Allergology International 69 (2020) 331e345

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Allergology International
journal homepage: http://www.elsevier.com/locate/alit

Invited Review Article

Japanese guidelines for allergic rhinitis 2020*

Kimihiro Okubo a, *, Yuichi Kurono b, Keiichi Ichimura c, Tadao Enomoto d,
Yoshitaka Okamoto e, Hideyuki Kawauchi f, Harumi Suzaki g, Shigeharu Fujieda h,
Keisuke Masuyama i, The Japanese Society of Allergology
a
Department of Otorhinolaryngology, Nippon Medical School, Tokyo, Japan
b
Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
c
Jichi Medical University, Tochigi, Japan
d
Tottori University Faculty of Medicine, Tottori, Japan
e
Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
f
Department of Otorhinolaryngology, Shimane University Faculty of Medicine, Shimane, Japan
g
Nasal and Paranasal Sinus Disease and Allergy Institute, Tokyo General Hospital, Tokyo, Japan
h
Division of Otorhinolaryngology, Head & Neck Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Science, University of Fukui,
Fukui, Japan
i
Department of Otorhinolaryngology, Suwa Central Hospital, Nagano, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only
Received 6 November 2019 type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life
Available online 27 May 2020 (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this
knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium
Keywords: held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is
Allergen immunotherapy
widely used today.
Mechanism
To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of
Pharmacotherapy
Pollinosis
evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis
Surgery in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for
children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy
for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed.
Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various
clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy
syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan
was added to the end of this guideline.
Copyright © 2020, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Definition and disease names allergic rhinitis caused by pollen antigens, frequently complicated
Allergic rhinitis is a type I allergic disease of the nasal mucosa, by allergic conjunctivitis.1
characterized by paroxysmal repetitive sneezing, watery rhinor-
rhea, and nasal blockage. The disease names, most commonly used
in publications, include allergic rhinitis, nasal allergy, nasal hyper- 2. Classification of rhinitis
sensitivity, and pollinosis. Allergic rhinitis is classified into peren- Rhinitis generally indicates nasal mucosal inflammation
nial and seasonal compared to ARIA guideline. Pollinosis is seasonal (Table 1). Histopathologically, nasal mucosal inflammation is an
exudative inflammation. Suppurative and allergic inflammation are
particularly common. Both are characterized by leakage of serum
components from vessels, edema, cell infiltration, and
*
This article is a minor revision of “Japanese guidelines for allergic rhinitis hypersecretion.
2017” published in Allergol Int 2017:66;205-19.
Infectious rhinitis is classified into acute and chronic rhinitis.
* Corresponding author. Department of Otorhinolaryngology, Nippon Medical
School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Hyperesthetic non-infectious rhinitis, that is nasal hypersensitivity
E-mail address: ent-kimi@nms.ac.jp (K. Okubo). complicated by sneezing and watery rhinorrhea, or all nasal symp-
Peer review under responsibility of Japanese Society of Allergology. toms including sneezing, watery rhinorrhea, and nasal blockade, is

https://doi.org/10.1016/j.alit.2020.04.001
1323-8930/Copyright © 2020, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
332 K. Okubo et al. / Allergology International 69 (2020) 331e345

Table 1 antibodies are produced in the nasal mucosa and regional

Classification of rhinitis. lymphatic tissues. Most causative antigens are inhalation antigens,
1. Infection such as Dermatophagoides (a major antigen in house dust), pollens
a. Acute b. Chronic (trees, grasses, and weeds), fungi, and pets. Of these, Dermato-
2. Hyperesthetic non-infectious rhinitis phagoides and pollens are most common.
a. Combined type (nasal hypersensitivity):
i) Allergic: perennial rhinitis, seasonal rhinitis
In sensitized individuals, antigens inhaled through the nasal
ii) Nonallergic: vasomotor (idiopathic) rhinitis, rhinitis with eosinophilia mucosa pass through the nasal mucosal epithelial cells to bind to
syndrome IgE antibodies on mast cells distributed over the nasal mucosa. In
b. Rhinorrhea type: gustatory rhinitis, cold inhalation rhinitis, senile rhinitis response to an antigen-antibody reaction, chemical mediators, such
c. Congestive type: medicament rhinitis, psychogenic rhinitis, pregnant
as histamine and peptide leukotrienes (LTs), are released from mast
rhinopathia, hormonal rhinitis, and cold rhinitis
d. Dry type: dry nose cells. These irritate the sensory nerve endings and blood vessels of
3. Irritant rhinitis the nasal mucosa to cause sneezing, watery rhinorrhea, and nasal
a. Physical b. Chemical c. Radiation mucosal swelling (nasal blockage). This is an early phase reaction.
4. Others Various inflammatory cells, such as activated eosinophils, infiltrate
a. Atrophic rhinitis b. Specific granulomatous rhinitis
into the nasal mucosa exposed to antigens in response to cytokines,
The hyperesthetic non-infectious rhinitis is characterized by hypersensitivity. chemical mediators, and chemokines. Leukotrienes, produced by
However, this is not inflammatory, except for the allergic rhi-nitis. Thus, this should
these inflammatory cells, cause nasal mucosal swelling. This is a
reasonably be eliminated from the classification of rhinitis and regarded as a disease
similar to allergy or hypersensitivity diseases. However, this was placed into this late phase reaction, seen at 6e10 h after antigen exposure.7
classification in view of potential clinical convenience. Vasomotor rhinitis is called
an idiopathic rhinitis in international classification. This term was used according to
4.1. Sneezing
the practices. The conditions listed in 4a and 4b should be classified under chronic
rhinitis in 1b. However, they were separately classified because of the small number Sneezing is caused by histamine irritation of the sensory nerve
of cases. (trigeminal nerve) in the nasal mucosa, transmitted to the sneezing
Adapted from reference.1 center of the medulla oblongata. The irritant effects of histamine on
the sensory nerve are enhanced by allergies to cause sneezing.

classified into allergic and nonallergic rhinitis. Nonallergic rhinitis

includes vasomotor rhinitis and rhinitis with eosinophilia syn- 4.2. Watery rhinorrhea
drome. Vasomotor rhinitis is symptomatically similar to allergic The sensory nerve irritation in the nasal mucosa causes para-
rhinitis. However, it cannot be identified as an allergy by tests. The sympathetic nerve excitement, resulting in sneezing reflex.
major cause of vasomotor rhinitis is dysautonomia of the nasal
mucosa. However, this definition is not recognized in international
classification and vasomotor rhinitis is classified as idiopathic
rhinitis.2 Rhinitis with eosinophilia syndrome is characterized by
nasal discharge eosinophilia, and other negative allergy tests.3
Noninfectious, nonallergic rhinitis also includes rhinorrhea,
congestive, and dry types. Rhinorrhea types include gustatory
rhinitis. Congestive types include medicament rhinitis and psy-
chogenic rhinitis, pregnant rhinopathy, hormonal rhinitis, and cold
rhinitis. Medicament rhinitis is caused by the long-term adminis-
tration of sympathomimetics, vasodilatory antihypertensives, b-
stimulatory antihypertensives, bronchodilators, antidepressants, or
contraceptive pills. However, the most common cause is the over- Fig. 1. Prevalence in 1998 and 2008. Adapted from reference.1
use and overdose of sympathomimetic nose drops prescribed for
nasal blockage.4

3. Epidemiology of allergic rhinitis

The number of patients with allergic rhinitis, particularly com-
mon sinusitis, has decreased since the 1960s. In contrast, the
number of patients with allergic rhinitis has increased. Recently,
the number of patients with pollinosis, particularly with Japanese
cedar pollinosis, has markedly increased. An epidemiological study
revealed a marked increase in the prevalence of allergic rhinitis
between 1998 and 2008 (Fig. 1).5 In particular, the number of pa-
tients with Japanese cedar pollinosis has increased. Data on prev-
alence by age shows that perennial allergic rhinitis is common
among young people and that Japanese cedar pollinosis is common
among middle-aged people (Fig. 2). According to the International
Study of Asthma and Allergies in Childhood (ISAAC), the prevalence
in Japan is at a medium level in the world (Fig. 3).6

4. Pathogenic mechanisms of allergic rhinitis (Fig. 4)

There are various diatheses for allergic rhinitis sensitization, but
their mechanisms remain largely unknown. Genetic factors and
diatheses for IgE antibody production are the most important. In
response to antigen entry into the mucous membrane, IgE Fig. 2. Prevalence by age. Adapted from reference.1
 K. Okubo et al. / Allergology International 69 (2020) 331e345 333

Fig. 3. Allergic rhino conjunctivitis symptoms within one year by ISAAC questionnaire (ISAAC phase I test). Survey in 1995 by ISAAC (The International Study of Asthma and
Allergies in Childhood). The survey point in Japan. is Fukuoka. Circles indicate the prevalence for each survey point (average 3,000 subjects/point).

