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 Controlled 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
Data regarding the relevant clinical benefit of newer
antihistamines are scarce.
Newer antihistamines are safe and efficacious treatment
options for AR but not generally superior to intranasal
corticosteroids.
The observed heterogeneous nature of the included studies warrants further, more standardized research.
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/s4027​2-020-00419​-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
1 Introduction
Allergic rhinitis (AR) represents one of the most commonly
diagnosed chronic diseases in childhood and its prevalence
highly varies among countries [1–3]. Common symptoms
are categorized as nasal or non-nasal, whereas major comorbidities include but are not limited to other 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 manifestations, the patient’s age, as well as the presence of co-morbidities. Antihistamines (AHs) are widely used via the oral or
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L. Velentza et al.
intranasal route. Due to the lack of H1-receptor selectivity
and their ability to cross the blood–brain barrier, first-generation 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 Rhinitis 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 outcome 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-histamines) and the disease of interest (allergic rhinitis) (Appendix, see electronic supplementary material [ESM]).
and single-dose or challenge studies. Three investigators
(LV, ZM, and EB) independently screened the titles and
abstracts of the retrieved citations. Disagreements were
resolved after discussion with a fourth reviewer (MM). Title
and abstract screening was completed using Abstrackr [11].
Full-text screening was conducted independently by three
authors (LV, ZM, and EB). In case of disagreement, a fourth
reviewer was added (MM). Data extraction was performed
by two authors (LV and MM). We developed a data extraction form in a Microsoft ­Excel® spreadsheet, which included
information on study details, participants’ characteristics,
type of interventions and comparators, symptom scores and
QoL scores, adverse events, and treatment discontinuations.
2.3 Quality Assessment
Two authors (EB and ZM) independently assessed the quality of the selected RCTs using the Cochrane Risk of Bias
Tool [12]. The items investigated were rated as of ‘low’,
‘high’, or ‘unclear’ risk of bias, and included sequence generation, allocation concealment, blinding of the patients,
health care providers, and assessors, attrition, and selective
outcome reporting. We assigned a low risk of bias judgement to studies that provided sufficient details for each item.
For instance, RCTs with insufficient reporting (e.g., ‘doubleblind’) were deemed of unclear risk of bias for this item.
2.4 Summary Measures and Data Presentation
We present the results of data synthesis in tables. The
summary of outcome measures is based on three comparison groupings: (1) newer AHs versus newer AHs, (2)
newer AHs versus older AHs, and (3) newer AHs versus
other treatments (including corticosteroids and montelukast). RCTs that provided data on total symptoms score
(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 figures with the use of Engauge Digitizer software [13].
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 rhinitis; 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, decongestants, cromolyn, or immunotherapy as the only comparators,
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 presented in Fig. 1.
Antihistamines in Pediatric Allergic Rhinitis
3.2 Trial Characteristics
The majority of RCTs enrolled patients with PAR (11 out
of 16 trials). The evaluation of symptoms was performed by
the patients/parents and/or the investigators. The patients’
ages ranged from 2 to 18 years; 4 out of 16 studies enrolled
patients > 12 years old [14–17]. Cetirizine was the most
commonly administered AH (9 trials), followed by loratadine (5 trials), desloratadine (2 trials), levocetirizine (2 trials) and levocabastine (1 trial). Newer AHs were compared
with first-generation AHs in six RCTs [18–23], montelukast
in three RCTs [24–26], and INCS in four RCTs [14–16,
17]. Treatment duration ranged from 10 days to 3 months
and the doses of the drugs corresponded to those regularly
administered in clinical practice. Data regarding comorbidities and use of concomitant medications were generally not
Fig. 1 Study selection process using the PRISMA [10] flow chart
reported. Table 1 summarizes the main characteristics of
the included RCTs.
3.3 Quality Assessment
Overall, the included RCTs did not provide adequate details
for most risk-of-bias items (Table 2). Only four of the eleven
RCTs reported a computer-generated randomization code
[18, 19, 24, 23] and allocation concealment was generally
not clearly reported [20]. Four studies [19–22, 26] received
a ‘high risk’ score in blinding domains, whereas only one
study [23] had a ‘low risk’ score in all blinding domains.
