Pediatric Drugs

https://doi.org/10.1007/s40272-020-00419-x

SYSTEMATIC REVIEW

Antihistamines in the Management of Pediatric Allergic

Rhinitis: A Systematic Review
Lilly Velentza1 · Zinovia Maridaki1 · Evangelia Blana1 · Michael Miligkos1,2

© Springer Nature Switzerland AG 2020

Abstract
Background The clinical benefit of newer antihistamines (AHs) versus other active treatments has not been assessed in
pediatric patients with allergic rhinitis.
Methods A systematic literature search was performed in MEDLINE, SCOPUS, and the Cochrane Central Register of
Con- trolled Trials from inception through August 2020. Randomized controlled trials (RCTs) comparing newer with older
AHs, corticosteroids, or montelukast were included. The Cochrane Risk of Bias Tool was used for quality assessment.
Results Out of 10,656 citations, 16 RCTs (N = 1653) with a duration from 10 days to 3 months were included. When
compared with older-generation AHs, the administration of newer AHs did not confer significant benefit and appeared less
effective compared with intranasal corticosteroids. However, newer AHs were more potent in achieving symptom control
compared with montelukast. Data regarding quality of life were generally missing. The incidence of adverse events was
low in all treatment groups. The included RCTs were characterized by moderate risk of bias.
Conclusions Newer AHs are effective in symptom control and well tolerated in the pediatric population. However,
inadequate reporting, variation in outcome measures, and a paucity of sufficient randomized comparisons precluded us
from quantifying the relative efficacy of newer AHs compared with other treatment options.

Key points 1 Introduction

Allergic rhinitis (AR) represents one of the most

g the relevant clinical benefit of newer
nes are scarce.
stamines are safe and efficacious treatment options for AR but not generally symptoms
ids.
heterogeneous nature of the included stud- ies warrants further, more standardized
Part of this work has been presented in the Pediatric Allergy and
Asthma Meeting 2019, Florence, Italy.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s40272-020-00419-x) contains
supplementary material, which is available to authorized users.
 Lilly Velentza
lilivele10@yahoo.gr
1
Pediatrics Working Group, Society of Junior Doctors, 5
Menalou Str, Maroussi, 15123 Athens, Greece
2
First Department of Pediatrics, National and Kapodistrian
University of Athens, Athens, Greece
commonly diagnosed chronic diseases in childhood and its
prevalence highly varies among countries [1–3]. Common
superior toare
intranasal
categorized as nasal or non-nasal, whereas
major comor- bidities include but are not limited to other
research.
allergic diseases such as asthma (15–38% of patients with
AR) [4]. Even though AR does not represent a life-
threatening disease, it severely affects patients’ quality of
life (QoL), causing— among others—fatigue and sleep
disorders. Children are
more prone to experience difficulties in social interactions,
learning, and attention impairment, which subsequently
lead to deterioration in school performance [5]. It is
estimated that almost 2 million school-days are lost every
year in the US, reflecting the significant socio-economic
burden of the disease [6].
During the past decades, great progress has been
achieved in order to both maximize the clinical benefit and
avoid the adverse effects caused by pharmacologic
treatment of AR. Different treatment strategies can be
followed, taking into consideration the severity and
duration of clinical manifesta- tions, the patient’s age, as
well as the presence of co-morbid- ities. Antihistamines
(AHs) are widely used via the oral or
 L. Velentza et
al.
decongest- ants, cromolyn, or immunotherapy as the only
intranasal route. Due to the lack of H1-receptor selectivity comparators,
and their ability to cross the blood–brain barrier, first-gen-
eration AHs have been associated with anticholinergic and
sedative adverse effects [7]. The use of newer-generation
AHs has marked a breakthrough in the management of AR
because of their ability to alleviate symptoms and the
lower incidence of toxicities. Intranasal corticosteroids
(INCS) are effective either as monotherapy or in
combination with oral AHs for the treatment of perennial
allergic rhinitis (PAR) and seasonal allergic rhinitis (SAR)
[8]. Montelukast is the only approved leukotriene receptor
antagonist (LTRA) for the treatment of AR [9]. According
to the Allergic Rhi- nitis and its Impact on Asthma
(ARIA) guidelines, either an LTRA or an oral AH may be
administered to patients with SAR, whereas oral AHs are
more preferable in PAR patients [8]. However, as these
recommendations are mainly based on adult studies and
there is no standardized way of reporting the efficacy of
different therapeutic regimens, the extrapolation of their
results to pediatric populations remains challenging.
Although AR is a frequent disease entity of childhood,
the relative benefits of newer AHs have not been
established. Therefore, we conducted a systematic review
of RCTs that compared newer-generation AHs with other
AHs or other active AR treatments (i.e. INCS,
montelukast) in children aged < 12 years diagnosed with
AR for patient-reported out- come measures used to assess
AR control.

