pathogens

Review
Diagnosis and Treatment of Local Allergic Rhinitis
Tetsuya Terada * and Ryo Kawata

Department of Otolaryngology, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi,

Takatsuki 569-8686, Japan; [email protected]
* Correspondence: [email protected]; Tel.: +81-726-83-1221

Abstract: Some patients with chronic rhinitis have a positive nasal allergen provocation test (NAPT)
without systemic IgE sensitization by skin prick tests or serum allergen-specific IgE (sIgE). This novel
concept is called local allergic rhinitis (LAR) and affects children and adults worldwide, but is
underdiagnosed. LAR is not just the initial state of allergic rhinitis (AR), it is a unique form of chronic
rhinitis that is neither classical AR nor non-AR. Many of the features of AR and LAR are similar,
such as a positive NAPT, positive type 2 inflammatory markers, including the nasal discharge of sIgE,
and a high incidence of asthma. A differential diagnosis of LAR needs to be considered in patients
with symptoms suggestive of AR in the absence of systemic atopy, regardless of age. The diagnostic
method for LAR relies on positive responses to single or multiple allergens in NAPT, the sensitivity,
specificity, and reproducibility of which are high. The basophil activation test and measurement of
IgE in nasal secretions also contribute to the diagnosis of LAR. Treatment for LAR is similar to that
for AR and is supported by the efficacy and safety of allergen exposure avoidance, drug therapy,
and allergen immunotherapy. This review discusses current knowledge on LAR.

Keywords: allergic rhinitis; nasal allergen provocation tests; diagnosis; local allergic rhinitis





 1. Introduction
Citation: Terada, T.; Kawata, R.
Chronic rhinitis may be divided into two groups: allergic rhinitis (AR) and non-allergic
Diagnosis and Treatment of Local
non-infectious rhinitis, often simplified as non-AR (NAR) [1,2]. Due to its increasing in-
Allergic Rhinitis. Pathogens 2022, 11,
cidence worldwide as well as its impact on quality of life, school performance, and pro-
80. https://doi.org/10.3390/
ductivity at work, AR has become an important public health issue [3]. Patients with
pathogens11010080
allergies are identified by skin prick testing or the presence of allergen-specific IgE in
Academic Editor: Minoru Gotoh serum [4,5]. Patients with AR test positive for at least one of these two diagnostic assess-
ments of atopy [1], whereas non-AR individuals test negative for both [2]. The simple
Received: 2 December 2021
Accepted: 7 January 2022
classification of chronic rhinitis into AR and NAR appears to be limited because it does not
Published: 9 January 2022
consider the form of rhinitis in which allergen-specific IgE produced locally in the nasal
mucosa contributes to pathogenesis. The term local LAR has been proposed to describe
Publisher’s Note: MDPI stays neutral Th2-type nasal mucosal inflammatory diseases in which antigen-specific IgE antibodies are
with regard to jurisdictional claims in
produced locally in the nasal mucosa, the nasal allergen provocation test (NAPT) is positive,
published maps and institutional affil-
and systemic atopy is not proven [6]. We herein discuss the clinical implications of local
iations.
allergy with a focus on the management of NAPT-positive patients without atopic rhinitis.

2. Epidemiology
Copyright: © 2022 by the authors.
LAR develops in a specific number of patients with chronic rhinitis, irrespective of
Licensee MDPI, Basel, Switzerland. nationality, ethnicity, or age [7–9]. Two recent systematic reviews and meta-analyses [10,11]
This article is an open access article showed the data from 3400 patients and healthy controls reporting a 24.7% probability of a
distributed under the terms and positive NAPT in rhinitis patients that were negative for both skin prick test and serum
conditions of the Creative Commons sIgE. In a study on 648 patients with non-atopic rhinitis, nasally secreted IgE (sIgE) was
Attribution (CC BY) license (https:// detected in 10.2% of all patients and in 19.8% of those with a history of allergies [11].
creativecommons.org/licenses/by/ The prevalence of LAR was previously suggested to be higher in Mediterranean
4.0/). countries (Portugal, Spain, Italy, and Greece) than in Nordic countries [12]. Furthermore,

Pathogens 2022, 11, 80. https://doi.org/10.3390/pathogens11010080 https://www.mdpi.com/journal/pathogens

Pathogens 2022, 11, 80 2 of 9

the prevalence of LAR due to house dust mites (HDM) was lower (<20%) in Asian countries
than in Western countries, suggesting a higher prevalence of LAR (range 36.7–66.6%) in the
latter than in the former [13–16].

