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\begin{document}

\title{NEW CONCEPTS IN PEDIATRIC RHINITIS}



\author[1]{Nikos Papadopoulos}%
\author[2]{Xenophon Aggelides}%
\author[1]{Sofia Stamataki}%
\author[3]{Emmanuel Prokopakis}%
\author[4]{Michael Katotomichelakis}%
\author[1]{Paraskevi Xepapadaki}%
\affil[1]{National and Kapodistrian University of Athens School of Medicine}%
\affil[2]{General University Hospital Attikon}%
\affil[3]{University of Crete School of Medicine}%
\affil[4]{Democritus University of Thrace}%


\vspace{-1em}



  
  \date{June 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Rhinitis and especially allergic rhinitis (AR) remain the most frequent
hypersensitivity condition, affecting up to a quarter of the population
and impacting upon the quality of life of individual patients and the
health economy. Data, especially in respect to underlying
pathophysiological mechanisms mainly derive from adult studies and are
subsequently extrapolated in the pediatric population. Therapeutic
algorithms for children with rhinitis in children are long based on the
same principles as in adults. We explore and describe novel aspects of
rhinitis, ranging from mechanisms to disease classification, phenotypes,
diagnostic and monitoring tools, and the use of treatments, with focus
on the traits of pediatric age groups.%
\end{abstract}%



\sloppy


\emph{Key message}

In this review, we describe novel aspects of pediatric rhinitis, from
mechanisms to phenotypes, diagnostic and monitoring tools, and the use
of treatments, focusing on the traits of pediatric age groups.

Type 2 innate lymphoid cells and defective Treg cells may play a
critical role in the pathogenesis of AR. Recent studies have identified
the neural pathways and mediators implicated in nasal hyperreactivity in
children, after exposure to environmental factors (pollutants, viruses,
allergens). Local allergic rhinitis is present and probably
underdiagnosed in pediatric populations. Polysensitization to inhalant
allergens is associated with multimorbidity of allergy-associated
diseases.

Personalized management of allergic rhinitis relies on the proper
assessment of disease control, a combination of multiple measurable
parameters with patient-reported outcomes, especially when validated for
children, being quite valuable. E-Health applications are
revolutionizing healthcare services, but data on their impact on
pediatric allergic diseases are scarce.

Second-generation antihistamines for mild and intranasal corticosteroids
for moderate-to-severe cases are the mainstay of allergic rhinitis
treatment in children. Data from real-world studies have confirmed that
allergen immunotherapy can prevent the occurrence of asthma in both
adults and children with \selectlanguage{greek}Α\selectlanguage{english}R. The need for global policies to mitigate
pollution and climate change is more relevant than ever.\emph{}

\emph{Introduction}

Allergic rhinitis (AR) remains the most frequent hypersensitivity
condition, affecting up to a quarter of the population and impacting
upon the quality of life of individual patients and the health economy
as a whole {[}1{]}. The complexity and variability of rhinitis is
particularly apparent in childhood, during which anatomical,
physiological, immunological and microbiological maturation, generates
clinical patterns that are difficult to generalize, but also to manage
{[}2{]}. Nevertheless, in the last few years, new concepts emerging
regarding the overall understanding and management of rhinitis are
having an influence on the way we see pediatric allergic rhinitis
today{[}3{]}. In this review, we explore and describe novel aspects of
rhinitis, ranging from mechanisms to disease classification, phenotypes,
diagnostic and monitoring tools and use of treatments, with particular
focus on the traits of pediatric age groups.

