International Journal of Pediatric Otorhinolaryngology 147 (2021) 110799

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International Journal of Pediatric Otorhinolaryngology

journal homepage: www.elsevier.com/locate/ijporl

Review Article

A systematic review of the clinical evidence and biomarkers linking allergy

to adeno-tonsillar disease
Eugenio De Corso a, Jacopo Galli a, Tiziana Di Cesare a, *, Daniela Lucidi b, Giancarlo Ottaviano c,
Veronica Seccia d, Francesco Bussu e, Giulio Cesare Passali a, Gaetano Paludetti a, Elena Cantone f
a
Fondazione Policlinico Universitario A, Gemelli IRCCS, Università Cattolica Del Sacro Cuore, Department of Head and Neck Surgery - Otorhinolaryngology, Rome, Italy
b
Department of Otolaryngology-Head and Neck Surgery, University Hospital of Modena, Modena, Italy
c
Department of Neurosciences, Otolaryngology Section, University of Padova, Padova, Italy
d
Otolaryngology Audiology, and Phoniatric Operative Unit, Department of Surgical, Medical, Molecular Pathology, and Critical Care Medicine, Azienda Ospedaliero
Universitaria Pisana, University of Pisa, Pisa, Italy
e
Azienda Ospedaliero Universitaria, Sassari, Otorinolarinoiatria, Dipartimento Delle Scienze Mediche, Chirurgiche e Sperimentali, Università di Sassari, Italy
f
Department of Neuroscience, Reproductive and Odontostomatological Sciences - ENT Section, University “Federico II”, Naples, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: allergy may be an important risk factor for adenotonsillar disease in children, although conflicting
Allergy results have been reported in the literature. In previous articles, authors often failed in distinguishing between
Allergic rhinitis adeno-tonsillar hypertrophy and recurrent tonsillitis and in not discriminating between isolated or combined
Adenoid
adenoid and tonsillar hypertrophy.
Tonsils
Aim: to evaluate clinical evidence and biomarkers linking allergy to different phenotypes of adeno-tonsillar
Adeno-tonsillar hypertrophy
Recurrent adeno-tonsillar infectious disease. Furthermore, we questioned whether anti-allergy treatment might prevent occurrence of adeno-
tonsillar disease or improve its specific management.
Methods: our systematic review, in accordance with the Preferred Reporting Items for Systematic Review and
Meta-Analysis (PRISMA) process, yielded 1010 articles finally screened. This resulted in 21 full texts that were
included in a qualitative analysis.
Results: literature data support the association between allergy and combined adeno-tonsillar hypertrophy and
isolated adenoid hypertrophy, whereas describe a mainly negative correlation between allergy and isolated
tonsillar hypertrophy. The results of this review suggest that local allergic inflammation may play a role in
adeno-tonsillar hypertrophy. Data correlating bacterial recurrent tonsillitis and allergy are few, although evi­
dence from the lab revealed that allergy might suppress innate immunity in tonsillar tissue by reducing levels of
anti-microbial proteins.
Conclusion: basing on our qualitative analyses allergy should not be misdiagnosed in children with combined
adenotonsillar hypertrophy or isolated adenoid hypertrophy, whereas evidence do not support a link between
allergy and isolated tonsil hypertrophy. Finally, some data support a link between allergy and recurrent adeno-
tonsillar infection although future studies are required to confirm this data. We summarized our conclusions in a
practical algorithm.

1. Introduction
The adenoids and tonsils are lymphatic organs part of Waldeyers
ring, located at the entrance of the respiratory tract, whose main func­
tions are antibody formation and resistance of the host against the
pathogens [1,2]. They are continuously exposed not only to antigens,
but also to allergens that enter the body and serve as the first contact
points with inhalant allergens. Previous studies reported that not only
adeno-tonsillar hypertrophy (ATH) and allergic rhinitis (AR) represent
the most common causes of upper airway obstruction but allergy itself
may be an important risk factors for ATH in children [3]. Nevertheless,
results about this topic are contradictory and confusing, although the
prevalence of adenotonsillar disease is described at least in the 20%–
22% of children with AR, some studies reported that the prevalence of

* Corresponding author.
E-mail address: Tizianadicesare90@gmail.com (T. Di Cesare).