3. Definition of Disease Concept and Etiological Classification

Nasal mucosal findings, nasal symptoms, the skin prick test, and the presence of
antigen-specific IgE antibodies in serum have been used to classify non-infectious rhinitis
as AR or NAR. However, after the establishment of a definition for LAR, these systemic
tests were clearly limited because of their inability to accurately detect allergic inflam-
mation in the nasal cavity. Therefore, a new etiological classification has been proposed
for rhinitis. The term LAR was suggested by Rondón et al. [6] as a disease concept with
Th2 inflammation of the nasal mucosa and the local production of antigen-specific IgE
antibodies, but without any evidence of systemic atopy.
LAR has been attracting increasing interest in the last 15 years, and it is a term
that is applied to patients with negative allergy skin and blood tests, but with a history
suggestive of allergic sensitization and local evidence of atopy diagnosed by sIgE in nasal
secretions, a positive nasal allergen challenge, or both, and who respond well to allergen-
specific immunotherapy [17,18].
Concerning the endotype, LAR is a type 2 inflammatory disease that is caused by a
localized allergic reaction in the nasal mucosa [19–21].

4. Pathophysiology of Local AR
The basic pathogenesis of LAR involves the localized production of antigen-specific
IgE antibodies in the nasal mucosa and the completion of the antigen-antibody reaction
locally. Previous studies revealed the localized production of sIgE in the nasal mucosa of
patients with AR [22–25]. Furthermore, the nasal secretions of between 20 to 40% of NAPT-
positive patients without systemic sensitization contained sIgE [20,21,26–28]. B cells in the
nasal mucosa have been shown to express epsilon germ-line gene transcripts and mRNA
for the epsilon heavy chain of IgE [29]. In situ hybridization revealed a type 2 inflammatory
pattern, with an increased number of IgE + B cells, mast cells, and eosinophils, in patients
with negative skin tests [19]. Although the mechanisms underlying the disease concept of
LAR and AR have not yet been elucidated, a Th−2 lymphocyte and IgE antibody-mediated
inflammatory reaction in the nasal mucosa of patients with LAR has been demonstrated.
The mast cells and eosinophils of patients with LAR were found to be immediately activated
in the nasal mucosa, releasing the characteristic inflammatory mediators tryptase and
eosinophil cationic protein (ECP) [6].
Antigen-specific IgE antibodies have been observed in the nasal mucosa 24 h after
NAPT, and are regarded as the basis for the localized production of antibodies in the
nasal mucosa [28,30].

5. Clinical Phenotypes of LAR

Some of the clinical features of LAR and AR are similar.
Patients with LAR are generally young, non-smoking women with persistent, peren-
nial symptoms of moderate to severe rhinitis that are often associated with complications
including conjunctivitis and asthma [9].
The most frequent symptom is an itchy and watery nasal discharge commonly trig-
gered by HDM [9]. The prevalence of LAR is higher in young adults [31]; however,
children [9,13,30,32] and the elderly [33] are also affected. Furthermore, patients with LAR
were found to be significantly younger than those with AR, and exhibited more severe
symptoms as well as a family history of atopy [10,31].
Pathogens 2022, 11, 80 3 of 9

Pathogens 2022, 11, 80 were found to be significantly younger than those with AR, and exhibited more severe
3 of 9
symptoms as well as a family history of atopy [10,31].

6. Diagnosis
6. Diagnosis
Diagnostic algorithm for chronic rhinitis is shown in Figure 1.
Diagnostic algorithm for chronic rhinitis is shown in Figure 1.

Figure 1.
Figure Diagnostic algorithm
1. Diagnostic algorithm for
for chronic
chronic rhinitis.
rhinitis.

• NsIgE: Nasal secretion IgE;