Fig. 4. Mechanism of allergic rhinitis. Hi, histamine; LT, leukotriene; TXA2, thromboxane A2; PGD2, prostaglandin D2; PAF, platelet activating factor; IL, interleukin; GM-CSF,
granulocyte/macrophage colony stimulating factor; IFN-g, Interferon-g; TARC, thymus and activation-regulated chemokine; RANTES, regulated upon activation normal T
expressed, and presumably secreted; TCR, T cell receptor. yOnly possible migration factors are listed because no theory has been established. zPresumed to be caused by allergic
reaction. Adapted from reference.1

Acetylcholine is released from the parasympathetic nerves. Hista- 4.3. Nasal mucosal swelling
mine acts directly on the nasal mucosal vessels to cause plasma Nasal mucosal swelling is caused by interstitial edema in the
leakage. However, it accounts for only 10% of rhinorrhea. Most nasal mucosa, due to plasma leakage, and congestion of the nasal
rhinorrhea is secreted from the nasal glands.8 mucosal vessels. The direct actions of chemical mediators, such as
334 K. Okubo et al. / Allergology International 69 (2020) 331e345

histamine, PAF, prostaglandin D2, kinin, and particularly leuko- 6. Classification of allergic rhinitis
triene, are essential. Leukotrienes released from infiltrating in- Allergic rhinitis is roughly classified based on causative antigens,
flammatory cells, particularly eosinophils, play a major role in nasal predilection time, disease types, and severity of symptoms.
mucosal swelling, observed in a late phase.7-9
Thus, the early phase reaction of allergic rhinitis is caused by an
6.1. Predilection time
IgE antibody-mediated type I antigen-antibody reaction. Then,
Allergic rhinitis is classified into seasonal and perennial.
infiltrating inflammatory cells induce a late phase reaction.
Perennial allergic rhinitis can be caused by some pollens.
Continuous antigen irritation cause chronic lesions.

6.2. Disease types

“Sneezing and rhinorrhea type” is collectively used because of a
5. Tests and diagnosis of allergic rhinitis
strong correlation between sneezing and rhinorrhea mainly by
5.1. Tests
histamine effect. “Nasal blockage type” is used for symptoms with
Nasal eosinophil staining in the nasal secretion and serum IgE
more severe nasal blockage by mainly by leukotriene or other lipid
antibody measurement are useful for diagnosis. Potential causative
mediators effect. Symptoms between these types are “combined
allergens should be identified based on skin reactions or serum
type.”
allergen-specific IgE antibody measurements. A nasal mucosa
provocation test can be conducted for house dust and ragweed, but
their assessments may be difficult. Rhinoscopy and CT scan are 6.3. Severity
performed for differential diagnosis. Determine severity based on symptoms, test results, and in-
spection for nasal mucosa. In general, the determined level of
severity based on symptoms is important (Table 2A, B).10

5.2. Diagnosis
A definite diagnosis is made based on three symptoms (sneezing 7. Assessment based on QOL
and nasal itch, watery rhinorrhea, and nasal blockade), together Allergic rhinitis is manageable when treated, but resists cure.
with positive nasal eosinophil tests in the season, and identified Thus, treatment is aimed at improvement in quality of life (QOL). A
causative allergens, based on skin reactions or serum allergen- QOL questionnaire for Japanese with allergic rhinitis was developed
specific IgE antibody measurements. in 2002 (Fig. 5).11

Table 2A
Classification of the severity of allergic rhinitis symptoms I.

Severity Paroxysmal sneezing or rhinorrheay

++++ +++ ++ + 

++++ Most severe Most severe Most severe Most severe Most severe

+++ Most severe Severe Severe Severe Severe

Nasal blockage ++ Most severe Severe Moderate Moderate Moderate

+ Most severe Severe Moderate Mild Mild

 Most severe Severe Moderate Mild No symptoms

Sneezing and rhinorrhea type, ; Nasal blockage type, ; Combined type, .

Severe, moderate, and mild symptoms are determined according to conventional classification. Uncontrollable severe symptoms are clas- sified into the most severe
symptoms, because they may occur during a heavy pollen dispersal period.
Adapted from reference1.
y
Select more severe one, sneezing or rhinorrhea.

Table 2B
Classification of the severity of allergic rhinitis symptoms II: severity of the symptoms.

Types Severity

þþþþ þþþ þþ þ e

Paroxysmal sneezing (Average number 21 times 20-11 times 10-6 times 5-1 times Below þ
of episodes of paroxysmal sneezing
in a day)

Rhinorrhea (Average number of 21 times 20-11 times 10-6 times 5-1 times Below þ
episodes of nose blowing a day)

Nasal blockage Completely Severe nasal blockage Severe nasal blockage causing Nasal blockage without Below þ
obstructed all day causing prolonged occasional oral breathing in a day oral breathing
oral breathing in a day

Troubles with daily lifey Impossible Painful and Intermediate between (þþþ) and (þ) Few troubles Below þ
complicating
daily life

Adapted from reference.1

y
Troubles with daily life: Troubles with work, study, household work, sleep, going out, etc.
 K. Okubo et al. / Allergology International 69 (2020) 331e345 335

Fig. 5. Japanese Allergic Rhinitis Standard Quality of Life Questionnaire (JRQLQ No. 1). Adapted from reference.12

8. Treatment of allergic rhinitis (1) Mast cell stabilizer: Since the development of disodium
8.1. Aim of treatment cromoglicate (DSCG), local agents (eye drops and nasal
The aim of treatment is to alleviate symptoms and remove dif- spray) and oral agents, such as tranilast, amlexanox, and
ficulties with everyday life. Choose a treatment based on severity, pemirolast potassium, have been on the market. They have
disease type, and lifestyle. mild effects. To achieve sufficient clinical effects, 2-week
prolonged administration is required. Amelioration rates are
increased by continuous administration. Adverse effects,
8.2. Treatment (Table 3) such as sleepiness and dry mouth, do not occur.
8.2.1. Natural courses and communication with patients (2) Chemical mediator receptor antagonists
Combinations of pharmacotherapies based on severity and a) Histamine H1 receptor antagonists (antihistamine)
disease types and communication with patients improve patients' (i) First-generation antihistamine: First-generation
satisfaction and QOL. Japanese cedar pollinosis, which developed antihistamine often cause adverse effects, such as
during childhood or early or late middle ages, should be treated in sleepiness, impaired performance, and dry mouth,
view of a prolonged course. but have immediate effects on sneezing and watery
rhinorrhea. First-generation antihistamine are con-
8.2.2. Elimination and avoidance of antigens (Table 4) traindicated for patients with glaucoma, prostatic
In addition to the cleaning, lowering humidity with dehumidi- hyperplasia, and asthma because of their potent
fier is effective in reducing mites. For Japanese cedar pollinosis, anticholinergic effects. They have less central nervous
refer to pollen dispersal information to consider measures to pre- system depressant actions in children than in adults.
vent pollen inhalation. For pet allergy, avoid contact with causative Caution should be exercised for excitatory effects,
pets and keep dogs and cats clean. such as convulsions. Most of first-generation antihis-
tamine are marketed as OTC.
8.2.3. Pharmacotherapy (ii) Second-generation antihistamine (Table 6): Second-
Therapeutic agents for allergic rhinitis, with different mecha- generation antihistamine, such as ketotifen fuma-
nisms of action, are classified as shown in Table 5. Alpha- rate, oxatomide, azelastine hydrochloride, emedas-
sympathomimetics (vasoconstrictor nose drops), which tempo- tine difumarate, and mequitazine, are effective to
rarily alleviate nasal blockage, are also used. some extent for nasal blockage aside from sneezing
336 K. Okubo et al. / Allergology International 69 (2020) 331e345