https://doi.org/10.1016/j.ijporl.2021.110799
Received 13 January 2021; Accepted 9 June 2021
Available online 12 June 2021
0165-5876/© 2021 Elsevier B.V. All rights reserved.
E. De Corso et al.
Fig. 1. Flowchart of article search and selection.
AR is similar to age-matched controls [1,4,5].
Although the etiology of AT disease has not been elucidated yet, it
seems that chronic and recurrent inflammatory events may have a
decisive role in immune response [4,6]. Children with AR show a hy­
persensitivity reaction of the nasal mucosa mediated by immunoglob­
ulin E and T helper 2 (Th2) cells [7], which causes eosinophilic
inflammation following allergen exposure of the mucous membranes.
Previous reports suggested that allergic diseases can initiate inflamma­
tory processes affecting the adenoid and tonsil tissues, leading to an
allergic inflammation, which causes a large number of IgE-positive
plasma cells/mast cells, allergen-specific IgE, and eosinophilic infiltra­
tion in the tissue [8]. Likely, lymphatic tissue of adenoids could produce
local specific IgE, and allergic/eosinophilic inflammation could occur in
adenoid and tonsil tissue of children with AR [4,9].
Many studies assessed the association between adeno-tonsillar dis­
ease and allergy, nevertheless they often reached inconclusive results.
One of the major critical points is that authors failed not only in dis­
tinguishing between adeno-tonsillar hypertrophy and recurrent tonsil­
litis but also in not discriminating between isolated or combined
adenoid and tonsillar hypertrophy. In addition, tonsils and adenoids
change in size according to age [10] and the rate of positive skin prick
tests may vary greatly during childhood [11]. The aim of the present
systematic review was to evaluate clinical evidence and biomarkers
linking allergy to different phenotypes of adenotonsillar disease such as
isolated adenoid or tonsillar hypertrophy (AH, TH), combined ATH, and
recurrent/chronic adeno-tonsillitis (rAT).
2
International Journal of Pediatric Otorhinolaryngology 147 (2021) 110799
2. Methods
2.1. Search strategy
We conducted a systematic review in accordance with the Preferred
Reporting Items for Systematic Review and Meta-Analysis (PRISMA)
process [12] to identify published experimental and clinical articles
about allergy and adeno-tonsillar disease 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 October 2020. Literature
searches were performed in November 2020.
We performed two different searches using MeSH-terms. One group
of authors focused on experimental studies matching the term as follow:
[(adeno-tonsillar disease) OR (tonsillitis) OR (adenoiditis) OR (adeno-
tonsillar hypertrophy)] 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 clinical studies,
matching the term as follow: [(adeno-tonsillar disease) OR (tonsillitis)
OR (adenoiditis) OR (adeno-tonsillar hypertrophy)] 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)].
2.2. Study selection
In the first screening authors read the title and abstract of articles
selecting those being as inclusive as possible. The abstracts were
E. De Corso et al.
Fig. 2. Practical algorithm based on different phenotypes of adenotonsillar disease in children.
screened independently by reviewers of the two groups. Any disagree­
ments 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, observa­
tional studies, randomized trials, and basic science articles), published
after January 2000, addressing allergy and adeno-tonsillar disease in
children. Furthermore, we questioned whether anti-allergy treatment
may prevent the occurrence of adeno-tonsillar disease 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 ar­
ticles 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.
2.3. Qualitative analyses
All included studies were assessed for quality using the Black and
Downs checklist for measuring study quality, consisting of 27 questions
designed to evaluate both randomized and non-randomized studies for
overall quality of reporting [13]. Quality levels were assigned to each