Fifteen studies received a ‘low risk’ of bias due to incomplete outcome data, as the participant attrition rate across
the intervention and control groups was balanced and below
20%. Of note, Sienra-Monge et al. [27] replaced two patients
withdrawn from the study with new ones. In the absence of
L. Velentza et al.
protocol details, we could not adequately assess the likelihood of selective outcome reporting. Furthermore, the small
sample size in the majority of studies may lead to baseline
imbalances with regards to important prognostic factors.
3.4 Data Synthesis
3.4.1 Newer‑Generation Antihistamines
Cetirizine was compared with loratadine [27, 28] and levocetirizine [29] in three RCTs. Sienra-Monge and colleagues
[27] reported that both cetirizine and loratadine improved
sneezing, rhinorrhea, nasal obstruction, and nasal and ocular
pruritus according to the investigators’ assessment, whereas
cetirizine was more effective in reducing NSS, based on parents’ assessment, after 28 days of treatment. In the study by
Nayak and colleagues [28], both cetirizine and loratadine
provided comparable nasal and non-nasal symptom control
over a 2-week period. When cetirizine was compared with
levocetirizine, cetirizine-treated patients had a greater reduction in TSS after 12 weeks of treatment, with a more prominent effect on nasal congestion. There was no significant
difference between the two AHs in terms of QoL parameters,
based on the scores of the Pediatric Rhinoconjunctivitis
Quality of Life Questionnaire (PRQLQ) [29].
3.4.2 Newer‑Generation vs Older‑Generation
Antihistamines
Two RCTs compared cetirizine and oxatomide [18, 19]. In
the study by Benedictis et al. [18], cetirizine and oxatomide
had similar clinical effects in PAR, regarding both patients’
and investigators’ evaluation (sneezing, rhinorrhea, obstruction, pruritus) after 10 days of treatment, whereas in the
study by Lai et al. [19], cetirizine was shown to provide
greater TSS reduction after 12 weeks. No difference was
observed in PRQLQ scores. Additionally, cetirizine administration once and twice daily was compared with chlorpheniramine in a 2-week study including SAR patients [20].
TSS was reduced in all groups but no significant difference
among the three interventions was noted. Although nasal
congestion was not included in the TSS, it was significantly
improved in both cetirizine-treated and chlorpheniraminetreated patients in a similar manner.
Moreover, the efficacy of loratadine was compared with
dexchlorpheniramine [21] and cyproheptadine [22]. Loratadine administration showed improved clinical efficacy
compared with cyproheptadine, whereas loratadine and
dexchlorpheniramine offered comparable therapeutic relief
from nasal and non-nasal symptoms. In a 1-week trial, no
statistically significant difference was observed between
desloratadine and dexchlorpheniramine regarding symptom
control [23].
3.4.3 Newer‑Generation vs Other Treatments
Two RCTs evaluated the efficacy of cetirizine versus montelukast in different age groups of PAR patients [24, 25]. In
both trials, cetirizine appeared to cause a greater reduction in
TSS after 12 weeks of treatment whereas there was no difference between cetirizine and montelukast in PRQLQ scores.
Interestingly, montelukast was shown to be more effective
than cetirizine in improving night sleep quality, according to
patients’ diaries [25]. One RCT compared desloratadine with
montelukast and intranasal mometasone during a 4-week
treatment period [26]. According to patients’ assessment,
mometasone exhibited the greatest improvement in symptom control while desloratadine and montelukast provided
comparable clinical effects. Intranasal levocabastine and
oral cetirizine were compared with intranasal beclomethasone dipropionate in patients with PAR [14, 17]. In both
studies, the administration of beclomethasone dipropionate significantly improved nasal symptoms compared with
the AHs. In addition, beclomethasone dipropionate-treated
patients appeared to have significantly improved PRQLQ
scores compared with the cetirizine group, after 3 weeks of
treatment [17]. Finally, loratadine and levocetirizine were
compared with fluticasone propionate aqueous nasal spray
(FPANS) for the treatment of SAR [15, 16]. Treatment with
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 Questionnaire, 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 severity 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 medicationrelated treatment discontinuations, the number of patients
who dropped out was the same when comparing newer and
older-generation AH treatment groups [16, 20, 23, 28].
