Special Issue

Turkish Guideline for Diagnosis and Treatment of Allergic Rhinitis (ART)

10.4274/tao.2021.suppl.1

  • Mustafa Cenk Ecevit
  • Müge Özcan
  • İlknur Haberal Can
  • Emel Çadallı Tatar
  • Serdar Özer
  • Erkan Esen
  • Doğan Atan
  • Sercan Göde
  • Çağdaş Elsürer
  • Aylin Eryılmaz
  • Berna Uslu Coşkun
  • Zahide Mine Yazıcı
  • Mehmet Emre Dinç
  • Fatih Özdoğan
  • Kıvanç Günhan
  • Nagihan Bilal
  • Arzu Yasemin Korkut
  • Fikret Kasapoğlu
  • Bilge Türk
  • Ela Araz Server
  • Özlem Önerci Çelebi
  • Tuğçe Şimşek
  • Rauf Oğuzhan Kum
  • Mustafa Kemal Adalı
  • Erdem Eren
  • Nesibe Gül Yüksel Aslıer
  • Tuba Bayındır
  • Aslı Çakır Çetin
  • Ayşe Enise Göker
  • Işıl Adadan Güvenç
  • Sabri Köseoğlu
  • Gül Soylu Özler
  • Ethem Şahin
  • Aslı Şahin Yılmaz
  • Ceren Güne
  • Gökçe Aksoy Yıldırım
  • Bülent Öca
  • Mehmet Durmuşoğlu
  • Yunus Kantekin
  • Süay Özmen
  • Gözde Orhan Kubat
  • Serap Köybaşı Şanal
  • Emine Elif Altuntaş
  • Adin Selçuk
  • Haşmet Yazıcı
  • Deniz Baklacı
  • Atılay Yaylacı
  • Deniz Hancı
  • Sedat Doğan
  • Vural Fidan
  • Kemal Uygur
  • Nesil Keleş
  • Cemal Cingi
  • Bülent Topuz
  • Salih Çanakçıoğlu
  • Metin Önerci

Turk Arch Otorhinolaryngol 2021;59(1):1-157 PMID: 34212158

Object:

To prepare a national guideline for Otorhinolaryngologist who treat allergic rhinitis patients.

Methods:

The study was conducted by three authors, namely the writing support team. The support team made the study plan, determined the writing instructions, chose the subgroups including the advisory committee, the advisors for authors and the authors. A workshop was organized at the very beginning to explain the details of the study to the team. Advisors took the chance to meet their coworkers in their subgroups and determined the main headings and subheadings of the guideline, together with the authors. After key words were determined by the authors, literature search was done in various databases. The authors keep in touch with the advisors and the advisors with the advisory committee and the support group at every stage of the study. National and International published articles as well as the abstracts of unpublished studies, imperatively presented in National Congresses, were included in this guideline. Only Guideline and meta-analyses published in last seven years (2013-2017) and randomized controlled studies published in last two years (2015-2017) were included. After all work was completed by the subgroups, support team brought all work together and edited the article.

Results:

A detailed guideline about all aspects of allergic rhinitis was created.

Conclusion:

The authors believe that this guideline will enable a compact and up-to-date information on allergic rhinitis to healthcare professionals. This guideline is the first in the field of Otolaryngology in Turkey. It should be updated at regular intervals.

Keywords: Allergic rhinitis,guideline,rhinitis

1. Why have we composed this guide?

Allergic rhinitis (AR) is a frequently seen global upper airway disorder affecting individuals at all ages. The upper airway is in continuum with a number of important regions, and disorders of upper airway cause significant comorbidities. The most frequent comorbidity of AR is asthma. Acute or chronic rhinosinusitis, otitis media with effusion, adenoid hypertrophy and gastroesophageal reflux may accompany AR. AR affects quality of life negatively since it is a frequent disease affecting individuals at all age groups, and may lead to complications.