included study, using the categories according to literature evidence:
excellent (Black and Downs score ≥ 26), good (20–25), fair (15–19), and
poor (≤14). The scoring methodology of the checklist is structured so
that only randomized controlled trials can receive a score of 26 or
greater [13]. Each author scored included studies individually, with
quality levels assigned only after consensus was reached.
3. Results and discussion
Fig. 1 shows the details of the systematic search. After duplicates
removal, we yielded in total 1789 articles. Then due to time of publi­
cation and type of article, we excluded 779 articles and 1010 were
screened. Finally, 21 publications were included in a qualitative anal­
ysis. We summarized in tables the included studies classifying evidence
using GRADE methodology and quality by Black and Downs method
[13,14]. No studies were included in a quantitative synthesis
(meta-analysis).
Authors frequently analyzed children subjected to surgery without
distinguishing between adeno-tonsillar hypertrophy (ATH) and chronic/
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International Journal of Pediatric Otorhinolaryngology 147 (2021) 110799
recurrent adenotonsillitis (rAT), and do not discriminate between iso­
lated or combined adenoid (AH) and tonsillar hypertrophy (TH). For this
reason, we attempted to highlight in the tables when authors used age-
matched case-controls and when they distinguished between AH, TH,
and rAT. We finally resumed our conclusions basing on several pheno­
types of adenotonsillar disease in Fig. 2.
3.1. Allergy and adenotonsillar hypertrophy (ATH)
Adeno-tonsillar tissues are continuously exposed to inhalant aller­
gens; for this reason, many studies assessed the association between
adeno-tonsillar hypertrophy and allergy. In our systematic review we
included not only clinical studies but also laboratory manuscripts link­
ing biomarkers of allergic inflammation to ATH. We found a large
number of studies that we analyzed separately basing on phenotypes as
follows: combined ATH, isolated AH and TH.
3.1.1. Clinical and laboratory evidence linking allergic inflammation to
combined adenotonsillar hypertrophy
We found several experimental studies aiming at defining the
immunologic and cytokine profile of adeno-tonsillar tissue in children
undergoing surgery for ATH. These studies provided evidence of Th2
oriented chronic inflammation in a significant number of children with
ATH, thus supporting an important role for local atopy in adeno-tonsillar
hypertrophic tissue. Cho et al. [15] demonstrated that 70.6% of children
with ATH were sensitized to more than one allergen. The authors also
demonstrated that 36.2% of children with negative specific IgE in serum
had positive specific IgE in adeno-tonsillar tissues. In addition, the rate
of specific IgE was significantly higher in local tissue than in serum and
in the adenoids than in tonsils. The authors suggested that local allergic
inflammation may play an important role in childhood adeno-tonsillar
hypertrophy. Yücel Eki˙ci˙ et al. [4] investigated the same topic evalu­
ating the serum and tissue eosinophilia in children undergoing adenoi­
dectomy/tonsillectomy due to AH or ATH, and investigated the
correlation of serum and tissue eosinophilia in children allergy. They
found that adenoid and tonsil tissue, and serum eosinophilia were higher
in allergic children than in nonallergic. However, they did not find
relationship between tissue and serum eosinophilia suggesting the
presence of local atopy in childhood with ATH. In addition, they found a
significant correlation between eosinophilia in the tonsil and adenoid
tissue. Although, they differentiated the two phenotypes, AH and ATH,
they did not correlate allergy with them, separately [4]. Accordingly,
other authors demonstrated that IgE-antibodies are produced locally,
supporting the hypothesis that local atopy may have an important role in
E. De Corso et al. International Journal of Pediatric Otorhinolaryngology 147 (2021) 110799