2 Methods

2.1 Data Sources

For this review, we implemented the Preferred Reporting

Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines [10]. We searched MEDLINE,
SCOPUS, and the Cochrane Controlled Register of Trials
(CENTRAL) from inception through August 2020, using
a combination of terms relevant to the interventions of
interest (anti-hista- mines) and the disease of interest
(allergic rhinitis) (Appen- dix, see electronic
supplementary material [ESM]).

2.2 Study Selection and Data Collection

Process

The inclusion criteria were as follows: RCTs in children

aged ≤ 12 years with persistent or intermittent allergic
rhini- tis; comparison of newer AHs with corticosteroids,
LTRAs, or older AHs; inclusion of at least one of the pre-
specified outcome measures important to patients (i.e.,
symptom scores, QoL, adverse events); English language
publication. We excluded RCTs that investigated the use of
terfenadine or astemizole, RCTs that used either placebo,
Antihistamines in Pediatric Allergic
Rhinitis
3.2 Trial
and single-dose or challenge studies. Three investigators Characteristics reported. Table 1
(LV, ZM, and EB) independently screened the titles and summarizes the main
abstracts of the retrieved citations. Disagreements were characteristics of the
The majority of RCTs
resolved after discussion with a fourth reviewer (MM). enrolled patients with PAR included RCTs.
Title and abstract screening was completed using (11 out of 16 trials). The
Abstrackr [11]. Full-text screening was conducted evaluation of symptoms 3.3 Quality
independently by three authors (LV, ZM, and EB). In case was performed by the Assessment
of disagreement, a fourth reviewer was added (MM). Data patients/parents and/or the
extraction was performed by two authors (LV and MM). investigators. The patients’ Overall, the included RCTs
We developed a data extrac- tion form in a Microsoft did not provide adequate
® ages ranged from 2 to 18
Excel spreadsheet, which included information on study years; 4 out of 16 studies details for most risk-of-
details, participants’ characteristics, type of interventions enrolled patients > 12 bias items (Table 2). Only
and comparators, symptom scores and QoL scores, years old [14–17]. four of the eleven RCTs
adverse events, and treatment discontinuations. Cetirizine was the most reported a computer-
commonly administered generated randomization
2.3 Quality Assessment AH (9 trials), followed by code [18, 19, 24, 23] and
lorata- dine (5 trials), allocation concealment
Two authors (EB and ZM) independently assessed the desloratadine (2 trials), was generally
qual- ity of the selected RCTs using the Cochrane Risk of levocetirizine (2 tri- als) not clearly reported [20].
Bias Tool [12]. The items investigated were rated as of and levocabastine (1 trial). Four studies [19–22, 26]
‘low’, ‘high’, or ‘unclear’ risk of bias, and included Newer AHs were compared received a ‘high risk’ score
sequence gen- eration, allocation concealment, blinding with first-generation AHs in blinding domains,
of the patients, health care providers, and assessors, in six RCTs [18–23], whereas only one study
attrition, and selective outcome reporting. We assigned a montelukast in three RCTs [23] had a ‘low risk’ score
low risk of bias judge- ment to studies that provided [24–26], and INCS in four in all blinding domains.
sufficient details for each item. For instance, RCTs with RCTs [14–16, 17]. Fifteen studies received a
insufficient reporting (e.g., ‘double- blind’) were deemed Treatment duration ranged ‘low risk’ of bias due to
of unclear risk of bias for this item. from 10 days to 3 months incom- plete outcome data,
and the doses of the drugs as the participant attrition
2.4 Summary Measures and Data Presentation corresponded to those rate across the intervention
regularly administered in and control groups was
We present the results of data synthesis in tables. The clinical practice. Data balanced and below 20%.
summary of outcome measures is based on three com- regarding comorbidi- ties Of note, Sienra-Monge et
parison groupings: (1) newer AHs versus newer AHs, (2) and use of concomitant al. [27] replaced two
newer AHs versus older AHs, and (3) newer AHs versus medications were generally patients withdrawn from
other treatments (including corticosteroids and montelu- not the study with new ones. In
kast). RCTs that provided data on total symptoms score the absence of
(TSS), nasal symptoms score (NSS), or QoL scores are
presented in Table 3, whereas studies reporting individual
symptom scores are presented in a narrative form. When
means of TSS/NSS and measures of dispersion were not
reported, they were approximated from the available fig-
ures with the use of Engauge Digitizer software [13].