Table 3 b) Leukotriene receptor antagonists (antileukotrienes)

Therapy. (Table 7): Peptide leukotrienes, produced and released by
1. Communication with patients mast cells, eosinophils, and macrophages, have potent
2. Elimination and avoidance of antigens relaxing effects on the vascular smooth muscles of the
- Mites: cleaning, dehumidification, mite control blanket cover, etc. nasal mucosa, enhancing effects on vascular perme-
- Pollen: mask, glasses, etc.
3. Pharmacotherapy
ability, and stimulating effects on eosinophil migration.
- Chemical mediator receptor antagonists (antihistamine, leukotriene re- Pranlukast and montelukast are available. They are
ceptor antagonists, anti-prostaglandin D2/throm- boxane A2 agents) (nasal effective for nasal blockage. Their effects are increased by
spray, oral medication) prolonged administration. Comparable effects with those
- Mast cell stabilizer (nasal spray, oral medication)
of antihistamines can be achieved for sneezing and rhi-
- Steroids (nasal, oral medication)
- Autonomic drugs (a-sympathomimetics) norrhea within 4 weeks.13 Primary indications are
- Others treatment of symptoms of the moderate or milder nasal
4. Specific immunotherapy (conventional, rapid procedures, sublingual) blockage type and those of intermediate type with nasal
5. Operative treatment blockage as the chief complaint. No adverse effects of
- Coagulation necrosis (radiofrequency electrocoagulation, laser surgery,
trichloroacetic acid chemo-surgery, etc.)
sleepiness, occur.
- Resection (corrective surgery of nasal cavity, extensive turbinectomy, nasal c) Prostaglandin D2 and thromboxane A2 receptor antag-
polypotomy, etc.) onist (Table 8): Ramatroban enhances vascular perme-
- Vidian neurotomy and posterior nasal neurotomy ability in the nasal mucosa and suppresses eosinophil
Adapted from reference.1 migration by blocking thromboxane receptors, and
suppresses eosinophil migration by blocking CRTh2
(chemoattractant receptor-homologous receptor
expressed on Th2 cell), a part of the prostaglandin D2
receptor. They have strong delayed effects on nasal
Table 4 blockage.14 Primary indications are treatment of symp-
Elimination and avoidance of antigens.
toms of nasal blockage type and those of combined type
<Elimination of house dust mites> with nasal blockage as a chief complaint. The agents
1. For indoor cleaning, use an exhaust circulation-type cleaner. Clean room for interact with some other medicines, but cause no
20 s/m2 twice a week.
2. Avoid using textile sofa, carpet, and tatami wherever possible.
adverse effects of sleepiness.
3. Put antimite covers over mattresses, beds, and pillows. (3) Th2 cytokine inhibitors: IPD inhibits the production of Th2
4. Keep humidity at 50% and room temperature at 20e25  C. cytokines, such as IL-4 and IL-5, in T lymphocytes to alleviate
<Avoidance of cedar pollen> allergic inflammation. No adverse effects of sleepiness, occur.
1. Collect pollen information.
(4) Steroids
2. Stay at home during a heavy pollen dispersal period.
3. Shut windows and doors during a heavy pollen dispersal period. a) Nasal steroids (Table 9): Beclomethasone propionate,
4. When going out during a heavy pollen dispersal period, wear a mask and fluticasone propionate, mometasone furoate, fluticasone
glasses. furoate, and dexamethasone cipecilate are available. All
5. When going out, avoid wearing woolen coats. agents have strong local effects in small amounts, and are
6. When going home, shake dust off from suit and hair before entering. Wash
the face, gargle, and blow your nose.
poorly absorbed and readily degraded. Thus, they have
7. Clean rooms frequently. few systemic adverse effects. They are highly effective for
<Reduce pet (especially cat) antigens> sneezing, watery rhinorrhea, and nasal mucosal swelling,
1. Stop keeping pets if possible. and exert their effects within 1e3 days. A slight feeling of
2. Keeps pets outdoors and keep them away from bedroom.
nasal irritation, feeling of dryness, and epistaxis may
3. Clean pets and their environments.
4. Change carpet to flooring. occur.15
5. Improve ventilation, and clean rooms. b) Steroids for internal use: Only for intractable cases with
Adapted from Practical Guideline for the Management of Allergic Rhinitis in Japan
severe nasal blockage and laryngopharynx symptoms,
2009, digest version. uncontrollable with nasal spray steroids, prednisolone
(20e40 mg/day) can be administered for 4e7 days at the
start of treatment. Caution should be exercised for
adverse effects.
and watery rhinorrhea. However, they may cause (5) Alpha-sympathomimetics (nasal topical vasoconstrictor
adverse effects, such as sleepiness and impaired per- [decongestant]): Alpha-sympathomimetics act on the a-re-
formance, in early versions. Thus, caution should be ceptors of vascular smooth muscles to cause vasoconstriction
exercised in administering them. The adverse effects and temporarily alleviate nasal mucosal swelling. Long-term
of late versions, such as epinastine hydrochloride, continuous administration causes medicament rhinitis. For
ebastine, cetiridine, fexofenadine, loratadine, olopa- the most severe pollinosis, they can be administered 2e3
tadine hydrochloride, bepotastine besilate, and levo- times a day for 1e2 weeks.
cetirizine, have been reduced.12 Priority indications (6) Other pharmacotherapy (Table 10): Nonspecific allassother-
are mild to moderate sneezing and rhinorrhea type. apy agents, biological preparation, and herbal medicines can
Combine them with topical steroids depending on be used.
severity. A combination drug containing an antihis- (7) Adverse effects and drug interactions of therapeutic agents
tamine (fexofenadine) and an oral decongestant for allergic rhinitis (Table 11, 12): Therapeutic agents for
(pseudoephedrine) is now available. However, the allergic rhinitis are those for symptomatic treatment, used to
priority indication for this combination drug is alleviate symptoms. Caution should be exercised for harmful
limited to the moderate to severe nasal blockage type adverse effects and drug interactions during treatment. If
of pollinosis and the severe nasal blockage type of they occur, take immediate measures and switch to a
perennial allergic rhinitis. different treatment.
 K. Okubo et al. / Allergology International 69 (2020) 331e345 337

8.2.4. Specific immunotherapy Table 6

Subcutaneous specific immunotherapy (SCIT) has been used Characteristics of second-generation antihistamine (compared with first-generation
antihistamine).
over the past century. Its demonstrated effects may be exerted via
immunological mechanisms. Of note, local mast cells are decreased, 1. Few adverse effects, such as central sedation and anticholinergic effects
the Th1/Th2 balance is altered, and regulatory T cells are increased. 2. Slightly favorable general improvement
3. Slightly effective for nasal blockage
It takes several months to develop effects, requiring routine injec- 4. Mild, delayed, and prolonged effects
tion for 3 years. Furthermore, a systemic anaphylaxis response 5. Improvement rate is increased by prolonged administration.
may develop in a small number of cases.16 The characteristics of this
Relatively effective; however, it takes about 2 weeks to achieve sufficient effects in a
method are shown in Table 13. clinical test on perennial allergic rhinitis. This is the time required to suppress hy-
(1) Indications: This therapy is indicated for the treatment of persensitivity with a single treatment.
patients aged 6 years, without severe systemic symptoms, Modified from Practical Guideline for the Management of Allergic Rhinitis in Japan
2009, digest version.
to whom emergency adrenaline may be administered.
Exclude patients on b-blocker therapy or with severe asthma.
While this therapy has no harmful effects on pregnant
women, it should not be started during pregnancy.
Table 7
(2) Implementation
Characteristics of leukotriene receptor antagonists.
a) Specialists should prescribe antigen extracts and take
measures against systemic reactions, such as anaphylactic 1. Suppress the vascular dilation and permeability of the nasal mucosa, and
improve nasal blockage.
shock.
2. More effective for nasal blockage than second-generation antihistamine.
b) In patients with asthma complications, avoid this therapy 3. Suppress eosinophilic infiltration and nasal secretion, and improve sneezing
during a paroxysmal period. In patients with pollinosis, and rhinorrhea by  2-week prolonged administration.
avoid starting this therapy during dispersal of causative 4. Effects are noted at 1 week after start of oral administration, reaching a peak
pollen. at 4 weeks.