Table 1
Clinical and laboratory evidence linking allergy and combined adenotonsillar hypertrophy.
Author Year ( ) Type of article No. of cases (mean Methods Relevant results Level of Quality Link to
ref age) evidence allergy

Sadeghi- Observational N = 117 children Both groups were examined for the Children with ATH had positive Level III Good (+) with
Shabestari case-control (aged 1–14 yr) with incidence of positive SPT and serum SPT n 70.3% of cases vs 10% of ATH
et al., 2011 study. ATH (Cases) and 100 IgE levels. controls. High total IgE levels
[1] controls were observed in 48% of
children with positive SPT
Yücel Eki˙ci˙ Retrospective N = 125 children 57 atopic children (positive SPT and Sensitivity and specificity of Level IV Fair (+) with
et al., 2019 study undergoing symptoms of allergic rhinitis) versus tissue eosinophilia were found to ATH for
[3] adenoidectomy 68 non-atopic one (no allergic be higher than those of serum local
/tonsillectomy symptoms and negative SPT). Total IgE eosinophilia, particularly in atopy
6.4 ± 2.2 (range level and the serum and tissue adenoid tissue. The discrepancy
3–10 years) eosinophilia were evaluated. in eosinophilia between tissue
and serum may indicate a role of
local atopy in adenoid and tonsil
tissue.
Cho et al., 2018 Cross sectional N = 102 children Types of specific IgE in the serum and 70.6% of children with ATH Level II Good (+) with
[15] study undergoing adenotonsillar tissues of children with were sensitized to more than one ATH for
adenoidectomy ATH were measured and the allergen; 36.2% of children with local
/tonsillectomy sensitization patterns of the serum and negative serum specific IgE had atopy
7.1 ± 3.9 years (range: local tissues were compared positive specific IgE in adeno-
5.0–16.0 years) tonsillar tissues; the rate of
specific IgE was significantly
higher in local tissue than in
serum and in the adenoids than
in tonsils.
Zhang et al., Cross sectional N = 142 children To investigate the presence of specific Positive serum sIgE patients in Level III Fair (+) with
2013 [16] study IgE (sIgE) in the serum and showed sIgE expression locally ATH for
adenotonsillar tissues in children with in adenoids (50%) and tonsils local
ATH. (42.9%). Negative serum sIgE atopy
ones had local sIgE in 36.0% of
adenoids and 43.8% of tonsils
cases. The rate of sIgE presence
in local tissue (adenoids or
tonsils) was significantly higher
than the serum one.
Ekici NY et al., Prospective N = 101 operated Hematoxylin-eosin stained sections The number of eosinophils in Level III Fair (+) with
2018 [17] study children (46 had were examined under 400 × adenoid and tonsil tissue was ATH for
positive SPT) age = magnification in a blinded fashion in significantly higher in sensitized local
6,02 ± 1.77 (range 10 random sections for all samples and patients. The number of atopy
3–9) compared the groups. eosinophils in the adenoid and
tonsil samples also were
interrelated too.
Adegbiji et al., Prospective N = 265 children with Determining the prevalence, Major associated comorbid Level III Fair (+) with
2018 [24] cohort study. AR (1–5 yr) sociodemographic features, comorbid illnesses among the patients ATH
illnesses, complications and quality of were TH and AH which
life in children with allergic rhinitis. accounted for 55.5% and 46.4%
respectively.
Carr et al., Prospective N = 117 children To determine the incidence of atopy by The study does not support the Level III Fair (− ) for
2007 [25] observational (mean age 4.5 yr, RAST to common airborne allergens in hypothesis that the ATH seen in ATH
study range 1–14 yr) children undergoing pediatric patients with OSA is
adenotonsillectomy for OSA contributed to by allergy to
airborne allergens.
Alexopoulos Retrospective N = 855 children Evaluate the association between Atopy was not related to ATH or Level IV Poor (− ) for
et al., 2014 observational (mean age 6.3 ± 2.5) atopy expressed as eczema and ATH in OSA ATH
[26] study. snoring children.
Liu J. et al. Cross-sectional N = 1085 children To compare sleep quality and AR is not an aggravating factor Level II Good (− ) for
[27] study ((mean age 6.7 ± polysomnographic data in habitually for the severity of ATH ATH
2.1yrs, range 3–14yrs) snoring children with ATH, with or
without AR.

ATH: adeno-tonsillar hypertrophy; AR: allergic rhinitis; AH: adenoid hypertrophy; SPT: skin prick test; IgE: immunoglobulin E; ENT: ear, nose and throat; TH: tonsillar
hypertrophy; RT: recurrent tonsillitis.
*Downs and Black scoring of quality assessment: 26–28 (excellent), 20–25 (good), 15–19 (fair), and ≤14 (poor).

childhood ATH. In particular, Zhang et al. [16] observed high levels of
sIgE expression in adenoid and tonsil tissue, trying to detect sIgE against
15 representative allergens. Fittingly, Ekici NY et al. [17] demonstrated
that the levels of IL-4 and that the number of eosinophils, CD1a +
Langerhans cells, and IL-5 mRNA-positive cells were significantly higher
in adenoid and tonsil tissue from sensitized patients compared to
non-sensitized ones. These results are very interesting, in fact the
importance of biomarkers such as eosinophilia, type 2 cytokine and local
IgE has been extensively studied in the sino-nasal mucosa [17–23],
whereas the studies on adenotonsillar tissue are limited. We believe that
future studies are needed to well define the role of a local type 2 oriented
inflammation in adeno-tonsillar pathologies.
From a clinical standpoint, the evidences ascertaining the clinical
correlation between adeno-tonsillar disease and AR are very confusing
because many authors often describe conflicting results and contradic­
tory conclusions. Several authors [1,24] observed a high prevalence of
positive SPT in children with combined ATH. Specifically,
Sadeghi-Shabestari et al. [1] demonstrated significantly higher total

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E. De Corso et al. International Journal of Pediatric Otorhinolaryngology 147 (2021) 110799

Table 2
Clinical evidence linking allergy and isolated adenoid hypertrophy.
Author Year Type of article No. of cases (mean age) Methods Relevant results Level of Quality Clinical
( ) ref evidence association