3 Results

3.1 Literature Search

We screened 10,656 citations, a total of 852 studies were

retrieved for full-text review, and finally, 16 RCTs were
included. The flowchart for the study selection is pre-
sented in Fig. 1.
 L. Velentza et
al.
cetirizine and oxatomide
had similar clinical effects 3.4.3 Newer-Generation vs
in PAR, regarding both Other Treatments
patients’ and investigators’
evaluation (sneezing, Two RCTs evaluated the
rhinorrhea, obstruc- tion, efficacy of cetirizine versus
pruritus) after 10 days of mon- telukast in different
treatment, whereas in the age groups of PAR patients
study by Lai et al. [19], [24, 25]. In both trials,
cetirizine was shown to cetirizine appeared to
provide greater TSS cause a greater reduction in
reduction after 12 weeks. TSS after 12 weeks of
No difference was treatment whereas there
observed in PRQLQ scores. was no differ- ence
Additionally, cetirizine between cetirizine and
admin- istration once and montelukast in PRQLQ
twice daily was compared scores. Interestingly,
with chlorphe- niramine in montelukast was shown to
a 2-week study including be more effective than
Fig. 1 Study selection process using the PRISMA [10] flow chart cetirizine in improving
SAR patients [20]. TSS
was reduced in all groups night sleep quality,
protocol details, we could loratadine provided according to patients’
not adequately assess the comparable nasal and non- but no significant
difference among the three diaries [25]. One RCT
likeli- hood of selective nasal symptom control over
interventions was noted. compared desloratadine
outcome reporting. a 2-week period. When
Although nasal congestion with montelukast and
Furthermore, the small cetirizine was compared
was not included in the intranasal mometasone
sample size in the majority with levocetirizine,
TSS, it was significantly during a 4-week treatment
of studies may lead to cetirizine-treated patients
improved in both period [26]. According to
baseline imbalances with had a greater reduc- tion in
cetirizine-treated and patients’ assessment,
regards to important TSS after 12 weeks of
chlorpheniramine- treated mometasone exhibited the
prognostic factors. treatment, with a more
patients in a similar greatest improvement in
promi- nent effect on nasal
manner. symp- tom control while
3.4 Data Synthesis congestion. There was no
desloratadine and
significant difference Moreover, the efficacy
of loratadine was compared montelukast provided
3.4.1 Newer-Generation between the two AHs in
with dexchlorpheniramine comparable clinical
Antihistamines terms of QoL parameters,
[21] and cyproheptadine effects. Intranasal
based on the scores of the
[22]. Lorat- adine levocabastine and oral
Cetirizine was compared Pediatric
administration showed cetirizine were compared
with loratadine [27, 28] Rhinoconjunctivitis
improved clinical efficacy with intranasal
and levo- cetirizine [29] in Quality of Life
compared with beclometha- sone
three RCTs. Sienra-Monge Questionnaire (PRQLQ)
cyproheptadine, whereas dipropionate in patients
and colleagues [29].
loratadine and with PAR [14, 17]. In both
[27] reported that both
dexchlorpheniramine studies, the administration
cetirizine and loratadine 3.4.2 Newer-
offered comparable of beclomethasone
improved sneezing, Generat
therapeutic relief from dipropion- ate significantly
rhinorrhea, nasal ion vs
nasal and non-nasal improved nasal symptoms
obstruction, and nasal and Older-
symptoms. In a 1-week compared with the AHs. In
ocular pruritus according Generat
trial, no statistically addition, beclomethasone
to the investigators’ ion
Antihis significant difference was dipropionate-treated
assessment, whereas
tamine observed between patients appeared to have
cetirizine was more
s desloratadine and significantly improved
effective in reducing NSS,
dexchlorpheniramine PRQLQ scores compared
based on par- ents’
Two RCTs compared regarding symptom control with the cetirizine group,
assessment, after 28 days
cetirizine and oxatomide [23]. after 3 weeks of treatment
of treatment. In the study
[18, 19]. In the study by [17]. Finally, loratadine
by Nayak and colleagues
Benedictis et al. [18], and levocetirizine were
[28], both cetirizine and
Antihistamines in Pediatric Allergic
Rhinitis
compared with fluticasone dropped out was the same
propionate aqueous nasal when comparing newer
spray (FPANS) for the and older-generation AH
treatment of SAR [15, treatment groups [16, 20,
16]. Treatment with 23, 28].
FPANS offered greater
benefit in nasal symptom
control compared with
loratadine in a 2-week
study [15], whereas no
significant difference
between on demand
levocetirizine and FPANS
was noted in a 12-week
study [16]. In the study by
Bender and Milgrom [15],
QoL was assessed based
on the Adolescent
Rhinoconjunctivitis
Quality of Life Ques-
tionnaire, a modified form
of the PRQLQ. The
analysis of five
parameters showed that
QoL scores were similar
in both treatment arms.
Table 3 lists the included
RCTs that report data on
TSS/NSS or QoL.