c) For initial injection, reduce the threshold concentration Modified from Practical Guideline for the Management of Allergic Rhinitis in Japan
for intradermal reaction to 1/10. Before injection, ask 2009, digest version.
more than one physicians or health care professionals
about concentration and dosage.
d) Before increasing an aqueous solution concentration or
changing lots, conduct an intradermal test. For patients Table 8
with erythema of 50 mm diameter, carefully conduct Characteristics of prostaglandin D2/thromboxane A2 receptor antagonists.

1. Suppress the vascular permeability of the nasal mucosa, and improve nasal
blockage.
2. More effective for nasal blockage than second-generation antihistamine.
Table 5 3. Inhibit eosinophil migration caused by PGD2, and improve sneezing and
Therapeutic agents for allergic rhinitis. rhinorrhea by  2-week prolonged administration.
4. Effects are relatively slow, reaching a peak at 4 weeks.
1. Mast cell stabilizer
Disodium cromoglycate (Intal®), tranilast (Rizaben®), amlexanox (Solfa®), Modified from Practical Guideline for the Management of Allergic Rhinitis in Japan
pemirolast potassium (Alegysal®, Pemilaston®) 2009, digest version.
2. Chemical mediator receptor antagonists
a. Histamine H1 receptor antagonists (antihistamine)
<First-generation>
d-chlorpheniramine maleate (Polaramin®), clemastine fumarate Table 9
(Tavegyl®), etc. Characteristics of nasal steroids.
<Second-generation>
Ketotifen fumarate (Zaditen®), azelastine hydrochloride (Azeptin®), oxa- 1. Potent effects
tomide (Celtect®), mequitazine (Zesulan®, Nipo- lazin®), emedastine 2. Relatively rapid effects
difumarate (Daren®, Remicut®), epinastine hydrochloride (Alesion®), 3. Few adverse effects
ebastine (Ebastel®), cetirizine hydrochloride (Zyrtec®), levocabastine hy- 4. Effective equally to the 3 symptoms of nasal allergy
drochloride (Livostin®), bepotastine besilate (Talion®), fexofenadine hy- 5. Effective only at administration site
drochloride (Allegra®), olopatadine hydrochloride (Allelock®), loratadine Modified from Practical Guideline for the Management of Allergic Rhinitis in Japan
(Claritin®), fexofenadine & pseudoephedrine (Dellegra®) 2009, digest version.
b. Leukotriene receptor antagonists
Pranlukast hydrate (Onon®), montelukast sodium (Singulair®, Kipres®)
c. Prostaglandin D2/thromboxane A2 receptor antagonists (anti-prosta-
glandin D2/thromboxane A2 agents)
Ramatroban (Baynas®) Table 10
3. Th2 cytokine inhibitor Characteristics of nonspecific allassotherapy agents, biological preparations, and
Suplatast tosilate (IPD®) herbal medicines.
4. Steroids
a. Nasal Nonspecific allassotherapy agents
Beclomethasone propionate (Aldecin® AQ Nasal, Rhinocort®), fluticasone Histamine added gamma globulin, bacterial vaccine, and gold preparations
propionate (Flunase®), mometasone furoate hydrate (Nasonex®), dexa- are available. They are rarely used alone. Their mechanisms of action are
methasone cipecilate capsule for external use (Erizas®) unclear.
b. Oral medication Biological preparations
Compounding agent of betamethasone/d-chlorpheniramine maleate Neurotropin is commercially available. Its mechanism of action is unclear.
(Celestamine®) They have no instantaneous effect.
5. Others Herbal medicines
Nonspecific allassotherapy agents, biological preparations, and herbal Syoseiryuto, Kakkonto, Syosaikoto, etc., are used. A placebo-controlled test
medicines was conducted only for Syoseiryuto to demonstrate its efficacy.

Modified from Practical Guideline for the Management of Allergic Rhinitis in Japan Modified from Practical Guideline for the Management of Allergic Rhinitis in Japan
2009, digest version. 2009, digest version.
338 K. Okubo et al. / Allergology International 69 (2020) 331e345

Table 11 8.3. Choice of therapy

Adverse effects of therapeutic agents for allergic rhinitis. 8.3.1. Perennial allergic rhinitis
Medicines Adverse effects Select a therapy based on severity and disease type. Selection
First-generation Sleepiness, systemic malaise, dry mouth, etc.
criteria are shown in Table 15. For mild symptoms, second-gener-
antihistamine (asthma, dysuria, glaucoma, and ation antihistamines, mast cell stabilizers, Th2 cytokine inhibitors,
contraindication to driving) or nasal topical steroids are the first-line agents. For moderate
Second-generation Hepatic and gastrointestinal disorders, sleepiness, symptoms of sneezing and rhinorrhea type, choose one of the
antihistamine and myocardiopathy for some agents following: (i) second-generation antihistamine, (ii) mast cell sta-
Oral mast cell stabilizer Hepatic and gastrointestinal disorders, rash, and bilizer, and (iii) nasal topical steroids. Add (i) or (ii) with (iii) as
cystitis for some agents needed. For symptoms of nasal blockage or combined type, choose
Leukotriene receptor Leukopenia, thrombocytopenia, hepatic disorders,
an agent from (i) leukotriene receptor antagonists, (ii) prosta-
antagonists rash, diarrhea, abdominal pain, etc. glandin D2/thromboxane A2 receptor antagonist, (iii) Th2 cytokine
inhibitor, (iv) nasal topical steroids. Combine (i) or (ii) or (iii) with
Prostaglandin D2/ Bleeding tendency, hepatic disorders, rash,
thromboxane abdominal pain, headache, etc. (iv) as needed.
A2 receptor For severe cases with severe sneezing and rhinorrhea,
antagonists combine second-generation antihistamine with nasal spray
Th2 cytokine inhibitors Hepatic disorders, jaundice, nephrosis, etc. steroids. For symptoms of nasal blockage or combined type,
add nasal topical steroids with leukotriene receptor antagonists
Oral corticosteroids Infection, adrenocortical insufficiency, diabetes,
peptic ulcer, moon face, glaucoma, etc. or prostaglandin D2/thromboxane A2 receptor antagonists.
(contraindicated for treatment of infection, pep- tic Additionally, a combination drug containing an antihistamine
ulcer, hypertension, diabetes, glaucoma, etc.) and an oral decongestant is suitable for this type For all cases,
Nasal steroids Nasal irritation, feeling of dryness, epistaxis, etc. eliminate and avoid antigens. For cases in which treatment can
be continued, specific immunotherapy can also be chosen. For
Mast cell stabilizer and Nasal irritation and sleepiness (for some agents)
antihistamine cases of nasal blockage type, in which the effects of pharma-
for nasal spray cotherapy are insufficient, surgical treatment can also be
Vasoconstrictor nose Habituation, rebound phenomena, chosen.
spray hyporesponsiveness, etc.