• NsIgE: Nasal secretion IgE;
• BAT: Basophil activation test;
•• BAT: Basophil
AR: Allergic activation test;
rhinitis;
•• LAR:Allergic
AR: Local Allergic
rhinitis;rhinitis;
•• Non-AR: Non-allergic rhinitis.
LAR: Local Allergic rhinitis;
• LAR is diagnosed
Non-AR: Non-allergicbased on a detailed history, medical interview, a nasal allergic
rhinitis.
reaction by NAPT, and the exclusion of chronic sinusitis with or without nasal polyps
LAR is diagnosed based on a detailed history, medical interview, a nasal allergic re-
in patients with a negative skin prick test and undetectable sIgE [34,35]. NAPT and the
action by NAPT, and the exclusion of chronic sinusitis with or without nasal polyps in
identification of antigen-specific IgE antibodies in nasal secretions are central to confirming
patients with a negative skin prick test and undetectable sIgE [34,35]. NAPT and the iden-
a diagnosis of LAR.
tification of antigen-specific IgE antibodies in nasal secretions are central to confirming a
Since the measurement of IgE antibodies in peripheral blood and antigen identification
diagnosis of LAR.
testing by skin prick tests are inadequate diagnostic tools for LAR, difficulties are associated
Since the measurement of IgE antibodies in peripheral blood and antigen identifica-
with reaching an accurate diagnosis and, thus, the assessment of local responses in NAPT
tion testing by skin prick tests are inadequate diagnostic tools for LAR, difficulties are
is required [27].
associated
NAPT,with reaching ofansIgE
the detection accurate diagnosis
in the nasal cavity,and,
andthus, the assessment
the basophil activationoftest
local re-
(BAT)
sponses in NAPT
are helpful is required
diagnosis. NAPT[27]. is the current gold standard test for the diagnosis of LAR,
NAPT, the detection
but BAT and nasal sIgE test of sIgE
have in the
the nasal cavity,
limitation and
that thedifficult
are basophil toactivation test (BAT)
use in clinical prac-
are helpful diagnosis. NAPT is the current gold standard test for the diagnosis
tice, and nasal sIgE test shows low sensitivity and inconsistent results [9,20,21,27,36,37]. of LAR,
but BAT and
Although NAPT nasalmay
sIgEbetest
usedhaveto the limitationbetween
differentiate that are difficult
allergic (ARto use
andin LAR)
clinical
andpractice,
nonal-
and nasal sIgE test shows low sensitivity and inconsistent results
lergic disease, a saline test needs to be performed before NAPT to exclude non-specific[9,20,21,27,36,37]. Alt-
hough NAPT may[6,9,36,38,39].
hypersensitivity be used to differentiate
NAPT, a highly between allergic
sensitive (AR and LAR)
diagnostic andmay
method, nonallergic
be con-
disease, a saline test needs to be performed before NAPT to exclude
ducted on children. Several standardized allergen solutions, either ready-to-use solutionsnon-specific hyper-
sensitivity [6,9,36,38,39]. NAPT, a highly sensitive diagnostic
or freeze-dried lyophilizates, are produced by different companies [40]. method, may be conducted
on children.
NAPT isSeveral standardized
considered to be positive allergen
when solutions,
symptomeither ready-to-use
severity markedly solutions
increases or or
freeze-dried lyophilizates, are produced by different companies
combined objective and symptom measurements are moderately elevated [41]. [40].
NAPT is considered
The measurement to be
of sIgE in positive when symptom
nasal secretions severitymethod
is a non-invasive markedly increases
for the diagnosisor
combined
of LAR with objective and symptom
high specificity, but low measurements are moderately
sensitivity (22–40% elevated
of responses) [41].
[20,21].
A previous study demonstrated the diagnostic accuracy of nasal sIgE for LAR in
212 children with chronic rhinitis; 14 had nasal sIgE > 0.35 kU/L and 12 were diagnosed
with LAR based on significantly higher nasal sIgE than controls and a positive NAPT [42].
Pathogens 2022, 11, 80 4 of 9

BAT has a sensitivity of 50% and specificity of >90% for Dermatophagoides pteronyssinus [43]
and a sensitivity of 66% and specificity of >90% for Olea europaea [44], which is useful for
reaching a definitive diagnosis of LAR.

7. NAPT Procedure
NAPT is one of the most important tests for the diagnosis of LAR.
Members of the EAACI Task Force reviewed the evidence based on systematic reviews
involving NAPT over the past few years and proposed a method for standardizing the
NAPT procedure in clinical practice [41]. The Task Force team proposed the use of a stan-
dardized test solution, with two puffs (0.1 mL per nostril) of bilateral spray, and subjective
and objective assessment of the clinical outcomes. This technique aims to cover the mucosa
of the inferior and middle portion of the nasal mucosa with the test allergen.

8. LAR and Asthma

Concomitant asthma symptoms were previously detected in 20–47% of patients with
LAR [20,21]. Another study demonstrated that 50% of patients with LAR had a positive
methacholine test and were diagnosed with asthma [45]. Among patients with AR and
NAR, 83.3 and 57.9%, respectively, were diagnosed with asthma. Furthermore, the bronchial
allergen challenge (BAC) was positive in 28.8 and 83.3% of patients with LAR and AR,
respectively, but was negative in NAR patients and healthy controls [45].
After exposure to an allergen, a significant increase was noted in airway hypersensitiv-
ity testing with methacholine, and the numbers of eosinophils and monocytes in sputum
were significantly elevated [45].
Significant increases were also detected in eosinophils, monocytes, and ECP in the
sputum of BAC+ patients with and without atopy, but not in that of BAC-patients [45].