3.5 Adverse Events

Data regarding adverse

events were available in
12 out of 16 studies
(Table 4). In general, the
reported incidence of
adverse events was low
and newer-generation
AHs appeared to be well
tolerated. However, the
assessment of their sever-
ity varied across the
studies. Treatment-
related adverse events
included somnolence,
fatigue, sedation,
headache, epistaxis,
drowsiness, nausea, and
vomiting. No case of QT
prolongation was
reported. Considering
medication- related
treatment
discontinuations, the
number of patients who
Table 1 Trial characteristics

Study, year Region Disease type Treatment Treatment dose Treatment Patients, n Age, years Female, %
groups duration, mean (SD)
weeks

Boner et al. Italy Moderate/ LRD < 6 y, < 20 kg: 2 21 7.6 (2.9) 33.3
[21], 1989 severe SAR 2.5 mg po OD
(4–12 y) ≥ 6 y, ≥ 20 kg:
5 mg po OD
DCPN < 6 y, < 20 kg: 2 19 7.8 (3.0) 36.8
0.5 mg po TD
≥ 6 y, ≥ 20 kg:
1 mg po TD
Tinkelman et al. USA SAR (6–11 y) CTZ < 25 kg: 5 mg po 2 63 8.6 35.5
[20], 1996 OD
≥ 25 kg: 10 mg
po OD
CTZ < 25 kg: 2.5 mg 2 62 9.1 29.5
po BD
≥ 25 kg: 5 mg po
BD
CPN 2 mg po TD 2 63 8.7 30.2
Benedictis et al. Italy PAR (2–6 y) CTZ 5 mg po OD 10.2 days 53 4.6 (1.1) 34
[18], 1997 OXD 12.5 mg po BD 10.2 days 52 4.8 (1.1) 40.4
Baraldi et al. Italy PAR (5–17 y) LCBN 100 μg in BD 10 days 8 8.5 (0.7) 12.5
[14], 1998 BDP 200 μg in BD 10 days 13 10 (0.8) 15.3
Sienra-Monge Mexico PAR (2–6 y) CTZ 0.2 mg/kg po OD 4 40 4.3 (1.2) 40
et al. [27], LRD 0.2 mg/kg po OD 4 40 4.4 (1.1) 35
1999
Lai et al. [28], Taiwan Moderate/ CTZ 10 mg po OD 12 20 8.2 (2.4) 58.7
2002
severe PAR OXD 1 mg/kg po BD 12 20 8.3 (2.0) 56.6
(6–12 y)
KTF 1 mg po BD 12 20 7.4 (1.4) 56.2
Bender and USA SAR (8–17 y) LRD 10 mg po OD ND ND ND ND
Milgrom [15],
FPANS 100 μg/nostril OD ND ND ND ND
2004
Hsieh et al. Taiwan Moderate PAR CTZ 10 mg po OD 12 21 8.0 (2.4) 40
[24], 2004 (6–12 y)
MLK 5 mg po OD 12 21 8.2 (2.0) 35
Chen et al. [25], Taiwan PAR (2–6 y) CTZ 5 mg po OD 12 20 4.5 (0.9) 40
2006
MLK 4 mg po OD 12 20 4.5 (1.1) 45
Lee et al. [29], Taiwan Moderate/ CTZ 10 mg po OD 12 27 8.2 (2.2) 42
2009 severe PAR
LCTZ 5 mg po OD 12 26 8.8 (1.6) 37.5
(6–12 y)
Segundo et al. Brazil Moderate PAR DLRD 5 mg po OD 4 ND 9.9 (1.5) 42.9
[26], 2009 (6–12 y)
MTS 50 μg in OD 4 ND 8.1 (1.2) 28.6
MLK 5 mg po OD 4 ND 9.7 (2.3) 40
Wu et al. [22], Taiwan PAR (2–12 y) LRD > 30 kg: 10 mg 2 30 5.8 (2.4) 61.5
2012 po OD
≤ 30 kg: 5 mg po
OD
CPHD > 30 kg: 4 mg 2 30 6.6 (2.5) 34.8
po TD
≤ 30 kg: 2 mg po
TD
Table 1 (continued)
Study, year Region Disease type Treatment Treatment dose Treatment Patients, n Age, years Female, %
groups duration, mean (SD)
weeks

