Rhinitis is a common disease worldwide characterized by at least one symptom between nasal

obstruction, rhinorrhea, sneezing, and itching. Rhinitis is a general term defining nasal symptoms
attributed to the inflammation and/or dysfunction of the nasal mucosa. Classically, rhinitis can be
classified into three major endotypes which are infectious, allergic, and nonallergic. If all possible
etiologies of rhinitis are excluded, the rhinitis is classified as idiopathic rhinitis.
Rhinitis is a global health problem and ranks as the fifth most common chronic disease in the world.
The prevalence of rhinitis varies differently from 1% to 60% in different part of the world and
depends on the definition of rhinitis used. The median global prevalence of unspecified rhinitis,
allergic rhinitis, and nonallergic rhinitis is 29.4%, 18.1%, and 12%, respectively.
The prevalence of allergic rhinitis has significantly increased in the past few decades, and it was
predicted that 40% children and 10-30% adults globally suffer from allergic rhinitis. In Indonesia, the
prevalence of allergic rhinitis is approximately 10-20% with mean of age onset around 8-11 years old.
The high prevalence of rhinitis will make significant impact on economic problem and the quality of
life.
It is estimated that a total of 400 million world population affected by allergic rhinitis and the
diagnosis of allergic rhinitis is made by clinical evaluation (presence of typical symptoms, the
exclusion of other causes of rhinitis), and diagnostic evaluation to identify the presence of specific
immunoglobulin E to certain allergens, such as the skin prick test (SPT) and/or the serum specific IgE
(sIgE). The local allergic rhinitis (LAR) has emerged as a novel clinical entity in the past 40 years.
Nonallergic rhinitis patients were traditionally diagnosed as such based on the negative response in
SPT and absence of serum sIgE. However, a portion of these patients showed typical nasal symptoms
after the nasal specific allergen provocation test (NAPT) with common aeroallergens, such as house
dust mites. This evidence proved that those patients locally produced specific IgE in the nasal mucosa
and this findings has brought upon local allergic rhinitis (LAR) as a new etiological rhinitis
classification.
The exact prevalence of LAR is not yet to be known, but approximately 50-75% of all nonatopic
population experience nasal symptoms suggestive of atopy. A study by Rondón et al. mentioned that
the prevalence of LAR is approximately 27,5% and the most common etiology of allergen was house
dust mites (Dermatophagoides pteronyssinus). LAR is characterized by the production of local sIgE
antibody, a Th2 infiltration pattern in the mucous cells during the period of aeroallergen natural
exposure, and a positive NAPT response that manifests as clinical symptoms and an increased level of
sIgE, tryptase, and eosinophil cationic protein (ECP) in the nasal secretion.
In Indonesia, literature or studies on LAR are scarce. Therefore, this literature review is written to
summarize the novel knowledge about LAR, starting from its epidemiology, pathophysiology,
diagnostic approach, treatment, and complication, which can be helpful for future reviews and studies
about LAR, particularly in Indonesia.

Problem Formulation
The problem formulation in this literature review will comprise these substances:
1. What is the prevalence and incidence of LAR globally?
2. What are the etiologies and risk factors associated with LAR?
3. What is the pathophysiology of LAR?
4. How to diagnose a case of LAR?
5. What is the treatment recommendation for LAR?
6. What is the differential diagnosis of LAR?
 7. What are the possible complications of LAR?
Objectives
The objectives of this literature review are:
1. To summarize the novel knowledge about LAR, starting with its epidemiology,
pathophysiology, diagnosis, treatment, and complications.
2. To establish an excellent, evidence-based literature review that can be resourceful for future
research and reviews on LAR, particularly in Indonesia.

CHAPTER 2 LITERATURE REVIEW

2.1. Anatomy of the Nose
The anatomy of the nose is divided into the external aspect, the nasal septum, the nasal
cavity (nose), and the paranasal sinuses. The most involved anatomical structure in LAR
is the nasal cavity. The nasal cavity opens anteriorly through the anterior nares and opens
posteriorly into the nasopharynx through the choana. The base of the nasal cavity is lined
by the hard palate, which consists of the palatine process of the maxillary bone and the
horizontal part of the palatine bone. The roof of the nasal cavity is mostly composed of
the lamina cribrosa. The lateral part of the nasal cavity consists of the medial surface of
the maxillary bone and lacrimal bone which are the attachment site of three nasal
turbinates, i.e. inferior turbinate, medial turbinate, and superior turbinate. The supreme
turbinate is present in a few individuals. The medial part of the nasal cavity is the nasal
septum. The nasal septum is a structure with a bony part and a cartilaginous part. The
cartilaginous part is composed of the quadrangular cartilage, and the bony part is
composed of the vomer, the perpendicular lamina of the ethmoid bone, the nasal crest of
the maxillary bone, and the nasal crest of the palatine bone.
Fig 2.1. The anatomy of the nose (the lateral and medial wall of the nasal cavity)