Although late diagnosis of AR or errors in its treatment do not lead to fatal outcomes in the early phase, they may result in significant morbidity. Errors in diagnosis and treatment result in an economic burden and psychological dysfunction in the affected patients. Therefore, its epidemiology, and the basic principles for avoidance, diagnosis, treatment and alternative treatment must be known.

Physicians in various disciplines come across with AR patients due to high incidence and prevalence of disease in all age groups, and its relation and effect on multiple body systems. Not only allergists and pediatricians, but also otorhinolaryngologists frequently encounter with those patients. In Turkey, there are no Guideline prepared for all medical specialties. This guideline has been prepared to increase awareness of every physician at all disciplines and grades. It intends to give clear and practical messages on epidemiology, clinical picture, complications, and treatment of AR by transferring the experiences of the otorhinolaryngologists in Turkey.


2. Definition and pathogenesis of allergic rhinitis

AR was first described by Hansel in 1929, based on its clinical symptoms, namely sneezing, nasal obstruction, and rhinorrhea. Allergic Rhinitis and its Impact on Asthma (ARIA) working group was founded by World Health Organization in 1999. This group has prepared detailed Guideline for clinicians on definition, classification, treatment algorithms using data in the literature, and updated them regularly (1). The ARIA Working Group has defined rhinitis as a nasal mucosal inflammation characterized by nasal symptoms including rhinorrhea, sneezing, nasal obstruction and/or nasal itching. AR has been defined as a clinical form accompanied by immunoglobulin E (IgE)-related immune response.

AR is characterized by a chronic mucosal inflammation induced by an IgE-related type 1 hypersensitivity reaction based on the inflammatory mediators released after the process of the antigen presentation, T cell differentiation, IgE synthesis and mast cell degranulation. It is a hyper-responsive state in which eosinophils and lymphocytes play the principal role due to repetitive stimuli of antigens (2, 3).


2.1. IgE sensitization

The allergens contacting mucosa and skin are presented to T cells by antigen presenting cells (APC), they are processed by epitope peptides, and presented to T-helper (Th) lymphocytes together with major histocompatibility (MHC) class II molecules. Activated CD4+ Th2 lymphocytes release cytokines, mainly interleukin (IL)-4 and IL-13, and they communicate with B cells which synthesize allergen-specific IgE (IgE sensitization). IgE releasing memory and plasma cells also develop. Then, the allergen specific IgE binds to the high-affinity IgE receptors on the surface of the mast cells (3).


2.2. Early phase response

This phase starts minutes after allergen exposure in sensitized individuals, and lasts for 2-4 hours. Mast cell degranulation is the main component of the early phase response. A vast number of mast cells are present in the epithelial part of the nasal mucosa, and they are easily activated after re-exposure to antigen. IgEs binded to the high-affinity receptors cross-bind to release pre-synthesized and newly synthesized mediators from the mast cells (2). Pre-synthesized mediators are released to extracellular fluid within seconds / minutes. Those mediators include histamine, prostoglandins, leukotriens, proteases, proteoglycans, cytokines and chemokines, which are responsible for edema, increased vascular permeability and rhinorrhea in AR. Histamine is the main mediator. It stimulates the sensory nerve endings of the trigeminal nerve, and causes sneezing, itching, and increased mucosal secretions. It results in nasal congestion acting on vessels together with leukotriens and prostoglandins.


2.3. Late phase response

This response appears 4-6 hours after the allergen exposure, and follows the early phase response. It lasts approximately 18-24 hours. Nasal submucosal T lymphocytes, basophils and eosinophils play role in the late phase. They release leukotrien, kinin, histamine, chemokine and cytokines. IL-4, IL- 5, IL-9 and IL-13 that released from mast cells, early lymphocytes, basophils and Th2 cells initiate and maintain the late phase response. IL-4 and IL-13 increase the expression of vascular cell adhesion molecule (VCAM1), and cause eosinophil, Th2 lymphocyte and basophil infiltration into nasal mucosa. RANTES (Regulated on Activation Normal T Cell Expressed and Secreted), eotaxin, monocyte chemoattractant protein (MCP)-4 and Thymus and activation regulated chemokine (TARC) are released, which provide a strong chemotaxis for eosinophil, basophil and T lymphocytes. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases the survival of eosinophils that have invaded the nasal mucosa. Eosinophilic cationic protein (ECP), thrombocyte activating factor and major basic protein released by eosinophils also play role in the late phase. Late phase response is particularly related to nasal congestion. Both upper and lower airways are affected by the local inflammation of AR, and systemic inflammation appears (4).