Antihistamines in Pediatric Allergic Rhinitis
Table 1 Trial characteristics
Study, year
Region
Disease type
Treatment
groups
Treatment dose
Treatment
duration,
weeks
Patients, n Age, years
mean (SD)
Female, %
Boner et al.
[21], 1989
Italy
Moderate/
severe SAR
(4–12 y)
LRD
2
21
7.6 (2.9)
33.3
2
19
7.8 (3.0)
36.8
2
63
8.6
35.5
2
62
9.1
29.5
CPN
CTZ
OXD
LCBN
BDP
CTZ
LRD
< 6 y, < 20 kg:
2.5 mg po OD
≥ 6 y, ≥ 20 kg:
5 mg po OD
< 6 y, < 20 kg:
0.5 mg po TD
≥ 6 y, ≥ 20 kg:
1 mg po TD
< 25 kg: 5 mg po
OD
≥ 25 kg: 10 mg
po OD
< 25 kg: 2.5 mg
po BD
≥ 25 kg: 5 mg po
BD
2 mg po TD
5 mg po OD
12.5 mg po BD
100 μg in BD
200 μg in BD
0.2 mg/kg po OD
0.2 mg/kg po OD
2
10.2 days
10.2 days
10 days
10 days
4
4
63
53
52
8
13
40
40
8.7
4.6 (1.1)
4.8 (1.1)
8.5 (0.7)
10 (0.8)
4.3 (1.2)
4.4 (1.1)
30.2
34
40.4
12.5
15.3
40
35
CTZ
OXD
KTF
LRD
FPANS
10 mg po OD
1 mg/kg po BD
1 mg po BD
10 mg po OD
100 μg/nostril OD
12
12
12
ND
ND
20
20
20
ND
ND
8.2 (2.4)
8.3 (2.0)
7.4 (1.4)
ND
ND
58.7
56.6
56.2
ND
ND
CTZ
MLK
CTZ
MLK
CTZ
LCTZ
10 mg po OD
5 mg po OD
5 mg po OD
4 mg po OD
10 mg po OD
5 mg po OD
12
12
12
12
12
12
21
21
20
20
27
26
8.0 (2.4)
8.2 (2.0)
4.5 (0.9)
4.5 (1.1)
8.2 (2.2)
8.8 (1.6)
40
35
40
45
42
37.5
DLRD
MTS
MLK
LRD
5 mg po OD
50 μg in OD
5 mg po OD
> 30 kg: 10 mg
po OD
≤ 30 kg: 5 mg po
OD
> 30 kg: 4 mg po
TD
≤ 30 kg: 2 mg po
TD
4
4
4
2
ND
ND
ND
30
9.9 (1.5)
8.1 (1.2)
9.7 (2.3)
5.8 (2.4)
42.9
28.6
40
61.5
2
30
6.6 (2.5)
34.8
DCPN
Tinkelman et al. USA
[20], 1996
SAR (6–11 y)
CTZ
CTZ
Benedictis et al. Italy
[18], 1997
PAR (2–6 y)
Baraldi et al.
[14], 1998
Italy
PAR (5–17 y)
Sienra-Monge
et al. [27],
1999
Lai et al. [28],
2002
Mexico
PAR (2–6 y)
Taiwan
Moderate/
severe PAR
(6–12 y)
USA
Bender and
Milgrom [15],
2004
Hsieh et al.
Taiwan
[24], 2004
SAR (8–17 y)
Chen et al. [25], Taiwan
2006
PAR (2–6 y)
Lee et al. [29],
2009
Taiwan
Segundo et al.
