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\begin{document}

\title{OTITIS MEDIA IN CHILDREN: WHICH PHENOTYPES ARE MOST LINKED TO ALLERGY? A
SYSTEMATIC REVIEW}



\author[1]{Eugenio De Corso}%
\author[2]{Elena Cantone}%
\author[3]{Jacopo Galli}%
\author[4]{VERONICA SECCIA}%
\author[5]{DANIELA LUCIDI}%
\author[6]{TIZIANA DI CESARE}%
\author[7]{GIANCARLO OTTAVIANO}%
\author[8]{Bruno Sergi}%
\author[6]{GAETANO PALUDETTI}%
\author[3]{Anna  Fetoni}%
\affil[1]{Policlinico Universitario Agostino Gemelli}%
\affil[2]{University of Naples Federico II School of Medicine and Surgery}%
\affil[3]{Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia}%
\affil[4]{Azienda Ospedaliero Universitaria Pisana}%
\affil[5]{University Hospital Modena}%
\affil[6]{University Hospital Agostino Gemelli}%
\affil[7]{Università degli Studi di Padova}%
\affil[8]{Policlinico A Gemelli}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: allergic rhinitis is a common childhood disease responsible
for a major impact on quality of life and health care resources. Many
hypotheses have been proposed to explain the link between allergy and
otitis media, although a definitive mechanism has not been identified
yet. One of the major critical points is that authors failed in
distinguishing among different phenotypes of middle ear inflammation.
This review pointed out evidence from the laboratory and clinical
experience to link allergy to different phenotypes of otitis media in
children. Methods: we performed a systematic review in accordance with
the Preferred Reporting Items for Systematic Review and Meta-Analysis
(PRISMA) process. Our search yielded 3010 articles that were finally
screened. This resulted in 20 publications of which the full texts
included for the qualitative analysis based on different phenotypes of
otitis media. Results: clinical evidences and analyses of biomarkers
suggested that allergy may be linked to some phenotypes of otitis media
and, in particular, to otitis media with effusion and acute
re-exacerbations in children with middle ear effusion. It was not
possible to perform the analysis for allergy and acute and chronic
otitis media because of paucity and heterogeneity of data. Conclusion:
Allergy should be considered in the diagnostic work up of different
phenotypes of otitis media. Clinicians should evaluate prompt and
accurate treatment of allergy in improving outcomes, although futures
studies are required to increase evidence supporting that anti-allergy
treatment may be effective in the recovery and outcome of otitis media
with effusion.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Allergic rhinitis (AR) is the most frequent chronic condition in
childhood and adolescence, its prevalence varies from 1.5\% up to
42\%,\textsuperscript{1,2}reaching 8\% in 6--8-year-old children and up
to 35\% in 13--14 -year-old children, with a continuous increase in the
developed world.\textsuperscript{3-5}

Pediatric AR may have a significant impact on global quality of life,
including school performance, sleep disorders, and emotional
health.\textsuperscript{2} Furthermore, over the years many authors
tried to correlate allergy with the onset of the most frequent upper
airway disorders in childrenand in particular of otitis media.It has
been estimated that more than 75\% of AR children develop concomitant
conditions, including conjunctivitis, asthma, atopic dermatitis, upper
respiratory tract infections (URTI), rhinosinusitis, adeno-tonsillitis,
and otitis media, indicating that AR is not an isolated condition, but
it is part of a systemic disease,even though conflicting results are
frequently reached.\textsuperscript{6,7}

AR is an inflammatory condition of the nasal mucosa provoked by
environmental allergens interacting with immunoglobulin (Ig)E in
sensitized subjects. Repeated~exposure to allergens may lead to
long-term changes in systemic and local~inflammation, including
up-regulation of nasal eosinophils and~allergen-specific IgE, increased
levels of adhesion molecules in airway mucosa and
enhanced~systemic~response
to~allergen~challenge.\textsuperscript{8}Consequently, it is not
surprising that AR has been historically associated with comorbid upper
airway diseases,among which otitis media.\textsuperscript{9}

The association between AR and otitismedia isstill controversial.
However, AR can cause swelling of nasal mucosa resulting in Eustachian
tube (ET) dysfunction and subsequently otitis, in particular otitis
media with effusion (OME) characterized by inflammation of the mucous
membrane with fluid collection in the middle ear in the absence of acute
infection. If untreated, OME may be complicated with hearing loss
especially conductive type, poor school performance, behavioral
problems, and reduced the quality of life.\textsuperscript{10}