Eicosanoid, endopeptidase, cytokine and chemokines released from the nasal mucosa [IL-6, IL-8, IL-25, IL-31, IL- 33, TSLP, GM-CSF, tumor necrosis factor (TNF)-a, RANTES, TARC, eotaxin, stem cell factor (SCF)] result in the allergic inflammation. Matrix metalloproteinase (MMP)-2, MMP-9 and MMP-13 are released from the nasal epithelial cells, and they degrade the extracellular matrix. Human Leukocyte Antigen – DR isotype (HLA-DR) and CD86 expressed by nasal epithelial cells present antigen to T cells. IL-25, IL-33 and Epithelial cell-thymic stromal lymphoprotein (TSLP) are important inducers of AR. IL-4 is produced by natural killer (NK) 1+ T and mast cells, and induces Th2 differentiation. IL-12 is produced by macrophages and NK cells, and causes Th1 differentiation. An increase in IL-25 accentuates Th2-related inflammation. IL-33 enhances Th2 response, and activates type 2 innate lymphoid cells (ILC) that release IL-5, IL-9 and IL-13. These three cytokines contribute augmented Th2 response and tissue eosinophilia by increasing ILC. The allergens tend to destruct the epithelial barrier in AR. Proteolytic enzymatic activity of various allergens directly activates the epithelial cells, cause cytokine-chemokine release, and result in airway inflammation, independent of IgE.

Endothelial cell-derived VCAM-1 increases in the pollen season. RANTES and eotaxin are other important cytokine and chemokine released by the endothelial cells. H1 receptor is also expressed by the endothelial cells. Macrophage and dendritic cells (DC), too, release chemokines and influence Th2 cells as well as tissue fibroblasts. IL-4 induces allergic fibroblast proliferation, and GM-CSF production increases through histamine stimulation (3).

Allergen tolerance may occur by induction of T regulatory (Treg) cells that balance the hyper-activation of the immune system (5). All processes related to T cell subgroups determine the main targets of treatment in allergic diseases. There are two main Treg subgroups. The first one is the innate thymic FOXP3+, CD4+, CD25+Treg cells, and the other one is the inducible Treg cells that may be formed at the periphery under tolerogenic conditions (6).

FOXP3+Treg and IL-10 positive Tr1 cells, which are two subunits of inducible Treg cells, play role in development of allergen tolerance (7). The mutation of FOXP3, the main transcription factor in the development of Treg cells, may lead to allergic and autoimmune disorders. Treg cells influence Th2 cells as well as DCs, mast cells, basophils and eosinophils. Treg cells contribute the negative regulation of allergen specific IgE, increase production of blocking antibodies (IgG4 and IgA), and may inhibit mast cell degranulation directly by OX40-OX40 ligand interaction.

Together with other factors, it is evident that a decrease in Treg cells plays an important role in development of AR. CD4+CD25+Treg cell numbers decrease in vitro in patients with seasonal AR. In patients with persistent AR, the number and the functions of CD4+CD25+Treg cells are normal, however the number of IL-10 releasing Treg cells decrease (8, 9).


2.4. The effect of innate immune response on allergic rhinitis

The most important function of innate immune system in the upper airway is detection of the microorganisms. It is the host defense mechanism coded by the host genes. They include epithelium, mucus layer, cilia, soluble proteins, complement, defensin and a number of cytokines and chemokines. The Dcs, macrophages and mast cells in the upper airway contribute the process. There are two types of DCs: myeloid (mDC) and plasmocytoid (pDC). mDCs, are rich in microbial pattern recognizing receptors, which make a subepithelial network. pDCs express toll-like receptor (TLR)-7 and TLR-9, and release interferon alpha; they play a particular role in anti-viral response. Mast cells express complement receptors for TLR1, TLR2, TLR4,TLR6, C3a and C5a. Neutrophils and NK cells are crucial components of this system. First-line defense provided by innate immune system plays an important role in future development of tolerance or chronic inflammation.