Adapted from Practical Guideline for the Management of Allergic Rhinitis in Japan
8.3.2. Pollinosis
2009, digest version. Therapy is chosen based on severity and disease type. However,
the severity of pollinosis markedly changes with the amount of
the test and follow-up the patients for 20e30 min after pollen dispersal. Therefore, before starting treatment, determine
injection. the severity based on symptoms at a hospital visit, symptoms at
e) Perform therapy for at least 3 years. Therapeutic effects peak pollen dispersal, and amounts of pollen dispersal (Table 16).
often continue for several years after discontinuation of (1) Primary therapy (initial treatment) (Fig. 6): The aim of pri-
administration. mary care is to suppress allergic inflammation and nasal
f) Instruct patients to continue the therapy. mucosal hypersensitivity, which are aggravated by repeated
(3) Sublingual immunotherapy (SLIT) exposure to small amounts of antigen. For patients who
Presently, SLIT is permitted in Japan for reactions to the al- suffer from even mild symptoms simultaneously with or
lergens, Japanese cedar pollen and dust mites.17 The current before pollen dispersal, start pharmacotherapy when
indication for SLIT is confirmation of a positive allergen to symptoms develop. Administer second-generation antihis-
Japanese cedar pollen or dust mites by a skin reaction or a tamine or mast cell stabilizer for symptoms of sneezing and
specific IgE in a patient 5 years of age or older. The allergen is rhinorrhea type. Administer a leukotriene receptor antago-
administered as a liquid or tablet every day in a dose- nist, a prostaglandin D2/thromboxane A2 receptor antago-
escalation manner for at least 2 or 3 years. The contra- nist, a Th2 cytokine inhibitor, or a nasal topical steroid for
indications are serious illnesses that require the use of a b symptoms of nasal blockage and those of the combined type
blocker, unstable asthma in which a systemic steroid may be with nasal blockage as a chief complaint.19 If symptoms are
required, treatment with an anti-cancer drug, severe auto- exacerbated as pollen dispersal increases, use the combina-
immune disease, or cases in which it is assumed the treat- tion of nasal topical steroids early.
ment should not be used in the patient because of the side (2) Mild symptoms: For mild symptoms, administer a second-
effects. It cannot be begun from the dispersion period. Sub- generation antihistamine, mast cell stabilizer, leukotriene
lingual inoculation should be suspended in the case of receptor antagonist, prostaglandin D2/thromboxane A2 re-
pregnancy, mouth injury or ulcer, or if severe odonto-therapy ceptor antagonist, Th2 cytokine inhibitor, or nasal topical
is required. However, if pregnancy occurs while this therapy steroid. If symptoms are exacerbated, concomitantly use or
is being administered, allergen immunotherapy, including add nasal topical steroids early.
subcutaneous injection, is generally thought to be safe. (3) Moderate symptoms: For symptoms of sneezing and rhi-
norrhea type, start treatment by the combination of second-
8.2.5. Surgical treatment generation antihistamine and nasal topical steroids. For
Nasal blockage in allergic rhinitis is often caused by nasal de- symptoms of nasal blockage type, use a combination of
formities, such as deviated septum, hypertrophic rhinitis, and nasal leukotriene receptor antagonists or prostaglandin D2/
polyps. In this case, perform corrective surgery of nasal cavity to thromboxane A2 receptor antagonist and nasal topical ste-
improve nasal ventilation. Before pollen season, laser surgery is also roids. For symptoms of combined type, add second-
performed for Japanese cedar pollinosis, but the effects of this surgery generation antihistamine. A combination drug containing
do not continue in the following year.18 The main purpose is to alle- an antihistamine and an oral decongestant along with the
viate nasal blockage. Various techniques shown in Table 14 are used. use of a nasal topical steroid is suitable for this type.
For intractable rhinorrhea, perform posterior nasal neurectomy.
 K. Okubo et al. / Allergology International 69 (2020) 331e345 339

Table 12
Drug interactions of therapeutic agents for allergic rhinitis and measures.

Therapeutic agents Concomitant agents Effects Measures

Second-generation antihistamine Alcohol Enhanced central inhibition/Hypnosis, Caution should be exercised for
Sedatives, hypnotics, vertigo, weakness, malaise combined use./Reduce dose if adverse
psychotropics effects are noted.
Cold medicines

Ketotifen fumarate Tolbutamide Thrombocytopenia/Bleeding tendency

Oxatomide Antipsychotics Exacerbation of extrapyramidal disturbances

Tricyclic antidepressants /Tremor and difficulty in walking
Digestive function activators
Caution should be exercised for
Antiarrhythmics
combined use./Discontinue the
Tricyclic antidepressants Enhanced anticholinergic effects/Dry mouth combined use if adverse effects are
Anticholinergics and exacerbation of glaucoma noted.

b2 stimulants Exacerbation of tremor

Theophylline

Ebastine Erythromycin Inhibition of liver drug-metabolizing Caution should be exercised for

enzymes/Increased serum carebastine level combined use./Reduce dose if adverse
effects are noted.

Fexofenadine hydrochloride Antacids Decreased absorption/Reduced effects Caution should be exercised for
combined use./Discontinue the
combined use if adverse effects are
noted.

Erythromycin Increased absorption and decreased Caution should be exercised for

clearance/Increased serum level combined use./Reduce dose if adverse
effects are noted.

Loratadine Erythromycin Inhibition of liver drug-metabolizing enzymes Caution should be exercised for
Cimetidine /Increased serum levels combined use./Reduce dose if adverse
effects are noted.

Mast cell stabilizer Warfarin potassium Inhibition of liver drug-metabolizing Caution should be exercised for
Tranilast enzymes/Bleeding tendency combined use./Discontinue the
combined use if adverse effects are
noted.

Leukotriene receptor antagonists Itraconazole Inhibition of liver drug-metabolizing Caution should be exercised for
Pranlukast hydrate Erythromycin enzymes/Increased serum levels combined use./Reduce the dose if
adverse effects are noted.

Montelukast Phenobarbital Induction of liver drug-metabolizing Caution should be exercised for

enzymes/Decreased serum levels combined use./Increase dose if
adverse effects are noted.

Prostaglandin D2/thromboxane Antithrombotics Enhanced inhibitory effects on platelet

A2 receptor antagonist aggregation/Bleeding tendency
Ramatroban Caution should be exercised for
Aspirin Decline in plasma protein binding /Increased
combined use./Discontinue the
serum level of free aspirin
combined use if adverse effects are
Theophylline Competition of liver drug-metabolizing noted.
enzymes/Increased serum levels

Modified from Practical Guideline for the Management of Allergic Rhinitis in Japan 2009, digest version.

(4) Severe and the most severe cases: For symptoms of sneezing the nasal blockage type and those of combined type, add
and rhinorrhea type, use a combination of nasal topical ste- leukotriene receptor antagonists or a prostaglandin D2/
roids and second-generation antihistamine. For symptoms of thromboxane A2 receptor antagonist. A combination drug

Table 14
Table 13 Operative treatment for allergic rhinitis.
Characteristics of specific immunotherapy in WHO views report.
1. Surgery to contract and modulate nasal mucosa
1. Perform specific immunotherapy alone or in combination with a different Electrocoagulation, cryosurgery, laser surgery, 80% trichloroacetic acid
therapy to treat allergic rhinitis. chemo-surgery. Laser surgery is characterized by various procedures,
2. Effective also for allergic conjunctivitis and allergic asthma. instruments, and objectives, such as cauterizing the surface with a laser
3. Should be performed by a physician specialized in allergy. beam (CO2, semiconductor), evaporating to a deep layer (semiconductor,
4. Avoid using allergen mixtures for treatment. Use standardized allergen potassium-titanyl phosphate [KTP]), and widely excising the mucous
vaccines. membrane (KTP).
5. Gradually increase allergen to reach maintenance dose. 2. Corrective surgery of nasal cavity to improve nasal ventilation
6. Optimal maintenance dose contains 5e20 mg of a major allergen for each Submucosal turbinectomy, inferior turbinectomy, septoplasty, Takahashi
injection. operation method, extensive turbinectomy, and nasal polypotomy.
7. Because of the risks of anaphylaxis, respond appropriately in an emergency. 3. Surgery to improve rhinorrhea
8. Optimal duration is unknown, generally 3e5 years. Vidian neurectomy and posterior nasal neurectomy.