Wandalsen Brazil Moderate/ DLRD + PRD < 6 y: 1 105 ND 47.6

et al. [23],
severe PAR 1.25 mg + 10
2017 (2–12 y) mg OD
> 6 y:
2.5 mg + 20 mg
OD

DCPN + BMZ < 6 y: 1 105 ND 48.6

1 mg + 0.125
mg TD
> 6 y:
2 mg + 0.25 mg
TD
Wartna et al. Netherlands SAR (6–18 y) LCTZ 5 mg po OD on 12 48 11.0 (3.3) 45.8
[16], 2017
demand
FPANS (on < 12 y: 100 μg 12 52 11.8 (3.1) 42.3
demand) in
≥ 12 y: 200 μg
in
FPANS < 12 y: 100 μg 12 50 12.1 (3.3) 56
in OD
≥ 12 y: 200 μg
in OD
Nayak et al. USA SAR (6–11 y) CTZ 10 mg po OD 2 231 8.6 (1.7) 42.5
[28], 2017
LRD 10 mg po OD 2 221 8.9 (1.6) 42.2
Malizia et al. Italy PAR (6–14 y) CTZ 10 mg po OD 3 34 9.5 (2.4) 32
[17], 2018
BDP 100 μg/nostril BD 3 34 10.0 (2.4) 38

BD bis in die (twice daily), BDP beclomethasone dipropionate nasal spray, BMZ betamethasone, CPHD cyproheptadine, CPN chlorpheniramine,
CTZ cetirizine, DCPN dexchlorpheniramine, DLRD desloratadine, FPANS fluticasone propionate aqueous nasal spray, in intranasal, KTF
ketotifen, LCBN levocabastine, LCTZ levocetirizine, LRD loratadine, MLK montelukast, MTS mometasone, ND no data, OD omne in die (once
daily), OXD oxatomide, PAR perennial allergic rhinitis, po per os, PRD prednisolone, SAR seasonal allergic rhinitis, SD standard deviation, TD
ter in die (three times daily)
strongly recommend the use of newer AHs over older AHs
for both children and adults, as they are proven safer and
4 Discussion less