The aim of the present systematic review was toevaluate clinical and
laboratory evidence,linking allergy to different phenotypes of otitis
media in children. Allergy in these conditions may be evocated not only
as risk, but also as a worsening factor. Poorly controlled AR might
exacerbate comorbidities, whereas early diagnosis and its adequate
treatment might improve these disorders having a substantial impact on
the quality of life of children.\textsuperscript{8}

\textbf{METHODS}

\emph{Search strategy}

This systematic review was conducted in accordance with the Preferred
Reporting Items for Systematic Review and Meta-Analysis (PRISMA) process
to identify published experimental and clinical articles about allergy
and otitis media in children. Manuscript were screened primarily by Ovid
Medline and EMBASE and from other sources (Pubmed Central, Cochrane
review, Web of Science, and Google Scholar) and published from January
2000 to September 2020. Literature searches were performed in September
2020.

We performed two different searches using MeSH-terms. One group of
authors focused on \emph{experimental studies} matching the term as
follow: {[}(Eustachian tube disfunction) OR (middle ear cytokine) OR
(middle ear inflammation){]} AND {[}(allergy) OR (allergic rhinitis) OR
(atopy) OR (atopic) OR (allergic children){]} AND {[}(children) OR
(childhood) OR (pediatric){]}. The second group of authors focused
on\emph{clinical studies,} matching the term as follow: {[}(acute otitis
media) OR (chronic otitis media) OR (otitis media with effusion) OR
(recurrent acute otitis media) OR (middle ear effusion) OR (chronic
suppurative otitis media) OR (otitis){]} AND {[}(allergy) OR (allergic
rhinitis) OR (atopy) OR (atopic) OR (allergic children) OR (non-allergic
children) OR (immunoglobulin E) OR (immunotherapy) OR (antihistamine)
AND (children) OR (childhood) OR (pediatric){]}.

\emph{Study selection}

In the first screening authors read the title and abstract of articles
selecting those being as inclusive as possible. The abstracts were
screened independently by reviewers of the two groups. Any disagreements
were resolved by consensus. Inclusion and exclusion criteria were
established before the selection of relevant studies. The inclusion
criteria were primary research (including descriptive studies,
observational studies, randomized trials, and basic science articles),
published after January 2000, addressing allergy and otitis media in
children. Furthermore, we questioned whether anti-allergy treatment may
prevent the occurrence of otitis media or improve its specific
management.

We excluded secondary research studies (e.g., review articles or
systematic review), case studies, newspaper article, lecture, letter,
comment, personal narrative, consensus conference, editorial. Only
articles with full text available were included. Additional studies were
manually identified from the reference lists of retrieved literature. We
excluded all the article that did not meet the inclusion criteria or
deal directly with the issue investigated. Based on our review was not
possible differentiate between atopy or sensitization and allergy. We
included only English-language peer-reviewed papers.

\textbf{RESULTS AND DISCUSSION}

The details of the systematic search performed are shown in figure 1. In
total, our search yielded 3010 articles after duplicates removal. We
excluded 1169 articles due to time of publication and type of article,
then 1841 were finally screened. This resulted 20 publications included
in a qualitative analysis. We summarized in tables the included studies
per each phenotype classifying evidence using GRADE methodology. No
studies were included in a quantitative synthesis (meta-analysis).

\emph{Allergy and middle ear inflammation in children}

Based on signs and symptoms,otitismedia (OM) can be subclassified into
different phenotypes:acute otitis media (AOM), otitis media with
effusion (OME), chronic OME (cOME) and chronic suppurative otitis media
(CSOM). AOM is generally characterized by rapid onset of signs and
symptoms of inflammation in the middle ear accompanied by middle ear
effusion (MEE); OME is defined as MEE without signs and symptoms of
acute inflammation. AOM episodes are self-limited, but some children are
at high risk for frequently recurring AOM episodes (RAOM) and in a
sub-group of patients, MEE may be delayed for months to years and may
evolve in cOME.\textsuperscript{11,12}Eventually, CSOM may occur with or
without cholesteatoma and clinical history of both conditions can be
very similar in children.