9. LAR Treatment
9.1. Pharmacological Treatment
The administration of oral H1-antihistamines to prevent new sensitization is not
recommended for young children with nasal allergy and/or a family history of allergy
mainly due to the risk of side effects and the lack of sufficient evidence to show reductions
in the risk of developing new sensitization [46].
Similar to patients with AR, those with LAR respond well to topical nasal corticos-
teroids and oral antihistamines [20,21].
Oral antihistamines and intranasal corticosteroids are mainstay drugs for the treatment
of AR [47]. Clinical experience suggests that these drugs are equally effective in patients
with LAR and those with AR, and this may be attributed to their common clinical and
pathophysiological features, such as eosinophilic rhinitis and reactivity to allergens.
It currently remains unclear whether oral antihistamines or nasal steroids are therapeu-
tically effective for patients with LAR; however, a relationship between LAR and histamine
metabolites was recently demonstrated in a cluster analysis of rhinitis endotypes [48].

9.2. Immunotherapy
Rondón et al. [17] examined the effects of subcutaneous immunotherapy (SCIT) on
LAR by dividing patients with LAR sensitized to grass pollen into two groups: a group
receiving preseasonal grass-specific SCIT for 6 months and rescue medication in spring,
and a control group receiving only rescue medication. The findings obtained showed that
SCIT reduced symptoms in patients with LAR.
For the primary outcome, the SCIT group showed a significant improvement in nasal
tolerance compared with the control group (p = 0.001), with significantly higher threshold
concentrations of grass pollen in NAPTs after 6 (p = 0.001) and 12 (p = 0.001) months of
treatment, and 3 patients had negative NAPT responses.
Secondary outcomes were symptom and medication scores, medication-free days, and
severity of LAR symptoms. In the active group patients reported a clinical improvement in
Pathogens 2022, 11, 80 5 of 9

the following spring, with a median reduction in average daily rhinoconjunctivitis symptom
and rescue medication scores of 45% (p = 0.001) compared with the control subjects.
A 2-year randomized, double-blind, placebo-controlled clinical trial (RDBPCT) of SCIT
for D. pteronyssinus (DP-SCIT) [18], a 2-year RDBPCT (Phl-SCIT) on Phleum pratense [49],
and a 2-year RDBPCT (Bet-SCIT) that tested pollen from Betula verrucosa [50] provided
supportive evidence for these findings. Furthermore, these studies demonstrated that SCIT
exerted both short-term and sustained clinical effects for LAR [17,18,49,51].
SCIT also increased serum sIgG4 levels in patients with LAR in a volume-dependent
manner, and this increase was attributed to IL-10-producing Treg and IgG4-producing
Breg [52,53]; however, further studies are needed to assess the immunological effects of
SCIT in LAR in more detail.
Collectively, these findings provide supportive evidence for the clinical efficacy of
SCIT for LAR based on significant increases in tolerance to allergens and its positive effects
on the quality of life of patients (Table 1).
Table 1. Studies on clinical efficacy of SCIT for LAR.

Author Year Country Study Design Study Group Age (Year) Allergen Efficacy
Rondón, C. et al. [17] 2011 Spain observational 20 LAR (seasonal) adult Phl improve
Rondón, C. et al. [18] 2016 Spain DBPCT 36 LAR (perennial) adult DP improve
Rondón, C. et al. [49] 2018 Spain DBPCT 56 LAR (seasonal) 18–55 Phl improve
Bożek, A. et al. [50] 2018 Poland DBPCT 28 LAR (seasonal) 18–76 Bet v1 improve
DBPCT, Double-blind placebo-controlled trial.