Pharmacotherapy represents the cornerstone of AR

manage- ment. The aim of this systematic review was to
examine the state of evidence related to the benefits of
newer AHs com- pared with other treatments in pediatric
patients with AR. The results indicate that the
administration of newer-generation AHs provide both
nasal and non-nasal symptom relief and improve QoL. The
administration of newer AHs appeared to be well tolerated
and with a low risk of adverse events. However, the
available data regarding the relative efficacy of newer-
generation AHs compared with older-generation AHs,
corticosteroids, and montelukast remain inconclusive.
The majority of previously published studies regarding
AR treatment in childhood included placebo-controlled
studies and there is lack of systematic reviews exploring
the efficacy of AHs versus other AR treatments. Numerous
consensus statements, including the guidelines by ARIA,
sedative [2]. Results from systematic reviews and meta-
anal- yses support that intranasal corticosteroids provide
greater nasal symptom control compared with intranasal
and oral AHs in adults [30, 31]. However, as the growing
body of published evidence is characterized by a very low
to moder- ate level of certainty, the current guidelines
represent mostly conditional recommendations that are of
limited usefulness regarding AR pharmacotherapy in
children.
The evaluation of QoL is of outmost importance in AR
patients [8]. The PRQLQ represents a valuable tool that
ena- bles a standardized and objective assessment of AR
symp- toms, everyday activities, and practicalities [32].
However, only a limited number of studies have
implemented it in their protocols.
Although the relative efficacy of newer AHs in
pediatric patients with AR has not been reviewed before,
our study is characterized by various limitations. First, we
managed to identify only 16 RCTs that enrolled limited
number of participants, thus restricting the
generalizability of our con- clusions. In addition to the
small number of RCTs, the clini- cal and methodological
heterogeneity as well as the missing
Table 2 Risk of bias in included studies

Study, year Sequence Allocation Blinding/ Blinding/car- Blinding/asses- Attrition Selective Other potential
genera- conceal- patients egivers sors outcome sources of bias
tion ment reporting

Boner et al. Unclear Unclear High High Unclear Low Unclear

[21], 1989
Tinkelman et al. Unclear Low High High High Low Unclear
[20], 1996
Benedictis et al. Unclear Unclear Low Low Low Low Unclear
[18], 1997
Baraldi et al. Unclear Unclear High Unclear Unclear Low Unclear
[14], 1998
Sienra-Monge Unclear Unclear Unclear Unclear Unclear Low Unclear Patients with-
et al. [27], drawn were
1999 replaced
Lai et al. [19], Low Unclear Unclear Unclear Unclear Low Unclear
2002
Bender and Unclear Unclear Low Low Low Unclear Unclear
Milgrom [15],
2004
Hsieh et al. [24], Low Unclear Unclear Unclear Unclear Low Unclear
2004
Chen et al. [25], Unclear Unclear Unclear Unclear Unclear Low Unclear
2006
Lee et al. [29], Unclear Unclear Unclear Unclear Unclear Low Unclear
2009
Segundo et al. Unclear Unclear High High High Unclear Unclear Potential baseline
[26], 2009 imbalance
Wu et al. [22], Unclear High High High High Low Unclear
2012
Wandalsen et al. Unclear Unclear Low Low Low Low Unclear
[23], 2017
Nayak et al. Unclear Unclear Unclear Unclear Unclear Low Unclear
[28], 2017
Wartna et al. Low Unclear High High Low Low Unclear
[16], 2017
Malizia et al. Low Low High High High Low Unclear
[17], 2018

outcomes data precluded us from performing a meta-

analysis. Second, no study provided information regarding newer-generation AHs in the management of pediatric AR.
Although the use of older AHs is discouraged in all
differences in therapeutic response among different age
interna- tional guidelines, they are still widely
groups, which represents a significant clinical question to
administered. The lack of additional benefit compared with
be addressed. Third, only five studies reported PRQLQ
newer AHs as observed in our study and the potential for
data whereas some studies assessed individual symptoms,
serious adverse events as observed in various observational
without providing data on TSS. Furthermore, the included
studies should reinforce the notion of limiting their use
RCTs were character- ized by insufficient reporting
only to special circumstances. AHs are one of the most
regarding withdrawals, adverse events, patients’
commonly used medications in the pediatric population in
comorbidities, and concomitant medications as well as by
general. However, most RCTs are placebo-controlled and
the absence of definitions regarding treatment failures.
outcome measures not necessarily important to patients are
Consequently, the overall safety profile and toler- ability of
frequently employed (e.g., single- dose studies with nasal
newer AHs compared with other active treatments could
provocation tests). The recent imple- mentation of mobile
not be assessed. Finally, only publications in the Eng- lish
technology seems to be a promising tool that could
language were included.
facilitate recording of symptoms and evalua- tion of
In this systematic review, we aimed to examine the state treatment response by the patients [33, 34]. We sug- gest
of the evidence regarding the benefit–risk profile of the
that RCTs with sufficient numbers of participants and
Table 3 Primary outcome measures in the included RCTs