[26], 2009
Brazil
Moderate/
severe PAR
(6–12 y)
Moderate PAR
(6–12 y)
Wu et al. [22],
2012
Taiwan
Moderate PAR
(6–12 y)
PAR (2–12 y)
CPHD
L. Velentza et al.
Table 1 (continued)
Study, year
Region
Disease type
Treatment
groups
Treatment dose
Treatment
duration,
weeks
Patients, n Age, years
mean (SD)
Female, %
Wandalsen
et al. [23],
2017
Brazil
Moderate/
severe PAR
(2–12 y)
DLRD + PRD
< 6 y:
1.25 mg + 10 mg
OD
> 6 y:
2.5 mg + 20 mg
OD
1
105
ND
47.6
DCPN + BMZ
< 6 y:
1 mg + 0.125 mg
TD
> 6 y:
2 mg + 0.25 mg
TD
5 mg po OD on
demand
< 12 y: 100 μg in
≥ 12 y: 200 μg in
< 12 y: 100 μg in
OD
≥ 12 y: 200 μg in
OD
10 mg po OD
10 mg po OD
10 mg po OD
100 μg/nostril BD
1
105
ND
48.6
12
48
11.0 (3.3)
45.8
12
52
11.8 (3.1)
42.3
12
50
12.1 (3.3)
56
2
2
3
3
231
221
34
34
8.6 (1.7)
8.9 (1.6)
9.5 (2.4)
10.0 (2.4)
42.5
42.2
32
38
Wartna et al.
[16], 2017
Netherlands SAR (6–18 y)
LCTZ
FPANS (on
demand)
FPANS
Nayak et al.
[28], 2017
USA
SAR (6–11 y)
Malizia et al.
[17], 2018
Italy
PAR (6–14 y)
CTZ
LRD
CTZ
BDP
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)
4 Discussion
Pharmacotherapy represents the cornerstone of AR management. The aim of this systematic review was to examine the
state of evidence related to the benefits of newer AHs compared 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,
strongly recommend the use of newer AHs over older AHs
for both children and adults, as they are proven safer and less
sedative [2]. Results from systematic reviews and meta-analyses 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 moderate 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 enables a standardized and objective assessment of AR symptoms, 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 conclusions. In addition to the small number of RCTs, the clinical and methodological heterogeneity as well as the missing
Antihistamines in Pediatric Allergic Rhinitis
Table 2 Risk of bias in included studies
Study, year
Sequence
generation
Allocation
concealment
Blinding/
patients
Blinding/caregivers
Blinding/assessors
Attrition Selective
outcome
reporting
Boner et al.
[21], 1989
Tinkelman et al.
[20], 1996
Benedictis et al.
[18], 1997
Baraldi et al.
[14], 1998
Sienra-Monge
et al. [27],
1999
Lai et al. [19],
2002
Bender and
Milgrom [15],
2004
Hsieh et al. [24],
2004
Chen et al. [25],
2006
Lee et al. [29],
2009
Segundo et al.
[26], 2009
Wu et al. [22],
2012
Wandalsen et al.
[23], 2017
Nayak et al.
[28], 2017
Wartna et al.
[16], 2017
Malizia et al.
[17], 2018
Unclear
Unclear
High
High
Unclear
Low
Unclear
Unclear
Low
High
High
High
Low
Unclear
Unclear
Unclear
Low
Low
Low
Low
Unclear
Unclear
Unclear
High
Unclear
Unclear
Low
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Low
Unclear
Low
Unclear
Unclear
Unclear
Unclear
Low
Unclear
Unclear
Unclear
Low
Low
Low
Unclear
Unclear
Low
Unclear
Unclear
Unclear
Unclear
Low
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Low
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Low
Unclear
Unclear
Unclear
High
High
High
Unclear
Unclear
Unclear
High
High
High
High
Low
Unclear
Unclear
Unclear
Low
Low
Low
Low
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Low
Unclear
Low
Unclear
High
High
Low
Low
Unclear
Low
Low
High
High
High
Low
Unclear
outcomes data precluded us from performing a meta-analysis.
Second, no study provided information regarding differences
in therapeutic response among different age groups, which
represents a significant clinical question to be addressed.