\emph{Mechanisms}

The immunological processes underlying IgE-mediated AR are not
dissimilar in children and adults, involving activation of the adaptive
immunity and class switching towards production of IgE antibodies.
Nevertheless, the vast amount of evidence derives from adult studies
with extrapolation on younger ages, while data from mechanistic studies
in children are limited. Of importance, despite innate immunity being
present from infancy, quantitative differences and qualitative
maturation, potentially affecting downstream responses have been
observed from early life though preschool and teenage years {[}4{]}. AR,
which constitutes the most studied phenotype of Pediatric rhinitis, is
predominantly defined by type 2 inflammation, mediated by type 2 innate
lymphoid cells (ILC2) and Th2 lymphocyte-driven responses locally and
systematically{[}5{]}. In addition, infiltration of multiple
inflammatory cells in the nasal mucosa including T cells, eosinophils,
neutrophils, and mast cells has been confirmed {[}6{]}.
Activated/damaged by aeroallergens nasal epithelial cells secrete matrix
metalloproteinase, IL-25, IL-31, IL-33 and thymic stromal lymphopoietin
(TSLP), which augment Th2 inflammation either via ILC2s or through
antigen presenting cells located underneath the nasal epithelium
{[}7{]}. ILC2s express receptors such as CRTh2, CD127 (the interleukin 7
receptor) and ST-2, the receptor for IL-33 and release particularly
IL-9, IL-5 and IL-13, further activating type 2 inflammation. ILC2s also
express high levels of GATA3, contributing to CD4+ Th2 activation and
subsequent release of IL-4, IL-5, IL-9 and IL-13, which maintain the
Th2-cell lineage and furthermore interact with B lymphocytes to induce
class-switching and synthesis of allergen-specific IgE (IgE
sensitization) {[}8{]}. On re-exposure cross---linking of sIgE on
effector cells induce the early, within 2-4 hours and subsequently the
late phase response characterized predominant by a sustained nasal
congestion {[}9{]}. In an ex-vivo model, the presence of ILC2s, myeloid
and plasmacytoid dendritic cells (mDCs and pDCs respectively) was
documented in the nasal mucosa of AR patients. Of importance, mDCs
promoted ILC2 function and proliferation by the IL-33/ST2 pathway, while
activation of pDCs suppressed ILC2 function through IL-6 in AR patients,
suggesting a differential role for distinct dendritic cell subtypes
{[}10{]}.

T regulatory cells (Tregs) are key mediators in immune regulation thus
prevent airway allergic inflammation. Inflammation in AR appears to be a
functional defect of Tregs which results in decreased production of
IL-10 and transforming growth factor (TGF)-\selectlanguage{greek}β\selectlanguage{english} {[}11{]}. Certain microRNAs
(miRNAs) mediate Treg function {[}12{]}. In children with AR, miR-155
promoted Treg differentiation in CD4+ T cells, while other miRNA mediate
response to respiratory infections, providing new potential treatment
targets {[}13{]}. Moreover, other less studied T cell populations, such
as the gammadelta (\selectlanguage{greek}\emph{γ δ)}\selectlanguage{english} T cells, that facilitate eosinophil
migration, were significantly more abundant in the nasal mucosa of AR
patients compared to controls, while their number and distribution were
positively associated with eosinophils, macrophages and mast cells
locally, suggesting an essential role in mucosal inflammation {[}14{]}.
Earlier studies showed a dysregulated pattern of Th1 transcription
factors such as STAT6+ and GATA3+ potentially contributing to the
enhance Th2 responses in AR patients compared to controls {[}15{]}. More
recently the Notch signaling pathway which downregulates FOXp3
expression and differentiation of T-reg was significantly elevated in AR
patients {[}16{]}.

Studies on the role of B-cells in the pathogenesis of AR, indicate a
significant skewing of circulating B-cell population towards memory B
cells with markedly increased expression of CD23, which facilitate
antigen presentation and IgE synthesis in AR patients {[}17{]};
nevertheless, other studies were not confirmatory of differences in
B-regulatory cell populations or Il-10 production {[}18{]}.