Study, year Treatment Quality of life score [mean (SD)]

Patients’ symptoms score Investigators’ symptoms Symptoms
group (TSS/NSS) [mean (SD)] score (TSS/NSS) [mean score
(SD)] change from
baseline
Baseline End of Baseline End of Baseline Change from
[mean (SD)] baseline
follow-up follow-up
A. Newer antihistamines
Lee et al. CTZ 8.78 (2.01) ND NA − 5.54 48.65 (17.71) − 19.73
[29], 2009
(2.58) (11.04)
LCTZ 7.73 (2.94) ND NA − 3.30 (3.9) 52.09 (16.57) − 24.09
(16.82)
Nayak et al. CTZ a a a
7.5 (0.1) 5.5 (0.2) ND ND − 2.1 (0.2) NA
[28], 2017 a a a
LRD 7.6 (0.1) 5.8 (0.2) ND ND − 1.8 (0.2) NA
B. Newer vs other antihistamines
Boner et al. LRD ND ND 12.05 (3.48) 5.07 (5.22) ND NA
[21], 1989
DCPN ND ND 11.62 (2.31) 2.89 (2.67) ND NA
Tinkelman CTZ, OD 5.8 (3.0) ND 7.9 4.4 − 2.6 NA
et al. [20],
CTZ, BD 5.8 (3.3) ND 7.8 4.2 − 2.6 NA
1996 CPN 5.8 (3.2) ND 7.6 3.8 − 2.6 NA
Benedictis CTZ ND ND 8.92 (1.4) 2.36 (1.96) ND NA
et al. [18],
1997 OXD ND ND 9.31 (1.54) 2.6 (2.17) ND NA
Lai et al.
[19], 2002 CTZ 8.85 (1.97) 3.21 (1.9) ND ND ND 47.8 (20.1) 26.8 (15.3)
OXD 9.17 (2.65) 4.64 (1.9) ND ND ND 45.9 (16) 26.2 (17.9)
Wu et al.
[22], 2012 LRD ND ND 8.7 (1.69) 3.1 (2.97) − 64.5% NA
CPHD ND ND 7.4 (0.73) 5.0 (2.01) − 32.3% NA
Wandalsen
et al. [23], DLRD 8.9 (2.0) 2.1 (2.3) NA − 6.8 NA
2017 DCPN 9.1 (2.1) 1.9 (2.3) NA − 7.2 NA
C. Newer antihistamines vs other treatments
Baraldi et al. LCBN ND ND 7.2 5.6 ND NA
[14], 1998
BDP ND ND 7.5 2.8 ND NA
Bender and LRD ND ND ND ND ND
b
Milgrom
[15], 2004 FPANS ND ND ND ND ND
Hsieh et al.
[24], 2004 CTZ 8.86 (1.92) 3.31 (1.63) NA ND ND
MLK 8.99 (3.13) 6.16 (2.95) NA ND ND
Chen et al. CTZ 1.38 (0.41) ND NA − 0.6 (0.25) 76.15 − 31.15 (23.36)
[25], 2006
(16.25)
MLK 1.27 (0.44) ND NA − 0.43 67.4 (17.11) − 19.15 (20.71)
(0.23)
Wartna et al. LCTZ 12.4 (3.6) 4.63 NA ND NA
[16], 2017
FPANS 12.2 (2.6) 3.26 NA ND NA
FPANS 11.58 (3.2) 3.9 NA ND NA
c c
Malizia CTZ 8.56 (2.7) ND NA − 3.54 3 (1.21) − 0.69
8.21 (2.56) ND NA c 2.74 (1.13) c
et al. [17], BDP − 5.63 − 1.15
2018