Evcimik Case-control N = 1322 children with SPT for the same allergens was AH prevalence was higher Level III Good (+) with
et al., study allergic conditions (5.9 ± 3.3 performed for all patients. AH was in children with allergic AH
2015 [28] yr) and 100 controls analyzed by an ENT specialist. disease compared to
controls. The most common
sensitivity was to house
dust.
Huang 2001 Case-control N = 315 cases with AR + AH To determine the risk of AH in Positive reactivity to molds Level III Good (+) with
[29] study. (ages 1–18 years) versus 315 patients with AR. was significantly higher in AH
controls with AR the group with AR + AH.
The risk of AH was
positively correlated with
number of skin test
reactivity to mold spores.
Modrzynsi Case-control N = 436 children (4–9 yr) Analysis of AH in children with The probability of AH was Level III Fair (+) with
2007 [30] study atopic (house dust mites) and different allergic diseases. significant only in children AH
229 non-atopic from the study group with
AR.
Shin et al., Case-control N = 39 children sensitized to To evaluate the role of Alternaria- Both Alternaria- and Level IV Good (+) with
2012 [31] study more than one common and Aspergillus-specific IgE Aspergillus-specific IgE AH
aeroallergen and 39 non- antibodies in allergic inflammation were more prevalent in
atopic subjects undergoing of adenoid tissue. adenoid tissues from atopic
adenotonsillectomy (7.9 ± children than in tissues from
3.0) non-atopic children.
Alternaria-specific IgE
levels were significantly
correlated with serum and
adenoid total IgE and with
tryptase and eosinophil
cationic protein levels in
adenoid tissue.
Nguyen LH Prospective N = 45 patients undergoing The atopic status was determined for Within the atopic patient, Level IV Fair (+) with
et al., study both ventilation tube each patient using standard skin there is a predominant AH
2004 [33] placement for OME and testing. The cellular and cytokine expression of interleukin-4
adenoidectomy for adenoid profile of the adenoid tissues was (a Th2 cytokine) and an
hypertrophy investigated using increased infiltration of
immunocytochemistry and in situ eosinophils in adenoid
hybridization. tissue compared with the
nonatopic patient.
Ameli et al., Prospective N = 205 children (mean age Clinical visit, nasal endoscopy, and Decreased probability of Level IV Fair (− ) for AH
2013 [34] observational 6.7 yr, age range 4–12 yr) SPT were performed in all patients. greater adenoid volume was
study Adenoid size was graded using the associated with increased
Parikh’s classification. severity of nose obstruction
in patients with allergy
compared with non-allergic
patients.
Karaca Prospective N = 82 children with upper All patients underwent digital lateral Significant correlation Level II Good (− ) for AH
et al., observational airway obstructive symptoms soft tissue radiographs and SPT. found between tonsil size (+) for TH
2012 [35] study (5–14yr) Assessment of nasopharyngeal and positive SPT. However,
obstruction by Cohen and Konak there was no significant
method. correlation between
adenoid size and SPT
results.

SPT: skin prick test; AH: adenoid hypertrophy; OSA: Obstructive Sleep Apnea; ATH: adeno-tonsillar hypertrophy; AR: allergic rhinitis; *Downs and Black scoring of
quality assessment: 26–28 (excellent), 20–25 (good), 15–19 (fair), and ≤14 (poor).

serum IgE levels in children affected by ATH compared to controls.
Adegbiji et al. [24] observed that AH and TH were the most common
comorbidities observed in AR children. Conversely Carr et al. [25]
evaluating the incidence of atopy in children undergoing adeno­
tonsillectomy for obstructive sleep apnea (OSA) didn’t support the hy­
pothesis that ATH in pediatric OSA is contributed by allergy.
Accordingly, Alexopoulos et al. [26] in a large observational study on
855 children with obstructive sleep apnea (OSA) found that atopy was
not related to an increased risk of OSA, not supporting, therefore, a link
between the two entities. Despite the high prevalence of AR in children
with sleep disordered breathing, Liu J. et al. concluded that AR is not an
aggravating factor for the severity of ATH comparing polysomnographic
data [27].
The most relevant clinical articles included in the qualitative ana­
lyses are summarized in Table 1. The majority of articles have a fair and
good quality and support the hypothesis of a link between allergy and
combined ATH.
3.1.2. Clinical and laboratory evidence linking allergic inflammation to
isolated adenoid hypertrophy
Herein we included articles analyzing allergy and isolated AH. Spe­
cifically, Evmicik et al. [28] demonstrated that AH prevalence was
higher in children with allergic disease compared to controls and that
sensitization to house dust mite represents the most frequent allergy in
those patients; Huang et al. [29] demonstrated that sensitivity to mold
allergens was an important risk factor for AH in children with AR. In
particular, the authors pointed out that AH frequency is higher in chil­
dren with allergy than in controls. Interestingly, several authors [28–30]
noted that perennial allergens (in particular, house dust mites and mold)
were more frequently associated with AH. Specifically Shin et al. [31,