Recently, AR patients were shown to exhibit increased number of specific
sets of activated neutrophils\_CD16(high)-CD62L(dim)\_either locally or
systematically, resulting in T cell priming and enhancing eosinophil
migration {[}19{]}. Recently, activated neutrophils were shown to serve
as functional antigen presenting cells (APC) in late phase reactions and
activate allergen-specific effector CD4+ T-cells to synthesize
cytokines, thus they potentially contribute to magnified nasal allergic
inflammation {[}20{]}.

There is evidence that autophagy, a catabolic intracellular process
playing a substantial role in maintaining tissue and cellular
homeostasis, is implicated in immune response regulation and asthma
pathogenesis {[}21{]}. More recently, highly expressed autophagic
markers were observed in the upper airways of AR patients, strongly
associated with indices of nasal remodeling {[}22{]}.

\emph{Phenotypes and endotypes}

The concepts of phenotype and endotype have been increasingly used to
characterize variants under a wider disease umbrella, referring to
either the apparent differentiating features (phenotype) or the
underlying mechanisms (endotype). While disease variability is clearly
the norm rather than the exception in regards to most allergic diseases,
the realization that treatment response may vary radially between
groups, has given impetus to this approach {[}23{]}. Unfortunately, lack
of pathognomonic biomarkers, considerable overlap and unstable temporal
dynamics have not allowed, for the time being, the construction of
conclusive phenotype and/or endotype-based guidelines {[}24{]}.
Nevertheless, clear distinctions and differentiating factors can be
drawn, such as the hormonal or gustatory rhinitis -- all part of the
non-allergic rhinitis spectrum. A distinct pediatric example is rhinitis
in infants, which presents additional challenges in management choices,
requiring further evidence {[}25{]}.

\emph{Non allergic rhinitis (NAR)}

Non allergic rhinitis in children is poorly defined {[}26{]}. Previously
AR was clearly discriminated by NAR by means of increased local
total/local IgE specific levels and nasal eosinophils and these
differences were more pronounced in children than adults with AR,
suggesting that AR in children is a more distinct feature {[}27{]}.
However, inflammatory mediators related to different inflammatory
endotypes detected from nasal cytology cannot discriminate AR from NAR
adult patients {[}28{]}.

\emph{Local allergic rhinitis (LAR)} in children is an emerging disease,
highly underdiagnosed {[}29{]}. Increased levels of local IgE in the
nasal lavage fluid has been proposed as a useful biomarker in children
with suspected LAR {[}30{]}. Local production of ``T2'' inflammatory
mediators has been demonstrated following nasal allergen challenges in a
pediatric setting {[}31{]}. Nevertheless, AR and LAR share several
clinical and immune features, such as positive response to a nasal
allergen provocation test, increased risk of asthma occurrence and
increased nasal IgE production {[}32{]}. Moreover, the FcepsilonR1beta
genetic polymorphism has been linked both with LAR and AR prevalence
{[}33{]}.

\emph{Nasal hyperreactivity (NHR)} constitutes a cardinal clinical
feature both in AR and NAR {[}34{]} and has been previously documented
in children with allergic rhinitis, although respective techniques are
difficult to apply in clinical use and young ages {[}35, 36{]}. The most
well described pathogenetic mechanism involves a ``dysregulated'' neural
innervation network. In NAR and NHR, the role of the efferent component
via the activated transient receptor potential (TRP) ion channels
(receptor 1\_TRPA1 and subfamily V-TRPV1), induces the release of
neuropeptides, such as CGRP and substance P (SP), neurokinin A and B
from sensory nerve endings, which in turn induce sneezing, mucus
production and congestion {[}37{]}. In line, histological data are
indicative of increased expression of the aforementioned neuropeptides
of the nasal mucosa in patients with NHR and NAR {[}38{]}. Moreover, the
impact of environmental and microbial factors (i.e.; staphylococcus
Aureus enterotoxins) has been postulated for triggering local nerve
endings, more so in the presence of a disrupted epithelium barrier
{[}39{]}. It remains to be elucidated whether barrier dysfunction is a
primary (genetic) defect or secondary to infectious agents or allergens
{[}40, 41{]}.