There are many predisposing factors for otitis in children, including
genetic predisposition, young age, male gender, very low birth-weight,
pre-term birth, immature function of the immune system, little or no
breastfeeding, upper airway-infections, day-care attendance, older
siblings, tobacco smoke exposure, adenoid hypertrophy, craniofacial
abnormalities, dysfunction of the ET,use of a pacifier or push-and-pull
plastic bottle caps, and allergy.\textsuperscript{13} Among risk
factors, the role of allergy has been thoroughly investigated and has
been clearly implicated in pathogenesis of OME, whereasmore
controversial findingsare available for AOM.

\emph{Allergy and AOM or OME}

\emph{Physiopathologic theory linking allergy to increased risk of
middle ear inflammation.}

Multiple hypotheses may explain the link between allergy and otitis
media, even if a definitive mechanism has not been
identified.\textsuperscript{14} The ``shock organ'' hypothesis
speculates that the middle ear may act as a shock organ responding to
antigen similar to nasal and bronchial mucosa, according to the unified
airway theory hypothesizing that the respiratory tract may behave as one
integrated unit. The ``Eustachian tube dysfunction'' theory speculates
that allergy may lead to edema of nasal mucosa, muco-ciliary impairment,
and ET ostium blockage, reducing middle ear ventilation and continuous
negative pressure, and promoting otitis. Eventually, the most recent
hypothesis is that ET dysfunction may be related to chronic inflammation
of lymphoid tissues such as adenoids with retrograde aspiration of
bacteria and nasopharyngeal secretion into the middle ear cavity.

\emph{Laboratory Evidence and biomarkers linking allergic inflammation
to increased risk of middle ear inflammation.}

Several authors have tried to show an association between allergy and
middle ear inflammation by animal studies as well as experimental human
models. The phenotype more frequently involved in these studies was OME
as reported in table 1. The inflammatory substrate observed in atopic
OME patients seems to be similar to that of the late phase of allergic
response in AR and asthma patients.Several
authors\textsuperscript{15-17}have demonstrated a higher percentage of
TH-2 mediators, (eosinophils, T-lymphocytes, IL-4 and IL-5), as well as
a hyper-expression of major basic protein and eosinophilic cationic
protein in the middle ear fluid, adenoid tissue, and middle ear mucosa
in atopic versus non-atopic children with OME. Several other cytokines
as tumor necrosis factor alfa, IL-1b, IL-13, IL-6, and IL-8 are elevated
in middle ear fluid in children with OME.\textsuperscript{18} Smirnova
et al. have demonstrated that these cytokines might play a role as
molecular regulators of middle ear inflammation switching the acute
phase of inflammation to the chronic
stage.\textsuperscript{19}Furthermore, histologic studies have
demonstrated that there is an increased level of IL-4, IL-5, and
eosinophils not only in middle ear fluid but also at both ends of the ET
suggesting again the possibility of activating an allergic mechanism in
sensitized children.\textsuperscript{20}Accordingly, some authors
observed a significantly lower rate of neutrophils and IFN-gamma
(predominant in TH-1 inflammatory response) in atopic vs non-atopic
OME.\textsuperscript{16}

Previous authors have demonstrated that allergic inflammation in the ear
of children with OME is similar to that of other target organs
confirming the hypothesis that ear is part of unified
airway.\textsuperscript{21, 22}In addition, animal models demonstrated
that middle ear effusion can be preventedby inhibiting allergy
cytokines.\textsuperscript{22}

Experimental evidence showed that trans-tympanic histamine challenge
compromise muco-ciliary clearance and ventilating function of ET in rat
models.\textsuperscript{23}In particular, Hardy et
al.\textsuperscript{24} demonstrated that late-phase allergy leads to
significant ET dysfunction and subsequent formation of effusion by
impairing the ventilatory and clearance function of the ET. Furthermore,
Pollok et al.\textsuperscript{25} demonstrated that the late-phase
allergic inflammatory response and middle ear effusion may be prevented
by pre-treatment with soluble interleukin (IL)-4 receptors (sIL-4R) and
more modestly with IL-5 antibodies (IL-5Ab).

The most relevant articles included in the qualitative analyses are
summarized in table 1. The majority of articles supports the link
between allergy and otitis media with effusion.