Third, only five studies reported PRQLQ data whereas some
studies assessed individual symptoms, without providing data
on TSS. Furthermore, the included RCTs were characterized by insufficient reporting regarding withdrawals, adverse
events, patients’ comorbidities, and concomitant medications
as well as by the absence of definitions regarding treatment
failures. Consequently, the overall safety profile and tolerability of newer AHs compared with other active treatments
could not be assessed. Finally, only publications in the English language were included.
In this systematic review, we aimed to examine the state
of the evidence regarding the benefit–risk profile of the
Other potential
sources of bias
Patients withdrawn were
replaced
Potential baseline
imbalance
newer-generation AHs in the management of pediatric AR.
Although the use of older AHs is discouraged in all international guidelines, they are still widely administered. The lack
of additional benefit compared with newer AHs as observed
in our study and the potential for serious adverse events as
observed in various observational studies should reinforce
the notion of limiting their use only to special circumstances.
AHs are one of the most commonly used medications in the
pediatric population in general. However, most RCTs are
placebo-controlled and outcome measures not necessarily
important to patients are frequently employed (e.g., singledose studies with nasal provocation tests). The recent implementation of mobile technology seems to be a promising
tool that could facilitate recording of symptoms and evaluation of treatment response by the patients [33, 34]. We suggest that RCTs with sufficient numbers of participants and
L. Velentza et al.
Table 3 Primary outcome measures in the included RCTs
Study, year
Treatment
group
A. Newer antihistamines
Lee et al.
CTZ
[29], 2009
LCTZ
Patients’ symptoms score
(TSS/NSS) [mean (SD)]
Investigators’ symptoms
score (TSS/NSS) [mean
(SD)]
Baseline
End of
follow-up
Baseline
8.78 (2.01)
ND
NA
7.73 (2.94)
ND
NA
Nayak et al. CTZ
7.5 (0.1)a
5.5 (0.2)a
a
[28], 2017 LRD
5.8 (0.2)a
7.6 (0.1)
B. Newer vs other antihistamines
Boner et al. LRD
ND
ND
[21], 1989 DCPN
ND
ND
CTZ, OD
5.8 (3.0)
ND
Tinkelman
et al. [20], CTZ, BD
5.8 (3.3)
ND
1996
CPN
5.8 (3.2)
ND
CTZ
ND
ND
Benedictis
et al. [18], OXD
ND
ND
1997
Lai et al.
CTZ
8.85 (1.97) 3.21 (1.9)
[19], 2002 OXD
9.17 (2.65) 4.64 (1.9)
Wu et al.
LRD
ND
ND
[22], 2012 CPHD
ND
ND
8.9 (2.0)
2.1 (2.3)
Wandalsen DLRD
et al. [23], DCPN
9.1 (2.1)
1.9 (2.3)
2017
C. Newer antihistamines vs other treatments
ND
ND
Baraldi et al. LCBN
[14], 1998 BDP
ND
ND
ND
ND
Bender and LRD
Milgrom
FPANS
ND
ND
[15], 2004
Hsieh et al. CTZ
8.86 (1.92) 3.31 (1.63)
[24], 2004 MLK
8.99 (3.13) 6.16 (2.95)
Chen et al.