Antimicrobial peptides (AMP) kill microbes straight off. Cathelicidin is one of them, and it triggers tissue inflammation. Defensin is an antimicrobial against bacteria, viruses and fungi (10).


2.5. Mast cells

Mast cells play a crucial role in the first phase response of AR. They are the main producers of histamine, leukotriens and prostoglandins. They also release cytokines and chemokines that regulate the late phase response. IgE-activated mast cells express vast amounts of high-affinity IgE receptors (FceRI), CD40L, IL-4 and IL-13. They stimulate local IgE synthesis in nasal mucosal B cells. Mast cells auto-activate themselves by IgE or IL-4 mediated FceRI upregulation. In this way, they intensify the ongoing inflammation (2).

Th2 cells play a role in development and progress of cytokine-dependent inflammation. Basophils are present in the nasal lavage fluids of AR patients, and they are thought to be the main sources of histamine in the late phase reaction. Basophils are also important sources of LTC4 (11).


2.6. Basophils

They infiltrate the nasal mucosa in AR (12).


2.7. Group 2 innate lymphoid cells

Group 2 innate lymphoid cells (ILC2) release Th2 cytokines. They have been shown to be increased in the peripheral blood in cat antigen-related AR. Another study showed increased ILC2 in peripheral blood of the patients with pollen allergy, and their numbers decreased after subcutaneous immunotherapy (13).


2.8. Natural killer cells

AR patients produce type 2 cytokines, and they have a high NK cytotoxic capacity (14). Those cells are giant granular lymphocytes. They produce cytokines such as Interferon- gamma, TNF-alpha and GM-CSF. They do not need MHC receptors to identify their target cells.


2.9. Eosinophils

They play a crucial role in the nasal mucosa. The number of eosinophils and the amount of ECP increase in parallel with the severity of the symptoms (15).


2.10. Antigen presenting cells

The type and the amount of the allergens that come across with APC are important in an immunological reaction. The most significant APCs are the DCs (16). There are three types of DCs in the nasal mucosa: CD11c+ mDCs, CD123+ pDCs and Langerhans cells (CD1a+, CD207+). They trigger inflammation. DCs break antigen into small pieces, and present them to T cells in cooperation with MHC I and MHCII. They regulate Th2-type allergic reaction over Th1, Th17 and T regulatory reactions. The antigens presented by pDC usually induce tolerance, however mature DCs induce inflammation. DCs play role in allergic inflammation and appearance of symptoms (17, 18).


2.11. T and B lymphocytes

CD4 Th cells are formed by activation of DCs. These cells activate effector cells including eosinophils and neutrophils, and cause differentiation of B cells into plasma cells, releasing pathogen-specific immunoglobulin. Another specific T cell group, Tregs, inhibit the immune response. IL-10 and TGF- beta expressed by Treg cells inhibit activation of other T and B cells, DCs and mast cells (19, 20). Other T cells inhibit T cell-related activation in presence of Foxp3- CD25 positive Treg cells that do not express IL-10 or TGF-beta. These Treg cells have been reported as a component of symptom suppression mechanism of immunotherapy. Epigenetic research has been going on concerning specific genomic mutations, expression profiles, and epigenetic alterations of the T and B cells in allergic patients. The network of regulatory cells that control the activation of these cells is also a research topic.