\emph{Clinical evidence linking allergy to increased risk of middle ear
inflammation}

From a clinical point of view, it is extremely important to distinguish
among different phenotypes of otitis media, AOM, RAOM and OME. Clinical
evidence from the literature seems to be in favor of an association
between allergic rhinitis/atopic status and OME; whereas results about a
hypothetical correlation with AOM and RAOM are contradictory and
inconclusive because one of the major critical points is that some
authors fail to distinguish among the different phenotypes of middle ear
inflammation in children (articles included in the qualitative analyses
are reported in table 2). Salah et al. did not find evidence linking
atopy or allergy to AOM/RAOM\textsuperscript{26}, whereas other
authors\textsuperscript{10, 27, 28} demonstrated that children with AR
had a significantly higher risk of otitis, even if they did not
distinguish among different phenotypes of OM. Accordingly,
authors\textsuperscript{29,30} demonstrated that atopic children may
have a significantly increased risk of recurrent or persistent OM
needing repeated tympanostomy tube insertions without distinguishing
between AOM and OME. Finally, in a recent study authors demonstrated
that RAOM was significantly associated with turbinate hypertrophy in
children suffering from allergic rhinitis.\textsuperscript{31}

On the other hands most authors seem to be in agreement with
experimental data confirming also a significant clinical association
between allergy and OME. Several
manuscripts\textsuperscript{32-35}suggested that AR may specifically
influence the onset of OME. Authors demonstrated that AR prevalence was
notably higher among OME patients than in the controls, with remarkable
differences in eosinophil counts and serum IgE concentrations in the
allergic rhinitis patients, compared to other OME
patients.\textsuperscript{36} Cheng et al. in a metanalysis including
cross-sectional and case-controlled studies confirmed that OME and AR
are prevalent in pre-school and school-aged children and that allergy is
a risk factor for OME.\textsuperscript{32}Roditi et al. interestingly
demonstrated that allergic rhinitis was significantly associated to OME
even age was demonstrated as an effect modifier of the association;
indeed a significant relationship was observed in children 6 years of
age and older, whereas there was no significant association in younger
children.\textsuperscript{37}Furthermore, studies have documented thatAR
patients have a higher risk of~ET~dysfunction, particularly during
childhood, than non-allergic ones.\textsuperscript{27, 38}Therefore, AR
seems to be a common risk factor in children with OME and there is
significant hearing loss compared to non-AR children with OME; in
addition, the hearing levelimproved significantly with medical
therapy.\textsuperscript{10}

Recently, Torretta et al.\textsuperscript{39} demonstrated that allergy
or atopy were significantly higher in otitis-prone children with OME
than in those with simple RAOM: atopy was found in 73\% of the children
with both RAOM and OME versus 39.5\% of those with simple RAOM, while
allergy was found in 60\% and 36\%, respectively. The
authors\textsuperscript{39} suggested that children with both RAOM and
OMEare clinically different from children with simple RAOM, as they have
a more complex clinical presentation that may be sustained by underlying
allergy or atopy. Interestingly, in the same manuscript, children with
both RAOM and OME were more frequently affected by adenoidal hypertrophy
(AH) (p~= 0.016). This is the second critical point that makes it
difficult to analyze data in this regard, since ET dysfunction and AH
are frequently associated with OME. Quaranta et
al.\textsuperscript{40}analyzed children with AH showing that 60\% had
OME and that AR was rarely present in this group. AH may constitute a
concomitant clinical entity associated with allergy that exponentially
promotes the development of OME and may be a confounding factor in the
analysis. Accordingly, some authors demonstrated that adenoid tissue and
middle ear mucosa share the same inflammatory pattern in allergic
children affected by OME.\textsuperscript{33}

Most relevant clinical
articles\textsuperscript{33-37,39-42}investigating specifically
association between OME and allergy and included in the qualitative
analyses are summarized in table 3.

\emph{Does anti-allergy treatment prevent middle ear inflammation?}

The large amount of experimental and clinical data supports the
hypothesis that treatment of atopy can have a beneficial effect on some
phenotype of otitis, and in particular in OME.
Accordingly,Mari\selectlanguage{ngerman}ño-Sánchezet al.supported the concept that AR is
associated to a higher severity and duration of OME andthat anti-allergy
treatment may improve outcomes in OME
patients.\textsuperscript{4}However, it is difficult to demonstrate that
treatment of allergy can affect OME outcomes due to the contributing
factor of ET dysfunction and AH in the pathophysiology of OME.