\emph{Multimorbidity}

The term multimorbidity is used to indicate the clustering and
co-occurrence of different diseases in an individual, where,
conceptually, a ``primary'' disease in not obvious {[}42{]}.
Epidemiological data suggest that rhinitis/rhinoconjunctivitis, asthma
and dermatitis form a multimorbidity cluster, attributed to shared
genetic polymorphisms and pathogenetic mechanisms {[}43{]}. The MeDALL
(Mechanisms of the Development of ALLergy) project, including more than
12.000 children from 12 ongoing longitudinal cohort studies, clearly
showed that co-existence of asthma, rhinitis and eczema in the same
child is more prevalent than expected by chance {[}44{]}. IgE (poly)
sensitization was acknowledged as a fundamental component of a specific
phenotypical presentation, although not the sole one, significantly
associated with disease severity and multimorbidity risk {[}45{]}.
Moreover, prospective studies indicate that either sensitization per se,
or early polysensitization and co-sensitization to both perennial and
seasonal allergens, or to furry animals and molds, in case of sole
perennial sensitization, are associated with enhanced likelihood of AR
patients to present other allergy-associated diseases {[}46, 47{]};
however, it is well accepted that a significant proportion of children
with IgE sensitization do not develop any allergy-associated disease
{[}48{]}. In line, molecular studies identified eosinophilic-mediated
pathways, including IL-4 and~GATA3-related signals, with their
respective induced proteins as prominent mediators in allergic
multimorbidity {[}49{]}; nevertheless, more recently other cell types
and pathways have also been implicated in the AR-multimorbidity such as
TLR and IL-1 mediated responses {[}50{]}. In respect to the implicated
genes, several independent risk variants are identified with allergic
diseases specific effects have been identified, potentially by
dysregulating the expression of lymphocyte-mediated immunity {[}51{]}. A
recent meta-analysis of worldwide asthma-genome associations studies,
verified two loci (8q21.13 and 16p13.13) implicated in the comorbidity
of asthma and AR {[}52{]}.

In respect to allergy-associated disease progression, the MAS study
showed that parental history of allergy and broad polymolecular IgE
sensitization is a risk factor for presenting allergic multimorbidity
later in life {[}53{]}. From another perspective, AR combined with
ocular and skin allergic diseases is strongly associated with asthma
occurrence in adulthood, although this association wanes with age
{[}54{]}. Sex and puberty-related mechanisms are thought to be related
in the ``sex shift'' prevalence, from male to female predominance after
puberty, of allergic multimorbidity, as shown from individual
participant data (IPD) meta-analyses in the MeDALL and other cohorts
{[}55{]}. Of importance, patients with allergic multimorbidity present
increased disease burden, drug and healthcare use and costs in all age
groups {[}56{]}.

\emph{Control}

In accordance to the WHO proposal for chronic allergic diseases and in
parallel to the GINA guidelines for asthma, the concept of control was
introduced in AR, as a more feasible measure of both severity and
response to treatment {[}57, 58{]}. Most recent AR management algorithms
propose a stepwise approach based on the level of control achieved by a
therapeutic intervention {[}23, 59{]}. A series of criteria to evaluate
control were proposed in the PRACTAL report, including assessing symptom
severity, quality of life (QoL) by means of disease burden at school,
leisure and sleep, and upper respiratory function by objective
measurements such as nasal flow and/or patency. Information regarding
rescue medication use and (uncontrolled) comorbidities such as sinusitis
and/or asthma are also considered relevant {[}23{]}.