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E. De Corso et al. International Journal of Pediatric Otorhinolaryngology 147 (2021) 110799

Table 3
Clinical evidence linking allergy and isolated tonsillar hypertrophy.
Author Year Type of article No. of cases (mean Methods Relevant results Level of Quality Clinical
( ) ref age) evidence association

Karaca Prospective N = 82 children with All patients underwent digital lateral Significant correlation found Level II Good (− ) for AH
et al., observational upper airway soft tissue radiographs and SPT. between tonsil size and positive (+) for TH
2012 study obstructive symptoms Assessment of nasopharyngeal SPT. However, there was no
[35] (5–14yr) obstruction by Cohen and Konak significant correlation between
method. adenoid size and SPT results.
Ameli et al., Prospective N = 171 children Clinical visit, nasal endoscopy, and The authors investigate the Level III Fair (− ) for TH
2014 observational (mean age 6.6 yr) SPT were performed. TH and anterior relationship between tonsil
[36] study nasal obstruction were graded using volume and AR diagnosis. Tonsil
the Friedman’s classifications. volume was inversely associated
with AR diagnosis.
Eryaman Prospective N = 73 atopic and Investigate the possible relationship No significant difference was Level III Fair (− ) for TH
et al., observational non-atopic children between tonsil volume and AR found between tonsil sizes in
2011 study. (age range 6–12, diagnosis. All tonsil sizes were atopic and non-atopic groups of
[37] mean 8.20 SD ± 1.67) evaluated by the same observer using children.
the Brodsky L. Scala.

SPT: skin prick test; TH: tonsillar hypertrophy; OSA: Obstructive Sleep Apnea; ATH: adeno-tonsillar hypertrophy. *Downs and Black scoring of quality assessment:
26–28 (excellent), 20–25 (good), 15–19 (fair), and ≤14 (poor).

32] demonstrated that alternaria and aspergillus specific IgE and der­
matophagoides pteronyssimus specific IgE were prevalent in adenoid
tissues from atopic children than non-atopic ones. Expression of
interleukin-4 and infiltration of eosinophils in adenoid tissue were noted
to be increased in atopic children compared to controls [33].
Few authors [34,35] described a completely different scenario.
Specifically, Ameli et al. [34], in a cohort of 205 children, observed a
low probability of large adenoid volume in patients with allergy
compared with non-allergic patients. This real-life study showed that
large adenoids may be associated with absence of allergy, whereas large
turbinates may be associated with small adenoids. Accordingly, Karaca
et al. [35] reached overlapping conclusions in a cohort of 82 children
investigated with radiographic exams.
The majority of the article included in the analyses were of good
quality and specifically 5 were case control studies supporting the as­
sociation between allergy and isolated AH and 2 studies reached nega­
tive results. (Table 2).
on mixed cell cultures prepared from dissociated tonsils and adenoids
harvested intraoperatively from children with OSA [41]. Goldbart et al.
showed that treatment with montelukast leads to significant improve­
ments in OSA [42]. Kheirandish et al. [43] demonstrated that combined
anti-inflammatory therapy of oral montelukast and intranasal budeso­
nide effectively improves and/or normalizes respiratory and sleep dis­
turbances in children with residual OSA after tonsillectomy and
adenoidectomy, regardless of their allergic state.
The aforementioned studies do not allow, at present, a clear state­
ment about the association between allergy and ATH. The impact of the
available experimental and clinical data on therapeutic approaches is
rather poor, while protocols confirming the efficacy of an antihistamine
alone in reducing adenoid hyperplasia do not exist. The gold standard in
ATH, in addition to antibiotics for bacterial acute infections, is repre­
sented by oral and intranasal administration of corticosteroids [44]. This
pharmacological approach does not allow to distinguish between the
anti-allergic effect and nonspecific inflammatory outcome.