The structure between the inferior turbinate and the base of the nasal cavity is the inferior
meatus, the space between the inferior and medial turbinate is the medial meatus, and the
space between the medial and superior meatus is the superior meatus. The paranasal
sinuses are air-filled cavities which connect to the nasal lumen through the ostium. There
are four pairs of paranasal sinuses, i.e. the maxillary, ethmoid, sphenoid, and frontal
sinuses. Clinically, the sinuses are classified into the anterior group and posterior group
based on their locations relative to the basal lamina. The anterior sinuses group consists
of the frontal, maxillary, and anterior ethmoid cells sinuses, and they drain into the medial
meatus. The posterior sinuses group consists of the posterior ethmoid cells and sphenoid
sinuses, and they drain into the superior meatus. The other structure in the nasal cavity is
the nasolacrimal ducts which drain into the inferior meatus.

Vascularization and Innervation

Vascularization of the external aspect of the nose is supplied by branches of the facial
artery, branches of the ophthalmic artery, and the maxillary artery. The nasal septum has a
rich blood supply and is divided into anterior and posterior vascularization. The
posteroinferior part of the nasal septum is supplied by the sphenopalatine artery, which is
a branch of the maxillary artery. The major palatine artery supplies the anteroinferior part
of the nasal septum. A small part of the anterior septum is supplied by the superior labial
artery, which is a branch of the facial artery. The internal carotid artery branches out to be
the anterior ethmoid artery and the posterior ethmoid artery, and both supply the superior
 part of the septum. A group of blood vessels ends create an anastomosis in the anterior
part of the septum called the Kisselbach plexus. The lateral wall of the nasal cavity
vascularization originated from the internal carotid artery and the external carotid artery
system. The anterior and posterior ethmoid arteries supply the superior part of the nasal
cavity lateral wall. The sphenopalatine artery supplies the medial and inferior turbinates.
The major palatine artery and the facial artery supply the anteroinferior part of the nasal
cavity lateral wall.
The arterial blood flow in the nasal mucosa moves anteriorly opposite to the inspired air
and thus increases the warming process. The autonomic nervous system regulates the
blood vessels. Sympathetic stimulation will decrease the blood flow of the nose and cause
nasal congestion.
The muscles of the external nose are innervated by the VII cranial nerve, and the first and
second branches of the trigeminal nerve supply the sensory component. The sensory part
of the nasal cavity is mostly innervated by the second branch of the trigeminal nerve, and
the superior part of the septum is the olfactory area, which contains olfactory receptor
cells.

Nasal Mucous Membrane

The skin of the vestibulum is composed of the keratinized squamous epithelium with
vibrissae, sebaceous glands, and sweat glands.
In the nasal cavity, the epithelial cells change, and three types of cells can be observed.
One-third of the anterior nasal cavity, along with the anterior part of inferior and medial
turbinates, are lined by squamous and transitional epithelial cells. The transitional cells
are cuboidal cells with microvilli. In contrast, in one-third of the posterior nasal cavity,
the epithelial cells change into pseudostratified ciliated columnar epithelium (respiratory
epithelium), which consists of four types of cells: 1) ciliated columnar cells, 2) non-
ciliated columnar cells, 3) goblet cells, and 4) basal cells. The epithelium performs the
protective function of the upper and lower respiratory tracts by the mucociliary clearance
activity. The goblet cells produce acidic mucin with a unique viscoelasticity property,
vital in the clearance process. The ciliated cells are lined by numerous cilia, which beat
1000 times per minute with rapid forward beat (effective stroke) and slow return beat
(recovery beat) movements. Approximately 80% of the cells are ciliated cells, and the
ratio of columnar to goblet cells is 5:1. All of these epithelial cells in the nasal cavity are
located above the basement membrane and the lamina propia. The capillaries penetrate
the basement membrane so fluid can pass directly through these vessels onto the mucosal
surface. This permeability characteristic is a fundamental difference in the basement
membrane between the nose and the other organs. The lamina propia contains glands,
innervation, and vascularization.