Patient reported outcome measures (PROMs) are currently acknowledged as
valuable tools for assessing disease morbidity in a standard clinical
setting. In respect to AR patients the Allergic Rhinitis Control Test
(ARCT) {[}60{]} and the Pediatric Control of Allergic Rhinitis and
Asthma test (CARATkids) {[}61, 62{]} have been validated for children
and adolescents while the Rhinitis Control Assessment Test (RCAT) is
currently validated only for adolescents {[}63{]}. The Visual Analogue
Scale (VAS) is validated for control assessment only in adults with AR,
however it can be used in all ages including preschool children by proxy
{[}64, 65{]}. Thus, the ARIA algorithm has implemented VAS measurements
for daily monitoring in a mobile app for patients over 12 years of age
{[}66{]}. Nevertheless, it is well known that PROMs can be influenced by
poor adherence to treatment, patient's perceptions regarding disease'
severity and the individual's psychosocial background {[}58{]}.

\emph{eHealth and mHealth}

eHealth refers to the application of information and communication
technologies (ICT) in healthcare services. The WHO acknowledges digital
technology potential and encourages health systems to endorse, improve
and prioritize its implementation to benefit in terms of accessibility,
quality, and affordability of health care {[}67{]}. The term ``mobile
health'' (mHealth) refers to the use of mobile, wireless technologies to
health practice and research in this respect {[}68{]}.

Smartphones are most promising in promoting and supporting public
health, as they are widely available, equipped with sophisticated
microprocessors and a range of sensors which can communicate with other
mobile devices, and provide access to the internet even in remote
locations. As of mid-2020, 3.5 billion smartphones are in use, by
approximately 41\% of the world's population {[}69{]}. In the USA, 95\%
of teens have access to a smartphone and 83\% use it for learning
purposes {[}70{]}.

AR is often regarded as trivial by both patients and physicians and thus
not always managed properly. mHealth applications (apps) aim at
implementing personalized medicine strategies to patients and caregivers
by monitoring symptoms, visualizing the burden of the disease, thus
improving health literacy, and ultimately engaging in self-management
and shared decision making {[}71{]}. Moreover, eHealth services can
override access barriers to healthcare and reduce costs while providing
healthcare professionals with real-life data on several aspects of the
disease and its impact that otherwise would be difficult to identify.

Adherence to treatment is a common problem in chronic respiratory
diseases, such as AR, moreover in adolescents {[}72{]}. In the MASK
study, where a mobile app was used to assess real-world data from
adolescents and adults with AR, non-adherence was observed in 69\% of
participants. The effect of e-health services on adherence to nasal
steroids was studied in a randomized trial including children 5-18 years
old with moderate-severe seasonal AR {[}73{]}. Patients that used an
internet-based telemonitoring system instead of hard copy diaries, were
significantly more adherent to treatment and better educated on their
disease, although symptom scores and QoL were not affected. In addition,
services such as updates on local pollen counts, online medical access
and SMS reminders in case of missed entries can be provided.

mHealth apps are a booming market and caution should be taken on their
credibility. Up to day, only a few apps on AR have been validated, while
safety and efficacy data are scarce {[}74{]}. A recent study showed that
the majority of mobile apps providing grass pollen forecasts are
inaccurate and potentially harmful {[}75{]}. mHealth apps are now
acknowledged as medical devices by both the EU and FDA {[}76{]},
although FDA reserves the concern of potentially applying regulations in
case of identifying risk on patient's safety {[}77{]}. In Europe, the
General Data Protection Regulation is also applied to manufacturers for
ensuring consumers' data privacy {[}78{]}. A stricter framework of
regulations should be expected soon.

Currently, only a few mobile apps that monitor symptoms of both AR and
asthma are available {[}74, 79{]}. Mask-air and Allergy Monitor allow
patients to assess the time course of symptoms relative to treatment and
the effect of AR on sleep, productivity, QoL, etc. by sharing
information digitally {[}80{]}. Additionally, notifications prompt
answering clinical questionnaires and treatment adherence daily
{[}81{]}. In case of symptom worsening, patients are alerted to step up
treatment or contact their doctor for consultation. These are key
features for encouraging self-awareness and self-empowerment, especially
in chronic diseases like AR, where patients or their caregivers are
responsible for treatment administration {[}82{]}. Mask-air, a validated
tool for assessing AR control in adolescents and adults, may also be
integrated into a Clinical Decision Support System that guides
clinicians into pertinent interventions depending on their patient's
status {[}83{]}. Evolving algorithms are currently exploring the
possibility of data input automation, to improve uptake {[}84{]}.