Several studies have evaluated the role of oral steroids in OME
describing a potential benefit\textsuperscript{43}, although long term
outcomes are not as clearly established as short term
ones.\textsuperscript{44} Children treated with intranasal mometasone
experienced higher resolution rates of OME compared with control
subjects, and the size of the adenoid tissue decreased more in atopic
children.\textsuperscript{45} Tracy and
Demain\textsuperscript{46}compared the effects of prophylactic
antibiotics alone or in combination with intranasal beclomethasone or
placebo and demonstrated that subjects in the beclomethasone plus
antibiotic group improved more rapidly than those in the antibiotic
alone or placebo group.Nevertheless, no differences were seen
amongsubjects with and without allergy. Chimona et
al.\textsuperscript{47}assessed the role of antihistamines in OME in an
animal experimental model, but no clinical efficacy has been
demonstrated for antihistamine alone or in association with topical
decongestantsin humans\textsuperscript{48}, as confirmed by a
meta-analysis.\textsuperscript{49}

\emph{Allergy and CSOM}

An association between CSOM and allergy has long been debated, and only
afew studies have been performed. Interestingly, some authors observed
elevated IgE levels in the middle ear secretions of children with CSOM,
suggesting that allergy may play a contributory role in pathogenesis of
CSOM.\textsuperscript{50}

Fliss et al., in a case control study in children, observed that history
of acute and recurrent~OM, parental history of~chronic~otitis~media,
larger families, and more siblings were associated with high risk for
CSOM, whereas sex, parental age and education, allergy, sinusitis, and
recurrent URTI were not.\textsuperscript{51}There is paucity of data in
literature regarding the role of allergy or atopy as a significant risk
factor for CSOM in children and it was not possible to perform a
qualitative analysis. Additional studies evaluating are strongly
required.

\emph{Conclusions}

AR is a common disease in childhood in industrialized countries and has
a major impact on quality of life and health care resources. Recent
studies pointed out main differences between allergic children and
adults. For instance, AR in children seems to be more intermittent and
severe than in adults, with less symptoms but with a higher number of
comorbidities.\textsuperscript{52}Furthermore, children suffering from
AR often present additional conditions that may decrease response to
medical treatment, worsening QoL. So, AR in children should be
considered a disease with a high multimorbidity.

Experimental and clinical evidence strongly supports the existence of an
association between allergy and OME, although clear evidence is still
debated. Otherwise, the evidence linking atopy or allergy to AOM/RAOM or
CSOM is poor and contradictory. Further studies are needed, paying
particular attention to the inclusion criteria, the methodology of
research and, above all, the accurate phenotyping of otitis media.

From a clinical point of view, children with persistent moderate to
severe AR should be screened for otitis media and in particular, OME.We
summarized in a practical algorithm our conclusions per phenotype of
otitis in order to elucidate when prompt accurate diagnosis and
treatment of allergy is recommended (Fig. 2). Reviewing the data about
allergy and middle ear inflammation, we concluded that a clear link
exists to some phenotypes of middle ear otitis, and in particular OME
and acute re-exacerbation in patients with middle ear effusion.

IMPACT STATEMENT

Improving the understanding of the pathophysiology of allergy and
relationship with otitis media is important to develop preventive
measures as well as perform adequate monitoring and treatment
of~children~with allergy and otitismedia with effusion,although futures
studies are required to increase evidence supporting that anti-allergy
treatment may improve resolution and outcome of OME. The evidence
linking atopy or allergy to other phenotypes is poor and contradictory
and further studies are needed, paying particular attention to accurate
phenotyping of otitis media.