BD bis in die (twice daily), BDP beclomethasone dipropionate nasal spray, CPHD cyproheptadine, CPN chlorpheniramine, CTZ cetirizine,
DCPN dexchlorpheniramine, DLRD desloratadine, FPANS fluticasone propionate aqueous nasal spray, LCBN levocabastine, LCTZ levoceti-
rizine, LRD loratadine, MLK montelukast, NA not applied, ND no data, NSS Nasal Symptoms Score, OD omne in die (once daily), OXD oxato-
mide, SD standard deviation, TSS total symptoms score
a
SE
b
No statistically significant differences for any of the 5 QoL domains
c
Least square mean change
 Table 4 Adverse events and withdrawals reported in included RCTs

Study, year Treatment groups Total (n) treatment discon- Treatment discon- Drug-related treat- Adverse
tinuations due to adverse tinuations (irrespective of ment discontinua- events
reason) events (n) tions (n)

A. Newer antihistamines
Sienra-Monge et al. [27], CTZ 2 2 0 2
1999 LRD 0 0 0 0
Lee et al. [29], 2009 CTZ 0 0 0 1
LCTZ 0 0 0 1
Nayak et al. [28], 2017 CTZ 18 6 1 19.7%
LRD 19 10 1 21.8%
B. Newer vs other antihistamines
Boner et al. [21], 1989 LRD 3 0 0 2
DCPN 1 0 0 6
Tinkelman et al. [20], 1996 CTZ (once) 6 in all groups 0 ND
CTZ (twice) 0 ND 33.6%
CPN 1 ND 38.1%
Benedictis et al. [18], 1997 CTZ 0 0 0 0
OXD 0 0 0 0
Lai et al. [19], 2002 CTZ 0 0 0 3
OXD 1 0 0 3
Wu et al. [22], 2012 LRD 4 0 0 0
CPHD 4 0 0 3
Wandalsen et al. [23], 2017 DLRD 6 1 0 44
DCPN 7 2 0 67
C. Newer antihistamines vs other treatments
Baraldi et al. [14], 1998 LCBN 1 ND ND ND
BDP 0 0 0 ND
Hsieh et al. [24], 2004 CTZ 0 0 0 1
MLK 0 0 0 1
Chen et al. [25], 2006 CTZ 0 0 0 2
MLK 0 0 0 0
Segundo et al. [26], 2009 DLRD 5 in all groups ND ND ND
MTS ND ND ND
MLK ND ND ND
Wartna et al. [16], 2017 LCTZ 15 in all groups 0 1 ND
FPANS 0 1 ND
FPANS
Malizia et al. [17], 2018 CTZ 3 0 0 0
BDP 0 0 0 0

BDP beclomethasone dipropionate nasal spray, CPHD cyproheptadine, CPN chlorpheniramine, CTZ cetirizine, DCPN dexchlorpheniramine,
DLRD desloratadine, FPANS fluticasone propionate aqueous nasal spray, LCBN levocabastine, LCTZ levocetirizine, LRD loratadine, MLK mon-
telukast, MTS mometasone, ND no data, OXD oxatomide

standardization of study protocols are needed, as well as

the development of a universal outcome-report system,
includ- ing QoL questionnaires, so as to guide therapeutics
strate- gies both at a population- and an individual-based
level.
5 Conclusions
The available evidence presented in this systematic review
underscores the favorable tolerability profile of newer AHs
in pediatric AR patients and provides insights into their
rela- tive efficacy compared with other active agents. In a
limited number of RCTs, newer AHs were generally more
effective
than montelukast, whereas INCS appeared superior to
newer AHs for most outcomes. However, taking into
consideration the multiple limitations of the summarized
published data, future studies implementing more
consistent methodology and reporting are warranted.
Author contributions Conceptualization of the study and design: LV,
MM; screening of papers: LV, ZM, EB; data extraction: LV, MM;
gen- eral supervision of the research team: MM; manuscript drafting
and final approval: all authors.
Funding There is no funding source.
Declarations
Conflict of interest The authors declare that they have no conflict of
interest.
Ethics approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Consent to participate Not applicable.
Consent for publication Not applicable.
Availability of data and material All data generated or analysed
during this study are included in this published article [and its
supplementary information files].
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