\emph{Treatment/medications}

Therapeutic algorithms for children with rhinitis in children are long
based on the same principles as in adults {[}85{]}. During the past two
decades ARIA has proposed an evolving guideline for the management of
patients with AR. More recently, intergraded care pathways (ICPs) have
been proposed, based on technology-evident information, providing a
self-care plan by a multidisciplinary group of health professionals
centered around the patient {[}59{]}. In specific, an algorithm based on
the visual analogue scale (VAS) for assessing rhinitis symptoms has been
revised by the ARIA expert group for (1) selection of pharmacotherapy
for patients with AR and (2) to tailor treatment depending on control
{[}86{]}.

ARIA has been the first guideline in the field of allergy to have used
the GRADE system to formally evaluate and appraise evidence. In its
latest update, an important step is the addition or real-life evidence,
supported through an mHealth application {[}59{]}. Real-life approaches
are increasingly used to complement randomized trials, in order to
expand the scope and evaluate external validity of the findings
{[}87{]}.

Treatment of AR includes allergen avoidance whenever possible, use of
medications and allergen specific immunotherapy (AIT)

\emph{Environmental interventions}

Certain interventions aiming at reduced allergen (pollen, molds, house
dust mites, pets) or irritant (pollutants, tobacco smoke) exposure have
long been incorporated into the guidelines {[}57{]}. There is
substantial evidence that sensitization/exposure to molds correlates
significantly with exacerbation of AR symptoms, even in children with
non-allergic rhinitis {[}29, 88{]}. Mold and cockroach allergen
reduction leading to subsequent symptom relief, can be achieved by
combined interventions {[}89{]}. In general, control of indoor allergen
exposure in allergic subjects, is effective when multifaceted and
demanding approaches are followed {[}90{]}. With regards to house dust
mite control, although previous meta-analyses showed minimal protective
effects of interventions aiming at exposure reduction, recent data
deriving from asthmatic patients indicate that certain actions, such as
mite-impermeable bed encasings, may confer significant protection form
disease morbidity {[}91{]}. It is plausible that early, prolonged and
personalized interventions, tailored to individual sensitization and
exposure status, can be clinically beneficial {[}92{]}.

Exposure to AR-relevant outdoor pollens and molds can be reduced by
limiting exposure and field activities during peak pollen days, however
such recommendation is often unrealistic in the pediatric population and
counters the goal of reinforcing daily activity in children {[}93{]}.

Various epidemiological studies have shown that exposure to volatile
organic compounds

from building materials and consumer products exacerbate rhinitis
symptoms and although data on the effects on rhinitis of air pollution
exposure per se are inconsistent {[}94, 95{]}, their capacity to
increase the allergenicity and immunogenicity of aeroallergens has been
shown {[}96{]}. Heightened CO2 levels and global climate change have
been strongly associated with increased prevalence of rhinitis symptoms,
by increase in pollen levels both in volume and in time; policy
adjustments have recently been addressed in order to decrease pollution
and mitigate their effects on allergy-associated diseases {[}97{]}

\textbf{Pharmacotherapy}

Medications used for the treatment of AR in children include
non-sedating H1-antihistamines, leukotriene receptor antagonists,
chromones, intranasal corticosteroids (INCSs) and combination of INCs
and azelastine.