CTZ
1.38 (0.41) ND
[25], 2006
MLK
1.27 (0.44) ND
Wartna et al. LCTZ
[16], 2017 FPANS
FPANS
CTZ
Malizia
et al. [17], BDP
2018
12.4 (3.6)
12.2 (2.6)
11.58 (3.2)
8.56 (2.7)
8.21 (2.56)
4.63
3.26
3.9
ND
ND
End of
follow-up
Symptoms
Quality of life score [mean (SD)]
score
change from
baseline
Change from
[mean (SD)] Baseline
baseline
− 5.54
(2.58)
− 3.30 (3.9)
48.65 (17.71)
52.09 (16.57)
− 19.73
(11.04)
− 24.09
(16.82)
ND
ND
ND
ND
− 2.1 (0.2)a
− 1.8 (0.2)a
NA
NA
12.05 (3.48)
11.62 (2.31)
7.9
7.8
7.6
8.92 (1.4)
9.31 (1.54)
5.07 (5.22)
2.89 (2.67)
4.4
4.2
3.8
2.36 (1.96)
2.6 (2.17)
ND
ND
− 2.6
− 2.6
− 2.6
ND
ND
NA
NA
NA
NA
NA
NA
NA
ND
ND
8.7 (1.69)
7.4 (0.73)
NA
NA
ND
ND
3.1 (2.97)
5.0 (2.01)
ND
ND
− 64.5%
− 32.3%
− 6.8
− 7.2
47.8 (20.1)
45.9 (16)
NA
NA
NA
NA
7.2
7.5
ND
ND
5.6
2.8
ND
ND
ND
ND
ND
ND
NA
NA
NA
NA
NA
ND
ND
− 0.6 (0.25)
NA
− 0.43
(0.23)
ND
ND
ND
− 3.54c
− 5.63c
ND
ND
76.15
− 31.15 (23.36)
(16.25)
67.4 (17.11) − 19.15 (20.71)
NA
NA
NA
NA
NA
26.8 (15.3)
26.2 (17.9)
b
NA
NA
NA
3 (1.21)
2.74 (1.13)
− 0.69c
− 1.15c
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 levocetirizine, LRD loratadine, MLK montelukast, NA not applied, ND no data, NSS Nasal Symptoms Score, OD omne in die (once daily), OXD oxatomide, SD standard deviation, TSS total symptoms score
a
b
c
SE
No statistically significant differences for any of the 5 QoL domains
Least square mean change
Antihistamines in Pediatric Allergic Rhinitis
Table 4 Adverse events and withdrawals reported in included RCTs
Study, year
A. Newer antihistamines
Sienra-Monge et al. [27],
1999
Treatment groups Total (n) treatment discon- Treatment discontinuations (irrespective of tinuations due to adverse
events (n)
reason)
CTZ
LRD
Lee et al. [29], 2009
CTZ
LCTZ
Nayak et al. [28], 2017
CTZ
LRD
B. Newer vs other antihistamines
Boner et al. [21], 1989
LRD
DCPN
Tinkelman et al. [20], 1996 CTZ (once)
CTZ (twice)
CPN
Benedictis et al. [18], 1997 CTZ
OXD
Lai et al. [19], 2002
CTZ
OXD
Wu et al. [22], 2012
LRD
CPHD
Wandalsen et al. [23], 2017 DLRD
DCPN
C. Newer antihistamines vs other treatments
Baraldi et al. [14], 1998
LCBN
BDP
Hsieh et al. [24], 2004
CTZ
MLK
Chen et al. [25], 2006
CTZ
MLK
Segundo et al. [26], 2009
DLRD
MTS
MLK
Wartna et al. [16], 2017
LCTZ
FPANS
FPANS
CTZ
Malizia et al. [17], 2018
BDP
Drug-related treatment discontinuations (n)
Adverse events
2
0
0
0
18
19
2
0
0
0
6
10
0
0
0
0
1
1
2
0
1
1
19.7%
21.8%
3
1
6 in all groups
0
0
0
0
1
0
0
0
0
0
0
1
2
0
0
ND
ND
ND
0
0
0
0
0
0
0
0
2
6
ND
0
0
0
0
0
ND
ND
ND
0
0
ND
0
0
0
0
0
ND
ND
ND
1
1
ND
ND
1
1
2
0
ND
ND
ND
ND
ND
0
0
0
0
0
0
0
0
0
1
4
4
6
7
1
0
0
0
0
0
5 in all groups
15 in all groups
3
0
33.6%
38.1%
0
0
3
3
0
3
44
67
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 montelukast, MTS mometasone, ND no data, OXD oxatomide
standardization of study protocols are needed, as well as the
development of a universal outcome-report system, including QoL questionnaires, so as to guide therapeutics strategies 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 relative efficacy compared with other active agents. In a limited
number of RCTs, newer AHs were generally more effective
L. Velentza et al.
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; general supervision of the research team: MM; manuscript drafting and
final approval: all authors.
8.
9.
10.
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.
11.
12.
Consent to participate Not applicable.
13.
Consent for publication Not applicable.
14.
Availability of data and material All data generated or analysed during
this study are included in this published article [and its supplementary
information files].
15.
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