The third epithelium is the olfactory epithelium lining the superior turbinate and its
adjacent septum. The epithelial cells are pseudostratified and olfactory cells (bipolar
neurons acting like the peripheral receptors and first-order ganglia), basal cells, and
Bowman glands (small serous tubulo-alveolar glands). The basal cells are small
polygonal stem cells that uniquely enable the olfactory cells to regenerate after damage
caused by viral infection. The olfactory system is connected to the limbic system,
reticular formation in the brain stem for odor-alerting response, hippocampus, thalamus,
hypothalamus, and the frontal lobe.
Figure 2.2 The pseudostratified columnar epithelium consists of four types of cells.

2.2. The physiology of the nose

The nose is an important organ in the respiratory and olfactory system. In normal
individuals, the inspired air is filtered, warmed, and humidified by the nasal mucosa
before the air reaches the lungs. The nasal cavity also plays a role in resonance, protective
function against allergens, microorganisms, and other irritant substances by the
mucociliary transport system, inflammation, and the humoral and cellular immune
response.

Respiratory function
Inspired air enters the anterior nares in different flows through the shape of the meatus.
The air current makes a 60° angle and flows horizontally after passing the posterior part
of the vestibulum. The airflow speed at the opening of the nasal cavity is 2-3 m/s,
increasing to 12-18 m/s in the internal nasal valve, which is the narrowest part of the
nasal cavity. At the turbinates, the speed of the airflow decreases. The airflow will
become turbulent past the medial meatus, which is important for the warming and
humidifying process.

Filtration function
Another major function of the nose is to filter the air from big-sized particles. Very big
particles are usually blocked by the vibrissae. Small particles with a size of up to 12.5 µm
will be retained by the mucous blanket lining the nasal epithelium.
The aerodynamic equivalent diameter (AED) is the unit density diameter of the particle
that can enter the nose. Approximately 80-85% of particles of 5 µm or more AED will be
retained and cleared by the nose and the nasopharynx.
The mucous blanket is produced by the goblet cells and moves along with the continuous
flow generated by the ciliary beat, which pushes the particles posteriorly into the lateral
wall of the pharynx. The mucous flow average speed and particles movement is 6 mm/s.
Figure 2.3. The diagram of a normal ciliary beat cycle

The ciliary beat is the movement of cilia that consists of the effective (active) stroke,
which is a stronger forward beat causing the cilia to extend fully; the tip of the cilia
penetrates the upper layer of the mucous blanket and moves the mucous anteriorly. Then,
the movement is followed by the recovery stroke, which is stronger and slower – the shaft
of the cilia bends backwards and stops the mucous from moving. The active and recovery
stroke is metachronous with a pace of 1.000 or more beats per minute.
The mucous blanket is a bilayer with a thickness of 12–15 µm and gives lubricant
properties, prevents dryness, and retains particles and soluble gas. The daily production of
the mucous blanket fluid is 1-2 litres. The pH level of the mucous blanket is slightly
acidic; 2.5-3% of the composition consists of glycoproteins, 1-2% consists of salt and
95% consists of water. Immunoglobulins compose 70% of the protein composition. The
mucociliary transport is an inseparable harmony between the mucous blanket and ciliary
beat systems that complete each other and serve for filtration and protective function.

Humidifying function
The artery in the nasal cavity branches out into capillaries in the nasal mucosa, draining
into the sinusoid veins and forming an erectile mucosal tissue. This structure is dominant
in the anterior part of the inferior turbinate and the nasal septum. When the sinusoids are
filled, they form a vascular bed and act like radiators to warm the inspired air. In the nasal
cavity, the inspired air is warmed and humidified. The air is warmed by conduction,
convection, and radiation to a temperature like the body temperature, and the humidity is
adjusted above 80% before entering the lungs. Inspired air that is not warmed and
humidified will cause nasal crusting and infection.
Immunologic function
The specific and non-specific immunity systems are the two mechanisms that protect the
respiratory system against irritants, microorganisms, and allergens.
The non-specific system includes the nose filtering function by the mucociliary transport
system. The particles are brought into the nasopharynx, ingested, and destroyed by the
gastric enzymes, and these processes comprise the first line of protection in humans. The
second line of the non-specific immunity system is the inflammation response.
Vasodilation, increased capillary permeability, plasma exudation, and neutrophile
activation cause nasal obstruction and rhinorrhea. The activated inflammatory cells then
release several mediators that trigger the neural receptors, causing nasal itch and sneeze.
In a few days, the monocytes and macrophages will be involved to eliminate the
pathogens and cell debris. The specific system consists of the humoral and cellular
immunologic responses. This system is responsible for complete pathogen elimination
and inducing immunological memory.

