validity
The methodological information used that was relevant to the
assessment of internal validity was as follows: method of alloca-
tion; generation and concealment of randomization; blinding of
caregivers/outcome assessors; and the number of and reasons for
withdrawals. The quality of trials was quantified in duplicate
using the Jadad scale20,21that scores from 0 (lower quality) to 5
(excellent quality) [Table 1]. An interrater agreement was again
calculated by using the ? statistic.15,19,22
*From the Division of Allergy & Respiratory Diseases (Drs.
Penagos, Passalacqua, Compalati, and Canonica), Department of
Internal Medicine, University of Genoa, Genoa, Italy; the Uni-
versity of Cordoba (Dr. Baena-Cagnani), Cordoba, Argentina;
and the Allergy Service (Drs. Orozco and Pedroza), National
Pediatrics Institute, Mexico City, Mexico.
Dr. Penagos has received an educational grant from the Al?an
Program (E04D040885MX). Dr. Compalati has received a schol-
arship from the University of Genoa and ARMIA (Associazione
Ricerca Malattie Immunologiche e Allergiche). For Drs. Passal-
acqua, Baena-Cagnani, Orozco, Pedroza, and Canonica, funding
for this analysis came from their salary support.
Dr. Canonica and Dr. Passalacqua have received research grants
and lecture fees from Alk-Abello, Anallergo, Allergy Therapeu-
tics, A. Menarini, Almirall, Altana, AstraZeneca, Boehringer
Ingelheim, Chiesi Farmaceutici, Genentech, Gentili, Glaxo-
SmithKline, Lofarma, Merck Sharp & Dome, Novartis, Pfizer,
Schering Plough, Stallerge `nes, and UCB Pharma. Dr. Orozco has
received research funding from AstraZeneca, Aventis, Glaxo-
Smith Kline, and Schering Plough. Dr. Pedroza has received
research grants from AstraZeneca, Aventis, Boehringer In-
gelheim, and GlaxoSmithKline. Drs. Penagos, Compalati, and
Baena-Cagnani have reported to the ACCP that no significant
conflicts of interest exist with any companies/organizations whose
products or services may be discussed in this article.
Manuscript received August 4, 2006; revision accepted Septem-
ber 21, 2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Giorgio Walter Canonica, MD, Allergy and
Respiratory Diseases, DIMI, Padiglione Maragliano, Largo R
Benzi, 10, 16132 Genoa, Italy; e-mail: canonica@unige.it
DOI: 10.1378/chest.06-1425
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Table 1—Description of the Statistical Methods Used in This Review*
StepsRationale Interpretation References
Study quality and
data extraction
Jadad scaleAssesses the methodological quality of trials;
it takes into account the adequacy and
description of randomization, masking,
dropouts, and withdrawals in the report of
an RCT; the scale ranges from 0 to 5,
with higher scores indicating higher
methodological quality
Quantifies the interobserver variability that
occurs when two or more independent
observers evaluate the same thing; the ?
statistic represents the rate of agreement
remaining after chance agreement is
removed
The power of a statistical test is the
probability that the test will reject a false
null hypothesis; this probability is referred
as ?; therefore, power is equal to 1 ? ?;
power analysis can be conducted either
before (a priori) or after (post hoc) data
are collected
Scores 4–5, high methodological quality; score
3, sufficient; score ? 3, low methodological
quality
20, 21
? test Agreement within different observers (? value)
is considered: 0–0.2, very poor; 0.2–0.4, poor;
0.4–0.6, moderate; 0.6–0.8, good; 0.8–1.0,
excellent
19, 22
Statistical powerPower values lie between 0 and 1.0; a value of
0.80 is the standard for adequacy
64, 65, 73, 74
Effect size
SMDThe SMD is the difference in means divided
by an SD; this SD is the pooled SD of
participants’ outcomes across the whole
trial; the SMD does not depend on the
measurement scale used; if different trials
assess the same outcome using different
scales, the SMD converts all outcomes to
a common scale, measured in units of SD
Cohen71describes values of ? 0.20, 0.50, and
0.80, respectively, as small, medium, and
large effect sizes
28–30, 46, 71, 74
Heterogeneity
I2test
I2describes the percentage of total variation
across studies due to true heterogeneity
rather than to chance; I2can be calculated
and compared across metaanalyses of
different sizes, of different types of
studies, and for different types of outcome
data
Two methods are available in RevMan for
metaanalysis of continuous data: the FEM
uses the inverse variance approach, while
the REM uses the DerSimonian and
Laird28random-effects approach; REM
metaanalyses can increase statistical power
by reducing the SE of the weighted
average effect size; REM assumes that the
true treatment effects in the individual
studies may be different from each other;
that means there is no single number to
estimate in the metaanalysis, but a
distribution of numbers; this model
assumes that these effects are normally
distributed; the metaanalysis therefore
estimates the mean and SD of the
different effects; then, a goodness-of-fit
test for normality or a graphical
exploration of the outcomes should be
done
I2lies between 0% and 100%; a value of 0%
indicates no heterogeneity, and larger values
show increasing heterogeneity; a classification
has been proposed as low, moderate, and
high to I2values of 25%, 50%, and 75%,
respectively
26, 27, 32, 54
REMUnder the FEM, it is assumed that all studies
come from a common population, and that
the effect size (SMD) is not significantly
different among the different trials; this
assumption is tested by the heterogeneity
test; if this test yields a low p value
(p ? 0.05), then the FEM may be invalid; in
this case, the REM may be more
appropriate; methods used to combine
results in a metaanalysis use a weighted
average, in which the larger trials have more
influence than the smaller ones; weight is
attributed slightly differently when we use an
REM; however, studies with restrictive
eligibility criteria will be given greater weight
24, 28–32, 54,
65, 72
*RCT ? randomized controlled trial; FEM ? fixed-effects method.