3.1.3. Clinical evidence linking allergic inflammation to isolated tonsillar

hypertrophy
We found very few evidences linking allergy to isolated TH. Karaca
et al. [35] found a significant correlation between tonsil size and posi­
tive SPT. A particular negative association has been observed between
AR and TH when considered isolated by Ameli et al., 2014 [36] and by
Eryaman et al., 2011 [37]. The most relevant clinical articles included in
the qualitative analyses are summarized in Table 3. The quality was fair
but future studies should clarify if turbinate enlargement and nasal
mucosa congestion could affect the passage of antigens that are able to
stimulate tonsil tissue to enlarge.
3.1.4. Anti-allergy treatment and adenotonsillar hypertrophy
Treatment of adenoid hypertrophy with topical corticosteroids has
been widely reported in the literature, with uniformly good results, and
little has been explored regarding the influence of atopy on this treat­
ment outcome. Rezende et al. [38] demonstrated that topical mometa­
sone furoate significantly reduced the adenoid tissue area and improved
nasal symptoms, although the improvement was similar for atopic and
non-atopic patients. The authors suggested that the anti-inflammatory
action of topical glucocorticoids in adenoid tissue is not limited to
allergic conditions.
Tonsils of children with sleep-disordered breathing have enhanced
expression of cysteinyl leukotriene receptors 1 and 2 in T lymphocytes
which could potentially promote tonsillar enlargement in children with
obstructive sleep apnea [39,40]. Leukotriene antagonists exhibited
dose-dependent reductions in adenotonsillar cellular proliferation rates
3.2. Allergy and recurrent infectious adeno-tonsillar disease
In this paragraph, we focused on Clinical and laboratory evidence
linking allergic inflammation to bacterial recurrent/chronic adeno-
tonsillitis (rAT). The viral forms of AT are commonly part of the upper
respiratory tract infections (URTIs). Furthermore, the vast majority of
URTIs is self-limited, but deserves attention because in atopic children
they may lead to severe lower respiratory tract infections or asthma
exacerbations [45]. A systematic review, that we recently published,
reported a positive association between allergy and viral URTIs [46].
Evidence of a clinical association between recurrent bacterial
tonsillitis/chronic tonsillitis and allergy are very poor. Capper and
Canter [47] noted in a very large series that family history of atopy in
addition to history of parental tonsillectomy, were significant predictive
factors for number of episodes of tonsillitis in children. Experimental
evidence from the lab linking recurrent bacterial tonsillitis and allergy
are limited. Several manuscripts demonstrated that proteins related to
innate immunity such as HBDs and S100A7 are deficient in the tonsils of
allergic patients. Human β-defensins (HBDs) are a newly identified
family of antimicrobial peptides that are expressed by epithelia on
mucosal surfaces. S100A7 is a protein with antimicrobial and chemo­
tactic properties for neutrophils. Experimental exposure of airway
epithelial cells to TH2-type cytokines results in a significant decrease in
the antimicrobial activity of cells. Reduced mRNA levels of S100A7 were
detected in infected tonsils as well as in tonsils from allergic individuals.
A study by Choi et al. [48] demonstrated significant differences in
expression of HBDs on the epithelia of healthy tonsils of allergic versus

6
E. De Corso et al. International Journal of Pediatric Otorhinolaryngology 147 (2021) 110799

Table 4
Clinical evidence linking allergy and chronic tonsillitis/recurrent bacterial tonsillitis.
Author Type of No. of cases (mean age) Methods Relevant results Level of Quality Clinical
Year ( ) ref article evidence association

Capper & Case- N = 2918 children To study the influence of parental A history of parental tonsillectomy and Level III Good (+) with RT
Canter control awaiting tonsillectomy for smoking, parental surgical history, a family history of atopy are both
2001 study recurrent tonsillitis (3–11 parental tonsillectomy, family significant predictive factors for the
[47] yr) vs healthy children atopy upon the incidence of sore number of reported sore throats and
throats and tonsillitis episodes of tonsillitis in children.
Choi et al., Case- 30 children with allergic To investigate the effect of allergic HBD-2 mRNA and protein levels in the Level IV Fair (+)
2012 control rhinitis and nonallergic rhinitis on the expression of Human tonsils were significantly lower in the
[48] study rhinitis groups. (mean age b-defensins HBD-2 antimicrobial allergic rhinitis group than that in the
7 yr) peptides in tonsils and adenoids. nonallergic rhinitis group
Bryborn Case- Palatine tonsils obtained To investigate how the expression of Reduced mRNA levels of S100A7 were Level IV Fair (+)
et al. control from allergic and non S100A7 in human palatine tonsils is detected in infected tonsils as well as in
[49] study allergic patients (n = 109; affected by inflammatory processes tonsils from allergic individuals. The
mean age 15yr) results suggest a role for S100A7 in
recurrent tonsillitis and allergic disease.