TABLE1. Laboratory evidence and biomarkers linking allergy to OME.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{Author} \emph{Year} \emph{( ) ref}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
No. of cases\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
No. of cases\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Experimental models\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Methods\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Relevant results\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Association. (Level of evidence)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Sobol et al. 2002 (15)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N=26\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N=26\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Middle ear fluid specimens collected during myringotomy in OME patients
(Children).\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Fluid specimens were assessed by means of immunocytochemistry for T
lymphocytes (CD3), eosinophils (major basic protein), neutrophils
(elastase), mast-cells (tryptase) and basophils (BB1). IL-4, IL-5, and
IFN-\selectlanguage{greek}γ \selectlanguage{english}were assessed by using in-situ hybridization,\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Higher percentage of eosinophils, IL-4, IL-5 and T lymphocytes in
patients with atopic OME compared with non-atopic ones. Higher
percentage of neutrophils and INF-gamma in non-atopic patients with
OME.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{Yes} \emph{(Level V})\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Nguyen et al. 2004 (16)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N=55\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N=55\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Human torus tubarius and adenoid tissues collected during adenoidectomy
(children).\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Cellular and cytokine profiles were measured by immunocytochemistry and
in situ hybridization.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Predominant Th2 cytokine expression and infiltration of eosinophils in
atopic patientscompared with the non-atopic ones.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{Yes} \emph{(Level V})\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Wright et al. 2000 (17)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N=14\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N=14\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Middle ear biopsy from children with persistent OME. (children).\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Expression of CD3, majorbasicprotein (immunocytochemistry), IL-5 mRNA
(in situ hybridization) in mucosa of persistent OME patients \emph{vs}
controls.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Predominant expression of CD3, major basic protein, and IL-5 in atopic
persistent OME vs controls.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{Yes} \emph{(Level V})\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Downs, et al. 2001 (23)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N=13\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N=13\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Rat model\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Measure of mucociliary clearance and passive opening and closing
pressures of ET after challenge with either trans-tympanic or intranasal
histamine\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Increase in mucociliary clearance times and passive opening and closing
pressures with trans-tympanic histamine \emph{vs} control
solution.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{Yes} \emph{(Level V})\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Hardy et al. 2001 (24)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Rat model Brown Norway rats were sensitized to ovalbumin and later
challenged trans-tympanically.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ET ventilatory function and mucociliary clearance were assessed 2, 4, 8,
24, 28- and 32-hours post-challenge.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Exposure to transtympanic allergen induces ET dysfunction and subsequent
formation of effusion and a decreased ability to actively clear middle
ear pressure in allergic animals.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{Yes} \emph{(Level V})\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Pollok 2002 (25)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Brown-Norway rats were sensitized to ovalbumin (OVA) and challenged
trans-tympanically.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Two groups of rats received soluble IL-4 receptors (sIL-4R) and IL-5
antibodies (IL-5Ab) trans-tympanically 1 hour before challenge.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
sIL-4R-pre-treated rats showed no significant changes in ventilatory or
clearance functions of the ET, whereas IL-5Ab group showed significant
late ventilatory and clearance dysfunction as well as inflammatory
mucosal changes.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{Yes} \emph{(Level V})\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\emph{OME: otitis media with effusion; ET: Eustachian tube; IL:
interleukin.}

Table 2.Articles investigating clinical association between allergy and
otitismedia\emph{.}

Clinical evidence linking allergy to risk of middle ear inflammation\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\emph{Author} \emph{Year}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Type of article\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N (mean age)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Methods\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Relevant results\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Association. (Level of evidence)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Byeon, 2019 (27)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Epidemiologic observational study\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=472 (9.6yr \selectlanguage{ngerman}± 0.4)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Survey data\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Children with AR had twice significantly higher risk of OM.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level IV) No distinction between AOM and OME\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Martines et al. 2016 (28)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case-control study\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=204 children and 204 controls\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To investigate the main risk factors for AOM and OME and their
prevalence in Sicilian children\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Allergy and urban localization increased the risk of OM in children
exposed to smoke, respectively of 166\% and 277\%.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level III) No distinction between AOM and OME\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Salah et al. 2013 (26)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Retrospective study\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=340 infants with RAOM\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To analyze the risk factors that are likely to be responsible for RAOM
in children.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Authors did not find a significant association between RAOM and
allergy\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
None (Level IV) with RAOM\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Hardani et al. 2020 (10)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case-control study\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=625 children (6 months -- 7 years)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To investigate the relationship between the incidence of otitis media
(acute, chronic and with effusion) and risk factors.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Allergic rhinitis was identified as one of the most important risk
factors.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (No distinction between phenotypes)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\emph{AR: allergic rhinitis; OM: otitis media; AOM: acute otitis media;
OME: otitis media with effusion; RAOM: recurring acute otitis media
episodes; AH: adenoid hypertrophy.}