9.3. Prevention Sensitization to New Allergens

Important treatment aims for AR with identifiable allergenic triggers include prevent-
ing the progression to asthma or other respiratory diseases and improving the quality of
life of patients.
The concept of the allergic march has been proposed to describe the development of
pediatric allergic diseases, and refers to allergic diseases progressing with multiple patterns
of development from atopic dermatitis in infancy to bronchial asthma and AR. Infant-onset
atopic dermatitis generally has a favorable prognosis, with remission or complete recovery
being achieved by >90% of patients within several years. However, bronchial asthma
occurs in 30–40% of these patients in infancy, and the inhalation of antigens (mainly mite
antigens) contributes to the development of perennial AR by school age.
In a parallel group open study on AR and/or asthma patients with monosensitization
to HDM, including 85 treated with allergen immunotherapy (AIT) and 62 with medica-
tion only, Inai et al. [54] showed the potential of AIT to prevent new sensitization, which
suggested the importance of initiating AIT at an earlier age, particularly to prevent polysen-
sitization in patients with rhinitis and monosensitization to HDM. The number of patients
who did not show new sensitization after 5 years was significantly higher in the AIT group
(75.3%) than in the control group (46.7%) (p = 0.002). Furthermore, sensitization to at least
one new allergen was noted in 15 out of 21 patients in the AIT group, and to two or more
new allergens in only 1 out of 6. In contrast, in the control group, sensitization to one new
allergen was observed in 22 out of 33 patients, and to two or more new allergens in 11.
Although the mechanisms by which AIT reduced the risk of new sensitization in
children have not yet been elucidated, AIT is known to alter the balance between TH1
and TH2 cells [55]. It also suppressed the production of interleukin (IL)-4 and IL-5 [56,57],
promoted the production of interferon-γ [58], and decreased the number of inflammatory
cells in the nose [59]. The induction of peripheral T cell tolerance by AIT is crucial for its
efficacy and is attributed to increases in the levels of IL-10 and transforming growth factor-β
produced by antigen-specific regulatory T cells. Important immune changes caused by
AIT include increased tolerance to allergens and the development of specific tolerance by
Pathogens 2022, 11, 80 6 of 9

peripheral T cells in response to IL-10, which have been suggested to modify or prolong
the natural progression of respiratory allergic diseases [60].
Although the underlying mechanisms currently remain unclear, the most effective
early intervention for AR and LAR appears to be AIT, the initiation of which at earlier ages
is recommended for the prevention of new sensitization.

10. LAR in Children

The prevalence of LAR in children ranges between 3.7 to 66.7%, and is lower in Asian
countries (3.7–25%) [16,61,62] than in European countries (44.4–66.7%) [13,14,51]. HDM
is the most common allergen in children with LAR worldwide. Ha et al. [62] performed
NAPT with D. pteronyssinus on 145 children and diagnosed 5 with LAR. The largest study
investigating LAR in children was performed by Krajewska-Wojtys et al. [51]; NAPT with
P. pratense, Artemisia vulgaris, and birch pollens was performed on 121 patients aged between
12 and 18 years with confirmed NAR, but with typical seasonal nasal symptoms, and LAR
was confirmed in 73 (52.5%) patients against P. pratense, A. vulgaris, and birch pollens in
17 (16.6%), 6 (5.9%), and 9 (8.9%) of patients, respectively.
The prevalence of LAR is high in children and slightly increases with age. Patients
with LAR initially develop symptoms in childhood. Previous studies highlighted the
importance of not only LAR as the main differential diagnosis of AR in children, but also
target organ assessments by NAPT.
In a systematic review, nasal allergen reactivity was detected in 16.1% of children
younger than 16 years of age with NAR [10,14–16,51,63].

11. Therapeutic Options

In addition to the classical subcutaneous and sublingual administration routes,
the administration of allergens via intralymphatic, intradermic, or epicutaneous routes is
now being investigated for airway allergies [64].
We previously demonstrated that intralymphatic immunotherapy was safe and effective
for AR due to Japanese cedar pollinosis and also that clinical effects persisted for 1–2 years [65].
These routes have yet to be examined in detail in patients with LAR. A previous study
reported that intranasal AIT was effective in an allergic asthma mouse model [59]. LAR is
characterized by a local immune response in the nasal mucosa; therefore, the development
of intranasal AIT strategies and comparisons of their clinical and immunological effects
with those of SCIT are needed [17,18,49].
There is a lack of evidence for the efficacy of surgical treatment of LAR. As LAR
is thought to be a local inflammation of the nasal mucosa, surgical treatment to reduce
local inflammation in the submucosa might be effective against LAR. The reduction of the
mucosal surface tissue reduces the point of contact with the allergen [66].
Surgical treatment might be another treatment option for LAR as scar tissue devel-
ops in the submucosa, destroying blood vessels and glandular structures and inhibiting
regeneration through fibrosis.

12. Conclusions
A complete localized immune response in the nasal mucosa is the disease concept and
definition of LAR. In the absence of systemic atopy, the differential diagnosis of LAR is
currently based on the induction of allergic symptoms by antigen administration in the
nasal mucosa and the presence of IgE antibodies in nasal secretions.
Difficulties are associated with confirming allergic inflammation locally in the nasal
mucosa, starting from antibody production, sensitization, and the antigen-antibody reac-
tion; however, this is the essence of the disease concept of LAR.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Pathogens 2022, 11, 80 7 of 9

Conflicts of Interest: The authors declare no conflict of interest.

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