The olfactory function

This is a primary protective function to detect irritative and toxic substances. The odorant
particles must pass through the mucous and reach the receptor cells to induce smell
perception.

Definition and Epidemiology of Local Allergic Rhinitis

Definition and Classification of Rhinitis

Rhinitis is a common terminology to describe the nasal symptoms caused by the
inflammation of the nasal mucosa. Rhinitis is a chronic disease with two major
phenotypes: allergic rhinitis (AR) and non-allergic rhinitis (NAR). AR refers to the nasal
symptoms triggered by the response attributed to the involvement of IgE to allergen
exposure. NAR is defined as a group of heterogeneous nasal symptoms without allergen
sensitization.
Rondón classified rhinitis based on its etiology: infective and non-infective. Non-
infective rhinitis is differentiated into AR and NAR. Rhinitis with unknown etiology is
classified as idiopathic rhinitis (IR). However, the existing evidence has shown that some
patients initially diagnosed as NAR and IR exhibited typical nasal symptoms after the
nasal specific allergen provocation test (NAPT) with common aeroallergens such as
house dust mites. Evidence proved that these patients produced specific IgE locally in the
nasal mucosa, and thus, the novel etiological classification of rhinitis emerged: local
allergic rhinitis (LAR). Rondón purposed the classification of rhinitis based on the
etiology (Table 2.1).

Definition of Local Allergic Rhinitis (LAR)

LAR is a concept of novel disease entity that describes clinical allergic rhinitis without
evidence of systemic sensitization to aeroallergens. LAR is characterized by symptoms
suggestive of allergic rhinitis (nasal obstruction, rhinorrhea, sneezing, nasal itch) with a
negative skin prick test (SPT) and/or negative serum IgE test, the presence of local IgE
and eosinophil cationic protein (ECP) after aeroallergen exposure, along with a positive
NAPT, without systemic atopy.

Figure 2.4. Associations between AR, NAR, and LAR.

Epidemiology of Local Allergic Rhinitis (LAR)

The cases of LAR are still underdiagnosed, and the prevalence of LAR varies in different
parts of the world, ethnicity, and age. In 2012, Rondón et al. conducted a study among
428 adults with chronic rhinitis. They reported the prevalence of LAR, AR, and NAR is
25,7%, 63,1%, and 11,2%, respectively, with Dermatophagoides pteronyssinus (house
dust mites/HDM) as the most common causative allergen in LAR and AR. A study by
Bozek et al. proved similar results in which the prevalence of LAR and AR is 21% and
40,2%, respectively, with D. pteronyssinus as the most causative allergen.
The prevalence of LAR is higher in Western countries than in Asia. The difference in age
demography follows the geographical difference, and this finding is particularly in
contrast in children. The prevalence of LAR in children is higher in the West (ranging
from 36,7 to 66,6%) than in Asia.

Etiology and Risk Factors of Local Allergic Rhinitis (LAR)

Etiology
The etiology of LAR is aeroallergen. The most involved aeroallergen in LAR is similar to
the allergen in AR cases: house dust mites (Dermatophagoides pteronyssinus, D. farinae,
which is associated with perennial LAR symptoms). Other than that, allergens such as
grass pollen, Alternaria alternata, and pollen from olive trees are associated with seasonal
LAR symptoms.

Risk Factors
No study is available that describes the risk factors explicitly associated with LAR. The
evidence showed that the presence of local nasal response in LAR patients exhibited
typical symptoms of AR without atopy history, which was defined as a genetic tendency
to become an allergic disease. Approximately 3% of LAR patients evolve into AR in 10
years. LAR patients are usually young, non-smoking women with persistent moderate to
severe symptoms all over the year, and they are often associated with complications such
as conjunctivitis and asthma.