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Data Extraction
The outcomes measured were asthma symptom and medica-
tion scores. Two independent reviewers extracted data from the
selected articles, reconciling differences by consensus. Observer
variation for continuous data was quantified and plotted using the
Bland-Altman test.23,24We planned to perform an intention-to-
treat analysis and tried to include dropouts in the analysis if the
last observation carried forward for both continuous scores was
available; if not, we just included them in the analysis of patients
with a final assessment. When the results were only presented in
graphs, these were digitized and then converted to numbers
(DigitizeIt, version 1.5.7; DigitizeIt; Ko ¨ln, Germany).25Addition-
ally, we contacted most of the investigators to obtain more
information for data extraction.
Statistical Analysis
Outcomes were quantitative and continuous (ie, symptom
scores and medication scores). In the original studies, a wide
variety of scoring systems and scales were used for symptoms
(usually, a daily assessment of symptoms recorded on a diary, and
subsequently summarized and averaged) and medication usage
(typically, a daily score of the use of ?2-agonists and inhaled
corticosteroids). The investigators of each trial provided post-
treatment mean and SD values for both the active-treatment and
placebo groups. Since the outcome variables continuous data
were expressed in different scales, we used the standardized
mean difference (SMD). Heterogeneity was calculated with the
Cochrane Q statistic test and the I2test.26,27The I2test describes
the rate of variation across studies due to heterogeneity rather
than chance, and ranges from 0 (no heterogeneity) to 100
(maximum heterogeneity) [Table 1]. All results are reported with
95% confidence intervals (CIs), and all p values are two-tailed.
Given the significant heterogeneity found among the results of
the included studies, the random-effects model (REM) according
to DerSimonian and Laird28was used. This model assumes that the
truetreatmenteffectsintheindividualstudiesmaybedifferentfrom
each other and that these are normally distributed.28–30We ex-
plored the effect-size distribution with Q-Q plots and histograms.
The Q-Q plots compare the quantiles of an observed distribution
against the quantiles of the standard normal distribution. In a
metaanalysis, such a plot can be used to check the normality
assumption, to investigate whether all studies come from a single
population, and to search for publication bias.31Statistical meth-
ods are summarized in Table 1. The analysis was performed using
two statistical software programs (RevMan, version 4.2.8; The
Cochrane Collaboration; Oxford, UK32; and SPSS, version 14.0
for Windows; SPSS Inc; Chicago, IL).33
Data Synthesis
Search Results
The primary search identified 286 articles, 73 of
which were potentially relevant trials on SLIT in
infantile allergic asthma (Fig 1). Twenty-one stud-
ies34–42were randomized, but only 9 articles34–42met
the mentioned inclusion criteria for metaanalysis. The
? statistic for interrater agreement on study eligibility
was 0.85 (95% CI, 0.75 to 1.0). Consensus was reached
on the remaining trials. Some randomized trials were
excluded from the review for the following reasons:
threetrialswerenotblinded;twotrialsdidnotcompare
SLIT with placebo; two trials were duplicated; and five
trials had no suitable data (designed for safety evalua-
tion, postchallenge test studies, or information not
obtainable).
The mean and SD for scores were available in text
or graphics in three articles.34,37,42When the data
were not accessible in the articles, authors were
contacted, and they provided the data.35,36,38–41
Trial Characteristics
Table 234–42summarizes the characteristics of the
studies and subjects included in the metaanalysis. All
nine studies34–42reported 441 subjects who had
concluded treatment and had received a final clinical
assessment; consequently, their data were analyzed.
Four trials35–37,41included patients with either
asthma or rhinitis; but only those patients with
asthma were included in this analysis. The age range
of participants was 3 to 18 years. Each trial included
a median of 43 participants (range, 14 to 97 patients).
All patients had received a diagnosis of allergic
asthma (rhinitis, 77%; conjunctivitis, 59%). There
were not enough studies for a reliable evaluation of
FEV1as a primary outcome.
Table 334–42displays the characteristics of treat-
ments. The SLIT extracts used in the trials were all
standardized either biologically or immunologically in
the following units: specific treatment units (or STU);
index of reactivity (or IR); allergic units (or AU);
biologicalunits(orBU);andmicrograms.Theallergens
were mites (n ? 6), grass mix (n ? 1), Olea europaea
(n ? 1), and pollen mix (n ? 1). Glycerol was the
vehicle most frequently used. Eight studies34–36,38–42
provided the allergen information in drops; one study37
provided allergen information in tablets. The median
for SLIT and placebo administration was 12 months,
with a range of 3 to 32 months. Data on asthma
symptom scores were obtained from nine trials,34–42
and data on medication use were obtained from seven
trials.36–42
Methodological Quality of Included Studies
All the trials were randomized and DBPC. Each
trial reported dropouts, withdrawals, and patients
completing the trial; the dropout rate varied be-
tween 0% and 17%. Based on the Jadad criteria,
four studies35,37,38,41received a 5/5 quality score
and five studies34,36,39,40,42a 4/5 quality score. The
? score for interrater agreement on methodologi-
cal quality was 0.90 (95% CI, 0.80 to 1.0).
Among the 9 studies included in this review, only
two studies35,41calculated the statistical power. One
study41calculated this a priori with the purpose of
sample size estimation only. Another study35carried
out a post hoc calculation, but neither for asthma
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