Adapted from Practical Guideline for the Management of Allergic Rhinitis in Japan Adapted from Practical Guideline for the Management of Allergic Rhinitis in Japan
2009, digest version. 2009, digest version.
340 K. Okubo et al. / Allergology International 69 (2020) 331e345

Table 15
Treatment of perennial allergic rhinitis.

Severity Mild Moderate Severe

Disease types Sneezing and Nasal blockage type or Sneezing and rhinorrhea type Nasal blockage type or
rhinorrhea type combined type with nasal combined type with nasal
blockage as a chief blockage as a chief complaint
complaint

Treatments a. Second-generation a. Second-generation a. Anti-LTs agents Nasal steroids þ Nasal steroids þ Anti- LTs
antihistamine antihistamine b. Anti-PGD2/TXA2 Second-generation agents or anti-PGD2/TXA2
b. (Mast cell) stabilizer b. (Mast cell) stabilizer agents antihistamine agents
c. Th2 cytokine inhibitors c. Nasal steroids c. Th2 cytokine inhibitors or
d. Nasal steroids d. Second-generation Second-generation
antihistamine and antihistamine and
vasoconstrictor vasoconstrictor combination
combination
e. Nasal steroids

Choose one of (a), (b), (c), Choose one of (a), (b), Choose one of (a), (b), (c), Use vasoconstrictor nasal spray
and (d). (c). (d), and (e). for only 1e2 weeks at the start
Combine (a) or (b) with Combine (a), (b) or (c), of treatment as needed.
(c), as needed. with (e), as needed.

Perform surgery for cases with nasal deformities of a nasal

blockage type.

Allergen-specific immunotherapy

Elimination and avoidance of antigens

Even if symptoms are alleviated, do not discontinue the agent immediately, but confirm stability for several months to reduce dose gradually.
Mast cell stabilizer ¼ Chemical mediator release inhibitors, Anti-LTs agents ¼ Leukotriene receptor antagonists, Anti-PGD2/TXA2 agents ¼ Prostaglandin D2/Thromboxane A2
receptor antagonists.
Adapted from reference.1

containing an antihistamine and an oral decongestant along neutrophils and bacteria, resulting in purulent or yellow-green
with the use of a nasal topic steroid is suitable for this type. rhinorrhea. For cases with nasal discharge eosinophilia, consider
For cases with severe nasal blockade, concomitantly allergic rhinitis. However, in most cases with neutrophils coex-
administer nasal topical vasoconstrictor to start treatment. isting or predominating, symptoms cannot be improved by al-
For cases with severe nasal mucosal swelling and severe lergy therapy alone. Thus, sinusitis should be diagnosed and
pharyngeal and laryngeal symptoms at hospital visit, treated. Conduct X-ray examination (Caldwell and Waters
administer oral corticosteroids for up to 4e7 days. methods) to check opacities in the paranasal sinuses. In some
cases, causative bacteria should be identified from the bacterial
cultures of rhinorrhea or upper pharynx. For acute bacterial
9. Points to remember in treating complications sinusitis, administer an oral antimicrobial, amoxicillin, as a first-
9.1. Acute and chronic sinusitis line agent. For neutrophil dominant chronic sinusitis, 14-
In patients with allergic rhinitis, imaging tests may show membered ring macrolides are effective when long-term
opacities in the paranasal sinuses. Diagnose them as sinusitis administered in small amounts. Caution should be exercised for
complications. It is controversial whether sinusitis occurs in pa- the combination of theophylline and 14-membered ring macro-
tients with type I allergy. Among children, particularly infants, lides because serum theophylline levels may rise and cause
infectious sinusitis, including an acute one, is common, which poisoning symptoms.
requires composite treatment. Allergic inflammation is charac-
terized by transparent and watery or viscous rhinorrhea. Differ-
ential diagnosis of early infection is difficult because of serous 9.2. Eosinophilic sinusitis
and watery rhinorrhea. Mucin and neutrophils increase as pro- Some patients with chronic sinusitis present with massive
phylaxis reactions progress, resulting in viscosity increase of submucosal eosinophilic infiltration. Eosinophilic sinusitis is char-
rhinorrhea. Epithelial detachment causes the accumulation of acterized by multiple nasal polyps, viscous rhinorrhea, and

Fig. 6. Primal therapy for Japanese cedar pollinosis. Adapted from Practical Guideline for the Management of Allergic Rhinitis in Japan 2009, digest version.
 K. Okubo et al. / Allergology International 69 (2020) 331e345 341

Fig. 7. Severity classification of eosinophilic sinusitis. Adapted from reference.1

Table 16
Choice of therapy for pollinosis based on severity.

Severity Primal therapy Mild Moderate Severe

Disease Sneezing and Nasal blockage type or Sneezing and Nasal blockage type or
types rhinorrhea type combined type with rhinorrhea type combined type with
nasal blockage as a nasal blockage as a
chief complaint chief complaint

Treatments a. Second-generation a. Second-generation Second-generation Anti-LTs agents or Anti- Nasal steroids þ Nasal steroids þ Anti-
antihistamine antihistamine antihistamine þ Nasal PGD2/TXA2 agents þ Second-generation LTs agents or Anti-
b. (Mast cell) stabilizer b. (Mast cell) stabilizer steroids Nasal steroids þ antihistamine PGD2/TXA2 agents þ
c. Anti-LTs agents c. Anti-LTs agents Second-generation Second-generation
d. Anti-PGD2/TXA2 agents d. Anti-PGD2/TXA2 agents antihistamine antihistamine
e. Th2 cytokine inhibitors e. Th2 cytokine inhibitors or or
f. Nasal steroids f. Nasal steroids Second-generation Nasal steroids þ
antihistamine and Second-generation
vasoconstrictor antihistamine and
combination þ Nasal vasoconstrictor
steroids combination

Choose one of (a), (b), (f) for Choose one of (a)-(f). Use vasoconstrictor
sneezing and rhinorrhea Add (f) at the start of nasal spray for only 1
type, and (c), (d), (e), (f) for treatment with (a)-(e) as e2 weeks as needed.
nasal blockage type and needed. For cases with severe
combined type nasal blockage,
treatment may be
started with oral
corticosteroid ad-
ministration for 4e7
days.

Antihistamine for eye drops or stabilizer Antihistamine for eye drops, stabilizer, or
steroids

Perform surgery for cases with nasal deformities

of a nasal blockage type.

Allergen-specific immunotherapy

Elimination and avoidance of antigens

The primary therapy is for introducing the full-scale pollen dispersal period. Therefore, in case of years with small amount of pollen dispersal, the treatment is changed to
seasonal treatment according to the severity.
Mast cell stabilizer ¼ Chemical mediator release inhibitors, Anti-LTs agents ¼ Leukotriene receptor antagonists, Anti-PGD2/TXA2 agents ¼ Prostaglandin D2/Thromboxane A2
receptor antagonists.
Adapted from reference.1
342 K. Okubo et al. / Allergology International 69 (2020) 331e345