2.12. Cytokines and chemokines

Cytokines are soluble proteins or peptides that play role as the mediator hormones of the immune system. Their functions may change in relation with the target cell. Chemokines are a subgroup of the cytokines, and they cause migration of leukocytes into the site of inflammation in AR. IL-1 and IL-2 cause B cell activation. IL-33, IL-25 and TSLP are released by nasal mucosal epithelial cells, and mediate uptake of the allergen by antigen presenting DCs. T-cell informing cytokines interact with undifferentiated T helper (CD4+) cells to induce different immune responses. IL-12 and interferon-gamma induce formation of type 1 Th1 cells which fight against bacteria and viruses. IL-4 pioneers Th2 cells that fight against the parasites. Th17 battles with bacterial and fungal infections, and plays role in autoimmune diseases. Treg cells induce release of IL-10 and transforming growth factor (TGF)-b , inhibit migration of the inflammatory cells, and suppress inflammation by reducing Th function (21). Th-effector cytokines mediate activation of the Th cells. Th2 cells modify B cells to express allergen specific IgE, IL-4, IL-13, IL-5 that induce production of eosinophilic granulocyte, and IL-9 and IL-13 that induce nasal mucosal inflammation (2, 22).

Chemokines induce cell chemotaxis. They define the type of migratory inflammatory leukocyte (eosinophil, neutrophil, basophil, T or B cell). Some chemokines induce high concentration of mediator release from leukocytes, and play role in allergic inflammation. The most crucial chemokines in allergic inflammation are eotaxin-1 (CCL11), eotaxin -2 (CCL24) and eotaxin-3 (CCL26). All of them exert their action through CCR3 receptors located on eosinophils, basophils and Th cells. Another crucial Th2 chemokin is RANTES (CCL5) acting through CCR5 receptor.


2.13. The role of local and systemic IgE

In a small group of patients, serum specific IgE and skin prick tests are negative, however these patients have typical AR symptoms. Local IgE synthesis in the nasal mucosa has been presumed after identification of IL-4 and epsilon gene transcription in nasal mucosal B cells with in situ hybridization. Local IgE production may explain why some patients develop asthma and eczema and some others develop AR.

Absence of AR symptoms in presence of positive serum specific IgE and skin prick test may be due to lack of local IgE. It has been noted that some of the patients diagnosed with non-allergic or idiopathic rhinitis might in fact have local IgE-dependent rhinitis (23). A nasal provocation test must be performed in those patients. In a Spanish study, triptase, ECP and Th2 cytokines have been isolated in the nasal lavage fluids of these patients following nasal provocation. The local IgE levels were low, however it was supposed that this might be due to dilution in the nasal lavage fluid (24).


2.14. Lipid mediators in allergic rhinitis

Arachidonic acid is released from cell membrane phospholipids in cells activated by phospholipase A2. Arachidonic acid is metabolized through 5-lipoxygenase (5-LO) pathway into leukotriene (LT) B4 and cysteinyl leukotrienes (CysLT), namely, LTC4, LTD4 and LTE4. Neutrophils are the main sources of LTB4, on the other hand, mast cells, basophils and eosinophils produce mainly CysLT. CysLT play role in eosinophil migration, stimulation of airway mucus production, and upregulation of inflammatory cytokines. Prostaglandin (PG) E2, PGD2, PGF2alpha, prostacyclin and thromboxane (TXA2) are produced from arachidonic acid through cyclooxygenase (COX) pathway. Mast cells produce mainly PGD2. There are two forms of COX: basal (COX-1) and inducible (COX-2) forms. PGs have inflammatory functions (PGE2, PGD2, PG2alpha, TXA2), however they may act as anti-inflammatory endogenous molecules (PGE2, PGD2). Lipoxin (LX) A4 is produced by leukocytes from arachidonic acid through 15-LO pathway, or LTA4 is produced and metabolized into LXA4 in thrombocytes. Low LTE4 and PGD2 levels have been determined in nasal biopsy of the patients with AR. CysLT, LTB4 and PGD2 increases with nasal allergen provocation. Nasal symptoms improve with CysLT1 receptor antagonist treatment. LTA4 analogs have potential regulatory actions in inflammation of AR (25).