Pathophysiology
The exact pathophysiology of LAR and how allergic response only occurs locally in the
nasal mucosa is yet to be understood. LAR is a type 2 inflammation caused by localized
allergic reactions in the nasal mucosa. The basic pathogenesis of LAR involves the
production of specific IgE against antigens in the nasal mucosa and the complete antigen-
antibody reaction that occurs locally.
In the cases of atopy, the first step takes place in the nasal mucosa, where allergen-
specific IgE is produced; the second step involves the surface of the peripheral basophil
cells and the other immune target cells, followed by the third and the last step, which is
the detection of serum specific IgE along with the sensitization of the mast cells. The step
of sensitization to allergen are different between LAR and AR.
The inhaled aeroallergen will be retained in the nasal mucosa, processed by the antigen-
presenting cells (APCs), and presented to the T cells. This process will induce the
production of IgE by switching processes in the B cells (CSR).
It is generally known that the production of IgE-secreting plasma cells occurs in the
lymphoid tissue (the regional lymph nodes and spleen) by a class switch recombination
(CSR) mechanism. The dendritic cells are very abundant APCs in the mucosa of the upper
and lower respiratory tract in AR cases. The T lymphocytes play a significant role in the
immune response mediated by IgE because only the T cells can recognize the antigens
after being processed by the APCs. Then, the T cells produce IL-4, IL-13, and CD-40L to
induce CSR. To produce IgE, the CSR requires the first signal (IL-4 and IL-13), the
second signal (the CD-40 ligand), and then they bind to the CD-40 receptor on the surface
of B cells and enable the CSR to continue. The CD-40 ligand is expressed by the cells
activated by the T-helper 2 (Th2) cells and mast cells. Mast cells are the main effector in
the immediate phase of allergic reaction and maintain the IgE production. Nasal mast
cells activated by antigen produce higher IL-4 and IL-13 than the nasal T cells activated
by antigen, which results in the increase of IgE synthesis. The previously mentioned two
signals required by the CSR can be found in the mucosa, so it is assumed that the same
process may have occurred locally. The IgE antibodies produced by the plasma cells in
the nasal mucosa of AR patients are the primary source of local sensitization of mast cells
to common aeroallergens. The local IgE production in nasal secretion is also found in
healthy individuals.

The FcεRI receptor has a high affinity to IgE, so it is very possible that free IgE will only
be detected after all the FcεRI receptors are saturated. In AR cases, the locally produced
IgE in the nasal mucosa is associated with the FcεRI receptor on the effector cells and
exhibits a positive nasal allergen challenge (NAC) or NAPT, enters the systemic
circulation where IgE binds to the basophil FcεRI receptors and shows a positive basophil
activation test. The remaining free IgE then extravasates to the tissue, binds to the
receptors on the peripheral effector cells, and demonstrates a positive skin prick test.
Therefore, free IgE will only be found in the biological fluids if all the FcεRI receptors
are saturated. In the cases of LAR, the IgE production seems inadequate to reach the
peripheral tissue. Hence, it shows a negative skin prick test, no detection of free IgE in
the serum, and a negative or very low level of IgE in the nasal secretion. In contrast, the
NAC/NAPT and BAT examinations usually show positive results.
Fig 2.5. The pathophysiological mechanism involved in the production of local IgE in the
nasal mucosa.