SPT: skin prick test; TH: tonsillar hypertrophy; OSA: Obstructive Sleep Apnea; ATH: adeno-tonsillar hypertrophy. *Downs and Black scoring of quality assessment:
26–28 (excellent), 20–25 (good), 15–19 (fair), and ≤14 (poor).

non-allergic patients. The authors suggested that AR suppresses HBD-2
in tonsils. Bryborn et al. [49] observed that tonsils from allergic pa­
tients express lower levels of S100A7 compared with tonsils from
non-allergic individuals.
We included 3 articles in the qualitative analyses supporting a light
link between allergy and recurrent adeno-tonsillar infectious with a fair
quality of the evidence (Table 4).
4. Conclusion
The conclusions of our qualitative analyses on experimental and
clinical studies confirmed a link between allergy to ATH and isolated
AH, whereas studies described a mainly negative correlation between
allergy and isolated TH (Tables 1–3). We found interesting data with a
pretty good quality of the evidence supporting that local allergic
inflammation may play an important role in childhood adeno-tonsillar
hypertrophy. Future studies should establish whether a localized
allergic reaction in the lymphoid tissue of upper respiratory tract may be
prevalent compared to a systemic one, which may not be apparent
during routine clinical testing. Furthermore, clinical implications,
diagnostic tools and management modalities of local allergic rhinitis in
these patients should be investigated.
Some studies suggested that atopy should be routinely evaluated in a
pre-operative setting in children with ATH and OSA, because it can
affect post-surgical outcomes: as recently reported [50], children with
sleep-disordered breathing and atopy have a higher risk to develop a
deterioration, rather than an amelioration, in long-term quality of life
after adeno-tonsillectomy compared to non-atopic children. Moreover,
other authors demonstrated [51] that atopic children have a higher risk
of adeno-tonsillar regrowth after adenotonsillectomy and that children
with recurrence had more allergic disease and higher IgE, IL-4, and IL-5
levels than the children of the same age in the control group. Other
authors such as Hoffmann et al. [52] disagree, demonstrating that al­
lergy did not influence rates of resolution of symptoms following
adeno-tonsillectomy, thus concluding that routine allergy tests before
adenotonsillectomy or adenoidectomy are not justified. Therefore, atopy
may not be a causative factor in OSA, but it could be a comorbid aspect
that characterizes patients at higher risk of failure, and additional
studies are required to clarify if allergy in children with obstructive
respiratory syndrome should not be misdiagnosed because it can be
responsible for treatment failure after surgery (adenoidectomy or
adenotonsillectomy).
We found a very light evidence supporting the correlation between
bacterial recurrent tonsillitis and allergy, in particular some interesting
investigations from the lab revealed that allergy may suppress innate
immunity in tonsillar tissue by reducing levels of anti-microbial
proteins, such as HBDs and S100A7. Future clinical studies, again,
should be undertaken to clarify this aspect.
Finally basing on our systematic review of the literature, we suggest
that future investigations on this topic should avoid several limitations
frequently observed in the studies on pediatric adeno-tonsillar disease
that we analyzed. We focused on several distinctive limitations in the
pediatric population that may influence interpretation of results. First of
all, we cannot overlook that tonsils and adenoids change their size ac­
cording to age, with a peak of growth between 4 and 8 years, and
therefore all results should be age-matched in order to achieve the
correct conclusions. Furthermore, the positive rate of skin prick tests
(SPT) may vary greatly during childhood based on age, and allergens are
also differently expressed at various ages [53]; authors should not fail in
distinguishing between allergic rhinitis by other forms of allergy such as
atopic dermatitis, food allergy, etc. [54]. To the best of our knowledge,
this is the first review emphasizing the importance of analyzing results
basing on an adequate phenotyping of adeno-tonsillar disease.
Financial disclosure
Each author listed in this title page has no financial disclosures.
Declaration of competing interest
Authors have not actual or potential conflict of interest in connection
with the submitted article.
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