Table 17 asthma are complicated by allergic rhinitis. Additionally, 75% of

Risks of medication in pregnant women with allergic rhinitis. patients with atopic asthma and 40% of patients with nonatopic
Generic name Trade name Australian FDA asthma are complicated by allergic rhinitis. Most patients with
standards standards allergic rhinitis present with bronchial hyperreactivity. This also
Antiallergics (for internal use) suggests that allergic rhinitis is a risk factor for asthma. The
contribution rate of eosinophilic sinusitis to the severity of asthma
d-chlorpheniramine maleate Polaramin® A B
d-chlorpheniramine maleate Allergin® A B is 34.5%. Eosinophilic sinusitis is fundamental to considering the
Diphenhydramine hydrochloride Vena®, Restamin® A B pathology and treatment of asthma. Antigens, induced in the nasal
Cyproheptadine hydrochloride Periactine® A B mucosa, increase intercellular adhesion molecules and eosinophils
Promethazine hydrochloride Pyrethia®, Hiberna® C
in the lower respiratory tract, and exacerbate airway hyper-
Clemastine fumarate Tavegyl® A B
Diphenylpyraline teoclate Agiell®, Plokon® B2
responsiveness.21 In contrast, among patients with asthma,
Loratadine Claritin® B1 B complicated by allergic rhinitis, those who underwent treatment
Cetirizine hydrochloride Zyrtec® B2 B for allergic rhinitis showed significantly reduced emergency visits
Fexofenadine hydrochloride Allegra® B2 C and hospitalization as compared with those who were not treated.
Amlexanox Solfa® B
Surgical treatment (endoscopic sinus surgery) or medication for
Epinastine hydrochloride Alesion® C
Azelastine hydrochloride Azeptin® C eosinophilic sinusitis or nasal polyp improves pulmonary functions.
Ketotifen fumarate Zaditen® C Thus, to diagnose patients with asthma complicated by allergic
Nasal sprays rhinitis or eosinophilic sinusitis, examine both upper and lower
respiratory tracts. Examine the pathology in view of “one airway
Beclomethasone propionate Aldecin® AQ Nasal, B3 C
Rhinocort®
and one disease” to understand their correlation. Take an approach
Fluticasone propionate Flunase® B3 C based on the correlation.22
Disodium cromoglycate Intal® B
Amlexanox Solfa® B
Ketotifen fumarate Zaditen® C 9.4. Treatment of sinusitis in patients with aspirin intolerance
In treating eosinophilic sinusitis in patients with aspirin intol-
Adapted from Practical Guideline for the Management of Allergic Rhinitis in Japan
2009, digest version. erance, avoid using analgesics, antipyretics and antiinflammatory
drugs (nonsteroidal antiinflammatory drugs [NSAIDs]) because
olfactory disorder, and is often complicated by asthma (Fig. 7).20 they may cause an asthmatic attack. Basic antiinflammatory drugs
Eosinophilic sinusitis is extremely intractable and resistant to sur- cause no, or mild if any, asthmatic attacks. If pain occurs after
gery, resulting in repeated relapses. Oral corticosteroid therapy surgery for sinusitis, pentazocine can be injected intramuscularly.
often results in a complete response. Eosinophilic otitis media is a Intravenous injection of hydrocortisone may exacerbate asthma.
frequent complication. Eosinophilic otitis media is characterized by This may be caused by succinic acid ester contained in the injection.
an accumulation of sticky viscous liquid in the middle ear. Eosin- If corticosteroids are used for injection, choose betamethasone
ophilic otitis media is an intractable disease characterized by sodium phosphate.
eosinophilic infiltration in the accumulated liquid. Hearing loss is
often exacerbated. Tinnitus and aural fullness cause severe 9.5. Allergic conjunctivitis
discomfort. The symptoms of asthma complications, particularly Allergic conjunctivitis includes hyperemic conjunctivitis and
asthma attack, are often exacerbated. Systemic or intratympanic vernal keratoconjunctivitis (proliferative conjunctivitis). Atopic kera-
steroid administration is effective. toconjunctivitis, complicated by atopic dermatitis, has also become
common as the number of patients with atopic dermatitis increases.
9.3. Correlation between asthma and allergic rhinitis or Hyperemic conjunctivitis is a common complication. Complications
eosinophilic sinusitis in view of one airway one disease are common among patients with pollinosis. Most patients with
Approximately 30% of patients with allergic rhinitis are pollinosis suffer from ocular itching, lacrimation, hyperemia, eye
complicated by asthma. Reportedly, 28%e85% of patients with discharge, etc. Severe symptoms cause eyelid swelling. When children

Fig. 8. Classification of allergic rhinitis by ARIA. Modified from ARIA 2008, Japanese version.
 K. Okubo et al. / Allergology International 69 (2020) 331e345 343

Fig. 9. Step-by-step approach for treatment by ARIA. Modified from ARIA 2008, Japanese version.

rub their eyes with their hands, they cause dark circles to form under 10. Precautions
their eyes. Eye discharge shows eosinophilia. Eosinophilia can be 10.1. Precautions for pregnant women (Table 17)
detected only by scratching the conjunctiva. During pregnancy, congestive and allergic rhinitis often occurs,
For pollinosis, wear glasses and avoid wearing contact lens if and symptoms are exacerbated. Consider the impact of medication
possible. For prolonged administration of steroid eye drops, caution to pregnant and breast-feeding women on their fetuses and infants.
should be exercised for adverse effects, such as glaucoma and For the 4.5 months between early pregnancy and organogenesis in
corneal ulcer. Eye irrigation is effective in eliminating pollen.23 particular, perform treatment only when benefits outweigh risks.
344 K. Okubo et al. / Allergology International 69 (2020) 331e345

For nasal blockage, hyperthermia, bathing, steamed towel, and Practical Guideline for the Management of Allergic Rhinitis in Japan
masks are effective. If medication is required after the fourth month are described.
of pregnancy, minimize the use of local agents, such as DSCG, nasal
spraymast cell stabilizer, nasal spray antihistamine, and nasal 10.4.1. Classification of rhinitis
topical steroids. In the Japanese guideline, rhinitis is classified based on pathol-
ogy. In the ARIA2008, rhinitis is classified based on causes, with
10.2. Precautions for children some diseases overlapping (Fig. 8).
Allergic rhinitis is common among male infants, often
complicated by atopic dermatitis and asthma. Although it is less 10.4.2. Classification of pathology
common than atopic dermatitis and asthma, allergic rhinitis may In the Japanese guideline, rhinitis is roughly divided into
heal spontaneously. Severe nasal itching and nasal blockade often perennial and seasonal rhinitis based on the causative antigens of
cause nasal rubbing and facial movements and alterations (dark allergic diseases. In the ARIA2008, rhinitis is divided into persistent
circle under the eyes [allergic shiner] and horizontal lining on the symptoms, which continue 4 days a week for 4 weeks a year,
tip of the nose). Since children have large adenoids, palates, and and intermittent symptoms, which continue <4 days a week for <4
tonsils, caution should be exercised for various infections. Child- weeks a year. Behind this background, there are multiple sensiti-
hood allergic rhinitis is generally intractable and requires long- zations and a confusing classification of perennial and seasonal
term treatment. Thus, avoid irresponsible treatment and rhinitis symptoms. However, Japanese cedar pollinosis and peren-
frequent hospital visits. Allergic rhinitis may be exacerbated by nial mite allergic rhinitis, which affect most Japanese patients with
cold syndromes. Mite allergy is common among children. Elimi- rhinitis, are similarly classified as persistent rhinitis.
nate and avoid mites, and instruct children to stay away from
pets. 10.4.3. Classification of severity
Pharmacotherapy for adults is also indicated for children. In the ARIA2008, rhinitis is simply classified into “mild symp-
However, few therapeutic agents are indicated for the treatment of toms” and “moderate/severe symptoms.” This classification is
childhood allergic rhinitis. For elementary and junior high school based on patients' assessments regarding influences on sleep,
students, give half the adult dose. Perform specific immunotherapy everyday life, work, etc. Behind this background, QOL assessment is
for patients aged 6 years. For asthma complications, carefully emphasized. In the Japanese guideline, most patients who visit
adjust the antigen dose. Perform surgery to improve nasal venti- medical institutions are classified as having moderate or more se-
lation only for senior elementary students. vere symptoms. Thus, ARIA2008 classification is unsuitable for
actual treatment.
10.3. Oral allergy syndrome
Oral allergy syndrome (OAS) is an IgE antibody-dependent 10.4.4. Treatments (Fig. 9)
immediate food allergy, which causes hypersensitivity in the Treatments are simply described because of the simple classi-
oropharyngeal mucosa and local and systemic type I allergic re- fication of allergic rhinitis. For example, for persistent moderate/
actions after ingestion of food. OAS is often complicated by polli- severe symptoms, the main therapeutic targets in this classifica-
nosis or latex allergy. Potential allergens include cross reacting tion, first administer nasal spray steroids, and if the symptoms are
molecules, which is common between pollen antigens or latex not improved within 2e4 weeks, increase the dosage or use
allergens of fruits, vegetables, and cereals and causative food al- different agents. Most patients with Japanese cedar pollinosis are
lergens of OAS. In patients with allergies to the pollens of Betula classified into severe diseases according to the Japanese guideline.
platyphyla, Rosaceae fruits (e.g., apples and peaches) cause Because of exposure to large amounts of pollen, treating these
frequently OAS. Reportedly, the common causative foods of OAS patients with a single agent is often difficult. Thus, descriptions that
are tomato, melon, watermelon, and orange in patients with grass are more detailed are needed.
pollinosis. In patients with mugwort and ragweed pollinosis, the The ARIA2008 provides sufficient descriptions to allow the un-
common causative foods are melon, watermelon, and celery. derstanding of pathology, evidence of the therapy, etc. However,
Melon, watermelon, and kiwi fruit are relatively common causa- important issues in the ARIA2008, such as cost-benefit and the
tive foods. In patients with latex allergy, avocado, chestnut, ba- establishing evidence for inapplicable therapies to Japanese cir-
nana, and kiwi fruit are the common causative foods of OAS. In cumstances, where characteristic pollinosis like Japanese cedar
patients with Japanese cedar pollinosis, OAS caused by tomato has pollinosis exists, should be examined in Japan.
been reported. In most patients with OAS, local symptoms, such as
itching, tingling, and edematous swelling on the oropharyngeal Conflict of interest
KO received honoraria from Torii Pharmaceutical, Taiho Pharma, Mitsubishi
mucosa and lips, occur within 15 min after food ingestion. Diges-
Tanabe Pharma, Meiji, Novartis, and manuscript fee from Torii Pharmaceutical. YO
tive symptoms, such as diarrhea and abdominal pain, laryngeal received honoraria from Torii Pharmaceutical, Shionogi, Kyorin Pharmaceutical,
edema, watery rhinorrhea, and conjunctival hyperemia also occur. Taiho Pharma, Mitsubishi Tanabe Pharma, and research funding from Kyorin Phar-
Systemic symptoms include urticaria, eczema-like cutaneous maceutical, Yamada Bee Farm. SF is an adviser for GlaxoSmithKline, Kyowa Kirin,
symptoms, asthmatic symptoms, and sometimes anaphylactic Sanofi, and received honoraria from Kyorin Pharmaceutical, Taiho Pharma, Mitsu-
bishi Tanabe Pharma, and research funding from Maruho, Tsumura, Mitsubishi
shock. Avoiding causative food intake is the only the reliable
Tanabe Pharma, Sanofi. KM received honoraria from Taiho Pharma. The rest of the
treatment. authors have no conflict of interest.