\emph{Antihistamines}

Antihistamines are available as oral, intranasal, and ocular
preparations. Oral first generation, sedating antihistamines are no
longer recommended for the treatment of pediatric rhinitis due to their
impaired safety profile often associated with cardiac arrhythmias,
drowsiness, confusion, vision, and mental disorders etc. Of importance,
a recent report using data from the World Health Organization (WHO)
database, showed that the use of certain antihistamines has been
strongly associated with severe and unexpected reactions, more so in
preschoolers, where off-label use is frequent {[}98{]}. Second
generation antihistamines present a significantly improved safety
profile due to their high H1-receptor selectivity, low brain
permeability and longer duration of action {[}99{]}. Recently, cardiac
rhythm safety was documented for certain 2\textsuperscript{nd}
generation antihistamines, such as bilastine, cetirizine,
levocetirizine, ebastine, fexofenadine, loratadine, desloratadine,
mizolastine and rupatadine, even in the case of quadrupling the
recommended standard dose {[}100{]}. Antihistamines, act predominantly
on neutrally mediated symptoms such as sneeze, rhinorrhea, and nasal
itch. They should be used continuously, rather than no-demand in
persistent rhinitis patients {[}93{]}. Topical/nasal antihistamines have
rapid onset of action and minimum side effects {[}101{]}. In addition,
azelastine has been shown to have mast cell-stabilizing,
anti-leukotriene, anti-inflammatory and immunomodulatory effects
{[}102{]}.

\emph{Intranasal corticosteroids (INCs)}

INSc are the mainstay, particularly for moderate-to-severe allergic
rhinitis, due to their anti-inflammatory properties and significant
attenuation of late phase allergic reaction, thus acting on nasal
congestion {[}59, 103{]}. In respect to non-allergic rhinitis, a recent
Cochrane review showed that INCs use has only short term beneficial
effects on symptom severity, potentially depending on individual
phenotypic characteristics {[}104{]}. INCs have a rapid onset of action,
while the newer preparations such as mometasone furoate, fluticasone
furoate (FP) and fluticasone propionate present negligible systemic
absorption, thus they are mostly suitable for children {[}105{]}.
On-demand use can be an efficacious alternative in children with
seasonal AR symptoms, especially in families with safety concerns on
daily CS use, in order to increase adherence {[}106{]}. Recently, an
ARIA-EAACI statement suggested that, based on current evidence, patients
with COVID-19 infection should not discontinue their INCS prescribed for
AR symptoms {[}107{]}.

The recently formulated combination of azelastine and fluticasone
propionate (FP) has shown short and long term efficacy, with superiority
over FP both in speed of action and symptom relief, in children with AR
{[}108, 109{]}. Safety and tolerability have been documented in children
over 4-years of age, with minimal local adverse reactions such as
dysgeusia {[}110{]}. The combination has been granted approval for use
in children over 6 years of age by the U.S. Food and Drug Administration
{[}111{]}.

\emph{Antagonists of leukotriene receptors (LTRA)} block cysteinyl
leukotrienes receptors, which are important mediators of the
inflammatory response in both AR and asthma {[}112{]}. Several studies
have shown inferiority of LTRA compared to INCS and SGHA as therapeutic
choices in AR, while as of 03/04/2020 FDA required a boxed warning,
based on limited data reporting serious mental health side effects, thus
restricting montelukast use for AR {[}113{]}.

\emph{Biologicals}

Uncontrolled and severe forms of AR with substantial impact on quality
of life, have been considered as a potential target for biologicals
{[}114{]}. Recent reports and meta-analysis showed that anti-IgE
(omalizumab) significantly reduces rhinitis morbidity, severity and
rescue medication use and improve quality of life in uncontrolled
adolescents {[}115, 116{]}. There are also data indicating that
pre-treatment with anti-IgE in children undergoing seasonal AIT,
significantly decrease severe adverse reactions and improves daily
rhinitis symptoms {[}117{]}; nevertheless, Omalizumab is not indicated
in AR due to cost limitation.