Table 3. Articles investigating specifically clinical association
between allergy and otitismediawith effusion\emph{.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\emph{Author} \emph{Year}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\emph{Type of article}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\emph{N (mean age)}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\emph{Methods}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\emph{Relevant results}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\emph{Association. (Level ofevidence)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Cheng et al. 2016 (32)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Metanalysis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Metanalysis cross-sectional and case-controlled studies\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
OME and AR are prevalent in pre-school and school-aged children. The
study suggests allergy is a risk factor for OME.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level I)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Gultekin et al. 2004 (33)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Epidemiologic study\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=1800 school-children\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To determine the impact of environmental, epidemiologic and familial
factors in the development of persistent OME\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Allergy history was a statistically significant factor among children
with OME compared to normal children.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level IV)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Kreiner-M\selectlanguage{ngerman}øller 2012 (34)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Cohort study.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N= 291 children (6yr)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To investigate the association between atopic disease and OME.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
OME was diagnosed in 39\% of the cohort and was associated with AR
(OR~=~3.36, CI~=~1.26-8.96, P~=~0.02).\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level III)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Kwon et al. 2013 (35)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case-control study\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=370 children with OME and 100 controls\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To assess the relationship between OME and allergic diseases\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
The incidence of AR alone was significantly higher in children with OME
(33.8\%) than without OME (16.0\%);\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level III)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Sharifian et al. 2019 (36)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case-control study\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=37 OME children and 52 controls (2-15 years)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To investigate immunoglobulin E (IgE) mediated hypersensitivity as a
causative factor in the development of OME.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Allergic rhinitis prevalence was notably higher among OME patients than
in the control group; there were no differences in eosinophil counts,
serum IgE concentrations and nasal smear eosinophils in the two
groups.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level III) no correlation with biomarkers\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Roditi et al. 2015 (37)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Retrospective analysis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=133 (\textless{}18 years)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To determine whether there is a significant relationship between
allergic rhinitis and OME and whether age is an effect modifier of any
such association\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Age is an effect modifier of the association between allergic rhinitis
and OME; a significant relationship is observed in children 6 years of
age and older, whereas there is no significant association in younger
children.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level IV)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Torretta et al 2018 (39)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Retrospective study\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=153 (59.4\selectlanguage{ngerman}± 16.4months)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
A retrospective chart review evaluating the effect of allergy in the
development of recurrent AOM with or without OME.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Higher prevalence of allergy or atopy in children with RAOM with OME
than in those without OME\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level IV)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Quaranta et al. 2013 (40)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Epidemiologic study\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=81 children, Mean age 6.9 yr.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To evaluate the role of the different forms of chronic rhinitis in the
pathogenesis OME in children with AH.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
70\% of~children~had a chronic rhinitis with AH and 60\% of them had
OME. Nasal cytology together with Skin prick test showed that AR was
rarely present in this group.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level IV)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Norhafizh et al. 2020 (41)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Prospective cross-sectional study.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=130 children (4-18 years)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To determine the preva- lence of allergic rhinitis in children with
persistent OME\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
High prevalence of allergic rhinitis in children with persistent OME
(80.3\%); dust mites was the most common allergen.There was a
statistically significant improvement of the hearing threshold after
anti-allergy therapy.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level II)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Songu et al. 2020 (42)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Cohort study.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N=539 patients undergoing surgery for AH\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
To determine the most important risk factors in the development of OME
in children with adenoid hypertrophy.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Atopy and allergic rhinitis resulted as main risk factors for OME.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Yes (Level III)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\emph{AR: allergic rhinitis; OM: otitis media; AOM: acute otitis media;
OME: otitis media with effusion; RAOM: recurring acute otitis media
episodes; AH: adenoid hypertrophy.}

\textbf{Conflict of interest}

The research did not receive any specific grant from founding agency in
the public, commercial or nor-for-profit sectors. The authors do not
have any conflicts of interest to declare.

\subsection*{}

{\label{section}}



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\end{enumerate}

Figure Legends

Figure 1. Flowchart of article search and selection.

Figure 2: Practical algorithm based on different phenotypes of otitis in
children.

Abbreviations: OME: otitis media with effusion; AOM: acute otitis media;
RAOM: recurrent acute otitis media; CSOM: chronic suppurative otitis
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