2.15. Nasal mucosal epithelial barrier

Upper airway is the first barrier to allergens. The epithelial barrier of the nose and paranasal sinuses is composed of pseudostratified ciliated epithelium. The epithelial barrier contains antimicrobial proteins such as defensin, cathelicidin, lysosome and lactoferrin. S-100 proteins also have antimicrobial activity through innate immunity and Toll-like receptors (18). Tight junctions, constituted by integral membrane proteins, constitute a crucial part of epithelial barrier. Various antigens contacting nasal mucosa are presented to lymphocytes by the epithelial cells. Tight junction cells in the nasal epithelium are influenced by growth factors and cytokines. Epithelial TSLP increases the tight junction proteins in the epithelial barrier, and plays an important role in inflammation (26).


2.16. Neuroimmune mechanisms in allergic rhinitis

The nasal epithelium is innervated by unmyelinated type C trigeminal nerve endings. Sympathetic neurons innervate the arteriovenous anastomoses of the venous sinusoids. Histamine stimulates H1 receptors. Nociceptive receptors are depolarized, resulting in itching in patients with AR. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, and it is closely associated with neuromedin B and gastrin releasing peptide (GRP). Tachykinin, neurokinin A and substance P induce glandular exocytosis while glutamate is an excitatory amino acid neurotransmitter. Local CGRP release results in plasma exudation from the membrane vessels. The mediators such as leukotriene B4 and nerve growth factor induce expression of sensory receptors, neurotransmitters and inhibitory autoreceptors. Afferent receptor sensitivity is induced by an increased expression of endothelin and bradykinin receptors, transient receptor potential vanilloid 1 (TRPV1), purinergic P2X receptors and acid-sensing ion channel 3 (ASIC3). Damaged cells release potassium and calcium. The nociceptive neurons travel to pons, turn caudally at the trigeminal spinal pathway, and end at the dorsal horns of the caudal interneurons of the first three cervical segments. Glutamate and N-methyl-D-aspartic acid bind receptors and depolarize interneurons. GRP is the neurotransmitter of the itching neurons. They cross the midline to reach lateral trigeminothalamic tract, and end at the medial thalamus. Axonal branches travel to superior salivatory nucleus, and enrich parasympathetic reflex bilaterally. This reflex stimulates muscarinic M3 receptors, and glandular exocytosis and seromucous rhinorrhea are triggered. This mechanism explains the benefit of the patients from anticholinergic medications. Tertiary thalamic nerves transmit mucosal sensation to interoceptive cortex, situated at the posterior insula. The management of these perceptions is performed by the interactions in the brain, explaining the negative effect of AR on cognitive functions at school and work. Anterior insular efferent pathways activate brainstem sympathetic (right insula) and parasympathetic (left insula) stimulation (27).

Continuance of allergic symptoms despite use of H1 histamine antagonists has led to research on other receptors. H4 histamine receptor plays role in immune regulation, and it is one of the main targets for treatment of AR. Specific H4 antagonists have been investigated by various researchers, however we do not have clear data on their clinical efficacy (28).


2.17. Nasal hyper-reactivity

A number of patients report that their symptoms are triggered not only by allergic stimulation, but also with non-specific stimuli including smoke, cold air and perfumes. Increased sensitivity of nasal mucosa to stimuli is called as nasal hyper-reactivity, and may be evident in patients with AR and non-allergic rhinitis. Nasal epithelial damage and increased permeability of the epithelium lead to stimulation of sensory nerve endings, resulting in mediator release from the mast cells. In addition, non-adrenergic non-cholinergic neurotransmitters (neuropeptide Y and vasoactive intestinal peptide) activate the cholinergic system that leads to nasal vasodilatation and increased secretion. Nasal hyper-reactivity may be tested with nasal provocation using cold-dry air (29).


3. Classification of allergic rhinitis

AR is a frequent disease affecting both adults and children. It is considered as a significant health problem due to its negative effects on school / work performance and quality of life as well as its high economic burden. The classification of AR is based on the subjective clinical symptoms of the disease. It is classified in relation with the severity (mild/moderate-severe) and duration (intermittent-persistent) of the symptoms.