10.4. Relationship with ARIA (allergic rhinitis and its Impact

on Asthma)
In 2001, allergy researchers from many countries published a References
consensus report, “Allergic Rhinitis and its Impact on Asthma 1. Okubo K, Kurono Y, Ichimura K, Enomoto M, Okamoto Y, Kawauchi Y, et al.,
(ARIA)" with WHO's recommendation.21 This is sometimes editors. [Practical Guideline for the Management of Allergic Rhinitis in Japan]. 8th
considered as a standard international guideline for allergic ed. Tokyo: Life Science; 2016 (in Japanese).
2. Nuhoglu C, Nuhoglu Y, Bankaoglu M, Ceran O. A retrospective analysis of
rhinitis. As the title indicates, allergic rhinitis is examined regarding adenoidal size in children with allergic rhinitis and nonallergic idiopathic
the effects on asthma. Hereinafter, major differences from the rhinitis. Asian Pac J Allergy Immunol 2010;28:136e40.
 K. Okubo et al. / Allergology International 69 (2020) 331e345 345

3. Settipane GA, Klein DE. Non allergic rhinitis: demography of eosinophils in 14. Okubo K, Gotoh M. Effect of ramatroban, a thromboxane A2 antagonist, in the
nasal smear, blood total eosinophil counts and IgE levels. N Engl Reg Allergy Proc treatment of perennial allergic rhinitis. Allergol Int 2003;52:131e8.
1985;6:363e6. 15. Okubo K, Nakashima M, Miyake N, Uchida J, Okuda M. Dose-ranging study of
4. Varghese M, Glaum MC, Lockey RF. Drug-induced rhinitis. Clin Exp Allergy fluticasone furoate nasal spray for Japanese patients with perennial allergic
2010;40:381e4. rhinitis. Curr Med Res Opin 2008;24:3393e403.
5. Baba K, Nakae K. [National epidemiological survey of nasal allergy 2008 16. Okubo K, Gotoh M. Allergen immunotherapy for allergic rhinitis. J Nippon Med
(compared with 1998) in otolaryngologists and their family members]. [Prog- Sch 2010;77:285e9.
ress Medicine] 2008;28:2001e12 (in Japanese). 17. Okubo K, Gotoh M, Fujieda S, Okano M, Yoshida H, Morikawa H, et al.
6. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. Interna- A randomized double-blind comparative study of sublingual immunotherapy
tional study of asthma and allergies in childhood (ISAAC): rationale and for cedar pollinosis. Allergol Int 2008;57:265e75.
methods. Eur Respir J 1995;8:483e91. 18. Inamura S, Honda H. Carbon dioxide laser vaporization of the inferior turbinate for
7. Okubo K, Okuda M. Time-course changes in nasal airway resistance after house allergic rhinitis: short-term results. Ann Otol Rhinol Laryngol 2003;112:1043e9.
dust antigen challenge: with special reference to late phase response. Allergol 19. Yonekura S, Okamoto Y, Okubo K, Okawa T, Gotoh M, Suzuki H, et al. Bene-
Int 1998;47:225e32. ficial effects of leukotriene receptor antagonists in the prevention of cedar
8. Ichikawa K, Okuda M, Naka F, Yago H. The sources of chemical substances in pollinosis in a community setting. J Investig Allergol Clin Immunol 2009;19:
allergic nasal fluid. Rhinology 1991;29:143e9. 195e203.
9. Mezawa A. [Effects of chemical mediators on nasal allergy]. [Jpn J ORL] 1988;91: 20. Tokunaga T, Sakashita M, Haruna T, Asaka D, Takeno S, Ikeda H, et al. Novel
1444e55 (in Japanese). scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC
10. Okuda M. [Severity classification of nasal allergy]. [Jpn J Otolaryngol Head Neck Study. Allergy 2015;70:995e1003.
Surg] 1983;55:939e45 (in Japanese). 21. Gaga M, Lambrou P, Papageorgiou N, Koulouris NG, Kosmas E, Fragakis S, et al.
11. Okuda M, Ohkubo K, Gotoh M, Okamoto H, Konno A, Baba K, et al. Comparative Eosinophils are a feature of upper and lower airway pathology in non-atopic
study of two Japanese rhinoconjunctivitis quality-of-life questionnaires. Acta asthma, irrespective of the presence of rhinitis. Clin Exp Allergy 2000;30:663e9.
Otolaryngol 2005;125:736e44. 22. ARIA Workshop Group. Allergic rhinitis and its impact on asthma. ARIA
12. Okubo K, Gotoh M, Shimada K, Ritsu M, Kobayashi M, Okuda M. Effect of workshop report (chairman: Bousquet J). J Allergy Clin Immunol 2001;108:
fexofenadine on the quality of life of Japanese cedar pollinosis patients. Allergol S147e334.
Int 2004;53:245e54. 23. Japanese Ocular Allergology Society. [Guidelines for the clinical management of
13. Okubo K, Baba K. A double-blind non-inferiority clinical study of montelukast, allergic conjunctival disease]. Nippon Ganka Gakkai Zasshi [J Jpn Ophthalmol Soc]
a cysteinyl leukotriene receptor 1 antagonist, compared with pranlukast in 2006;110:101e40 (in Japanese).
patients with seasonal allergic rhinitis. Allergol Int 2008;57:383e90.