Diagnosis
The evaluation of a patient suspected of LAR requires a comprehensive history taking,
particularly the nasal symptoms (rhinorrhea, nasal obstruction, sneezing, and nasal itch),
allergic history in the family, and comorbidity assessment such as ocular, skin, and
bronchial symptoms. A complete history taking will help further evaluate systemic atopy
or differentiate NAR patients.
The following diagnosis step is a detailed physical examination comprised of the nasal
cavity inspection by nasal endoscopy, and several patients may require a CT scan to
exclude the other rhinitis etiologies.
A specific diagnostic examination is carried out to prove the sensitization towards
aeroallergen, such as the skin prick test (SPT) or serum specific IgE (sIgE). A negative
result demonstrates the absence of systemic sensitization, and the examination should be
continued to prove the local hyperreactivity of the nasal mucosa towards aeroallergens to
establish a diagnosis of LAR. There are three standard tests to diagnose LAR:
1. Nasal allergen provocation test (NAPT)
This test is the gold standard examination for diagnosing LAR. NAPT is conducted to
trigger the local nasal allergic response by allergen exposure. The expected responses
are rhinorrhea, nasal itch, sneezing, oedema of the nasal mucosa, and increased
airflow resistance after exposure to specific allergens in the nasal mucosa.
Around 60% of LAR patients respond directly to NAPT and demonstrate nasal
symptoms, increased level of tryptase (a marker of mast cell activation) and
eosinophil cationic protein (ECP; a marker of eosinophil activation).
The shortcoming of this test is a nasal challenge with saline, which is required before
the NAPT is done to exclude the possibility of non-specific nasal hyperreactivity,
which may result in a false positive result. In addition, the standardization of allergen
 extract (the dosing and timing) and the definition of NAPT for outcomes have yet to
be established.
2. sIgE in the nasal secretion
This test is carried out for the sample of fluid obtained from the nasal cavity after
natural allergen exposure, after NAPT, or after mucosal brushing. The sIgE
examination can also be done from the nasal mucosa biopsy sample, but it is
inconvenient, and a less invasive method is preferred.
The specificity of the nasal secretion sIgE test is high (> 90%), but its sensitivity is
low due to the dilution effect.
3. Basophil activation test (BAT)
Peripheral basophils are key cells of allergic response and are involved in the
immediate phase mediated by IgE. The primary role of basophils is to degranulate the
proinflammatory mediators after they are stimulated and activated by an allergen. The
flow cytometry can measure the activation of basophils, and the surface activation
marker, such as CD63, will be quantified.

Diagnostic Approach
Rondón et al. have proposed a diagnostic approach by evaluating the nasal
allergology in all the patients with a clinical history suggestive of AR but
demonstrated negative SPT and the absence of sIgE antibodies. The diagnosis of
LAR can be established based on the detection of the nasal sIgE, a positive NAPT
response, or both, without systemic atopy (Figure 2.5).

Treatment of LAR
The treatment of LAR hugely depends on the correct diagnosis by differentiating it
from NAR. The treatment applied to AR patients has proved beneficial for LAR
patients. The allergen avoidance, pharmacological treatments such as intranasal
corticosteroids, oral or intranasal antihistamines, and allergen immunotherapy (AIT)
can be applied to LAR patients.
Pharmacological treatment
Oral antihistamines and intranasal corticosteroids are still the main treatments for AR
patients, and both drugs are also beneficial for LAR patients.
The administration of oral H1 antihistamines to prevent a new sensitization is not
recommended for young children with nasal allergies and/or families with a history of
allergy because of the high adverse effect risk and lack of evidence.

Immunotherapy
The study by Rondón et al. showed that subcutaneous immunotherapy (SCIT) may
alleviate the symptoms in LAR patients. Immunotherapy also increased the serum
IgG4 levels in LAR patients, and this increase was attributed to the IL-10-producing
Treg and the IgG4-producing Breg. SCIT also increases tolerance to allergens and
increases patients’ quality of life.
Classic immunotherapy administration is done by subcutaneous and sublingual
routes. Other routes, such as intralymphatic, intradermal, or epicutaneous, are
currently studied in cases of respiratory tract allergy. Lack et al. reported that the
intranasal AIT has proven effective in the allergic asthma mice model. LAR is a
condition of local immune response in the nasal mucosa, so the strategy development
of intranasal AIT administration should be considered and studied further.

Consideration
The efficacy of surgical treatment in LAR patients is unknown. The rationale for
surgery in LAR is that the inflammation in the nasal mucosa occurs locally. The
surgery will decrease the surface area of mucosal tissue and prevent contact between
mucosa and allergens, so it is expected to be a potentially effective treatment for
LAR.
Surgical treatment might be another treatment option for LAR as scar tissue develops
in the submucosa, destroying blood vessels and glandular structures and inhibiting
regeneration through fibrosis.

Differential diagnosis
Rhinitis is the umbrella term for a group of upper respiratory tract diseases with nasal
symptoms caused by various etiologies and demonstrates unique symptoms. Mullol et
al. have summarized the differential diagnosis of various spectrums of rhinitis
phenotypes. These phenotypes can be classified based on 1) etiology (allergy, non-
allergy, atrophy, and idiopathic – Table 2.2) and 2) cellular inflammatory profile or
histopathology (Table 2.3).