Dupilumab is an anti-IL-4 monoclonal antibody currently approved for
uncontrolled atopic dermatitis and asthma {[}118{]}. In a Phase IIb
clinical trial dupilumab was efficient in ameliorating rhinitis symptoms
such as postnasal discharge, nasal blockage, runny nose and sneezing, in
patients with uncontrolled asthma and perennial AR {[}119{]}. The
results from a clinical study evaluating the efficacy of dupilumab as an
adjuvant therapy in patients undergoing AIT are awaited{[}120{]}.

\emph{Alternative therapies}

Nasal saline irrigation has long been perceived as an adjunct treatment
for rhinitis, although efficacy was only recently documented in a
meta-analysis with no reported adverse reactions {[}121{]}. Recently, a
real life study in children showed significant improvement of AR
symptoms and reduction of medications, as these were assessed by VAS and
CARAT, when nasal irrigation was added to standard treatment {[}122{]}.

Use of nasal filters in AR adults with grass allergy during a natural in
season exposure, provided significant efficacy, by means of improved
nasal symptom score, while safety and usability were also documented
{[}123{]}. It is however uncertain whether such intervention may be
tolerable in children. In respect to other `alternative' treatments,
acupuncture has moderate to high evidence of efficacy for the treatment
of subjects with rhinitis, while butterbar has shown showed moderate
beneficial effects on AR symptoms {[}124{]}. Capsaicin is efficient for
the treatment of non-AR in adults; however pediatric studies are lacking
{[}125{]}.

\emph{Immunotherapy}

Allergen immunotherapy (AIT), either in the subcutaneous (SCIT) or
sublingual (SLIT) form, has long been shown to result in improved AR
control in all age groups and aspires to be the only etiologic treatment
for respiratory allergies (allergic rhinitis (AR) and asthma) through
induction of immunologic tolerance {[}126{]} {[}127{]}. Pooled analyses
support the complementary use of AIT on pharmacotherapy in AR patients
moreover due to achievement of long-lasting therapeutic effect
{[}128{]}. Recently, data from a real-world study confirmed the
medication sparing effect and long-term symptom relief following AIT, in
a cohort of grass AR patients, including children. In agreement,
subcutaneous allergoid immunotherapy in house dust mite AR children
resulted in significant reduction in AR and asthma medication, even
after long-term cessation of AIT {[}129{]}.

Early-onset asthma is largely associated with IgE sensitization and AR
{[}130{]}, thus AIT has long been suggested as a disease modifying
strategy potentially preventing allergen sensitization and asthma
occurrence in children with AR {[}131{]}. Although early clinical
studies showed a preventive effect of AIT on the occurrence of new
sensitizations in children with rhinitis {[}132{]}, this is still
inconclusive {[}133{]}. A recent meta-analysis identified a short term
preventive effect of AIT on novel sensitization development;
nevertheless, the included studies were highly heterogenous {[}134{]}.
Nevertheless, the preventive effects of AIT on asthma development and
progression has been confirmed in real-world studies, assessing the
effect of SLIT immunotherapy in grass pollen subjects with AR {[}135{]}.
Moreover, a long-term randomized controlled trial, the Grazax Asthma
Prevention (GAP) study, {[}136{]}, showed significantly lower and
long-lasting incidence of asthma following 3-year AIT in grass AR
subjects, while significant lower levels of total and allergen specific
IgE and reductions in skin prick test response to grass were noted
{[}137{]}.

\textbf{Conclusion}

While the amount of knowledge on rhinitis and allergic rhinitis in
children is continuously increasing, novel approaches mostly deriving
from adult populations, have the potential of improving outcomes in
children. Considering that blinded randomized trials are more difficult
to perform in pediatrics, real-life approaches may be used to confirm
the usefulness of these proposals{[}138{]}. It is probable that, as in
the case of pediatric asthma {[}139{]}, prevention studies and
interventions on the natural history of rhinitis and/or respiratory
allergy as a whole, are the highest priority for research and health
policy.

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