Etiology
1. Allergic rhinitis (AR): IgE-mediated chronic inflammatory disease of the nasal
mucosa triggered by environmental aeroallergens. The diagnosis of AR is
established based on the patient’s sensitization to specific IgE (sIgE) to associated
allergen.
2. Local rhinitis allergy (LAR): localized nasal allergic response to perennial HDM
or seasonal pollen without evidence of systemic atopy. This disease is
characterized by local sIgE production and infiltration of T2 pattern (eosinophil)
inflammatory cells and mediators such as tryptase, ECP after aeroallergen
exposure and a positive NAPT result after associated allergen exposure. About
3% of LAR can convert into allergic rhinitis after 10 years.
3. Occupational rhinitis: the nasal symptoms is attributed to the allergen that is
clinically associated and present in the working environment, and the symptoms
worsen in the workplace.
4. Non-allergic rhinitis: chronic rhinitis characterized by at least 2 symptoms (nasal
obstruction, rhinorrhea or post-nasal drip, sneezing, nasal or ocular itching), at
least one hour daily for ≥ 12 weeks in a year. No underlying allergic mechanisms
are observed (negative serum sIgE, negative SPT, or negative NAPT).
5. Hormonal rhinitis can be caused by pregnancy or sexual hormone imbalance.
Rhinitis in pregnancy affects 20% of pregnant women. The exact pathogenesis of
rhinitis in pregnancy is unknown, but it may be due to 1) the hypertrophy of nasal
mucosa due to the placental trophoblastic hormone stimulation, 2) the increase of
histamine receptors on epithelial cells, 3) estrogen-induced microvasculature, or
4) progesterone-induced local vasodilation. Pregnant women experiencing rhinitis
before pregnancy usually have more severe nasal symptoms, particularly in the
second to third trimester, and usually, the symptoms resolve after delivery
(gestational rhinitis). Sexual hormone imbalances commonly cause rhinitis in
menopause or puberty period.
6. Gustatory rhinitis typically manifests as watery rhinorrhea after ingesting any
food, especially spicy food. The suggested mechanisms in this type of rhinitis are
1) neurogenic hyperactive, nonadrenergic, noncholinergic peptidergic neural
gustatory reflex that can be controlled by using capsaicin, 2) an abnormal neural
reflex and stimulation of the parasympathetic efferent nerves in the nasal mucosa.
 It responds well to nasal ipratropium bromide or neurectomy of the vidian or
posterior nasal nerve, but the latter is less necessary and performed these days.
7. Drug-induced rhinitis or rhinitis medicamentosa: nasal symptoms (mostly nasal
congestion) attributed to the administration of drugs, particularly intranasal
decongestants.
8. Reactive rhinitis, also known as vasomotor rhinitis or rhinopathy: excessive
response to physical and chemical stimuli such as cold air, strong odour, change
of humidity and temperature, or air pollution. The disease is caused by the
imbalance of sympathetic and parasympathetic systems which results in the
decrease of nasal patency by vascular engorgement (dysautonomia).

Atrophic rhinitis, also known as rhinitis sicca, is a disease that causes a subjective
sensation of nasal mucosa dryness and is characterized by crust formation and
mucosal atrophy as the main physical examination findings.
Idiopathic rhinitis is the exclusion diagnosis made when the symptoms of chronic
rhinitis are not caused by any mentioned etiologies.

The cellular inflammatory profile is a method to identify the phenotype and endotype
of rhinitis with a precision medicine concept by performing a nasal cytology test.
Table 2.3 summarizes the differential diagnosis of LAR and other diseases based on
cellular inflammatory profile.
Complication
A previous study conducted by Gracia et al. has proved that LAR is a unique
phenotype of rhinitis that does not evolve into systemic atopy as time passes.
However, the study by Mullol et al. discovered that approximately 3% of LAR
patients converted into LAR in 10 years. Gracia et al. reported that the conversion
rate into systemic atopy is not significantly different between LAR patients and the
general population (9,7% vs 7,8%; p=0.623), so it can be concluded that LAR is not
an initial state of allergic rhinitis.
The onset of LAR is most commonly seen in children, persistent in adults, and the
symptoms worsen, and it is associated with the comorbidities of other mucous organs.
By the time of the disease onset, 18.8% of patients reported symptoms suggestive of
asthma, a proportion increasing to 30.7% after 10 years. On the other hand, the cases
of conjunctivitis progressed from 52.3% to 61.9% during the same period.