Apart from its frequency, AR is a significant health problem due to its economic burden, absenteeism and comorbidities, including bronchial asthma. Classification of AR is crucial since it can be confused with other types of rhinitis, its treatment plan is based on symptoms and duration of the disease, and a common language among physicians is needed to determine the benefit from therapy. AR may be classified in accordance with the time of exposure to allergen, and frequency and severity of the symptoms (30, 31). Traditionally, AR may be divided into four subgroups according to time of exposure to the allergen.


3.1. Seasonal allergic rhinitis

This term is used for the disease that becomes symptomatic only in specific periods of the year, in presence of allergens in the environment. The responsible allergens are usually pollens. They are released into the air at the same time of year in regions with a moderate climate. Similarly, some mold spores increase in the summer, and cause seasonal symptoms in sensitive patients. The symptoms of some patients increase in cold seasons, and the responsible allergens may be indoor mold spores, house dust mites, and animal allergens, since their concentrations increase indoors when the inside temperature is high and windows are closed.


3.2. Perennial allergic rhinitis

Most of the patients have perennial symptoms. The responsible allergens may be animal fur, house dust mites and the spores of the indoor molds. The diagnosis and treatment of these patients is complicated in presence of a non-allergic rhinitis causing chronic nasal congestion.


3.3. Episodic allergic rhinitis

In this form of AR, the symptoms appear occasionally. Appearance of symptoms in contact with a cat in an individual with hypersensitivity to cat allergen may be an example. Another example may be becoming symptomatic after housecleaning in case of house dust mite hypersensitivity. A detailed history may help the diagnosis in this form of AR.


3.4. Seasonal exacerbation of chronic disease

These patients are sensitive to perennial allergens. Their symptoms exacerbate in relation with the periodical increase in the allergenic load (30, 31).

Traditional classification AR is not practical in many patients since most of the patients have multi-sensitivity to seasonal and perennial allergens. Therefore, ARIA working group of World Health Organization proposed a new classification of AR (1). In this classification, ARIA uses the terms “intermittent” and “persistent” instead of “seasonal” and “perennial”. It must be noted that “intermittent” is not the synonym for “seasonal”, and “persistent” is not the synonym for “perennial”. ARIA classification takes the severity of the disease into consideration, different from the traditional classification. The disease is classified as “intermittent” or “persistent” in relation with the duration (Table 3-1), and as “mild” or “moderate/severe” in relation with the severity of the symptoms (Table 3-2).


3.5. Intermittent allergic rhinitis

The term “intermittent rhinitis” indicates duration of the symptoms less than 4 days/week, or less than 4 consecutive weeks/year.


3.6. Persistent allergic rhinitis

The term “persistent rhinitis” indicates presence of symptoms more than 4 days/week and more than 4 consecutive weeks/year. These patients usually have symptoms every day of the year.

AR is classified as “mild” or “moderate/severe” in relation with the severity of the symptoms.


3.7. Mild disease

In this form of the disease, the patient has mild symptoms not influencing sleep, school or work performance, or sportive or daily activities.


3.8. Moderate-severe disease

This is the form of disease in which the symptoms have negative influence on sleep, school/work, leisure, or daily activities.

In the light of aforementioned information, AR may be classified into four groups as “mild intermittent”, moderate/severe intermittent”, “mild persistent” or moderate/severe persistent” in relation with the duration and the severity of the symptoms (1).


3.9. Local allergic rhinitis

This term is used for the patients who have classical AR symptoms in absence of systemic atopy, ie. negative skin tests and serum specific IgE (23). Most of the data on local allergic rhinitis (LAR) come from European centers. These data indicate that 47-62.5% of the patients with perennial or seasonal AR symptoms and negative skin tests and specific IgE in serum have LAR. The responsible allergens are house dust mites, grasses and olive tree pollens (32-34). Local IgE production has been claimed to play role in the pathophysiology, and has been detected in 22-35% of the patients (32, 33). LAR seen in the elderly is characterized by pronounced eye symptoms, and responds well to oral antihistamines and nasal corticosteroids (32, 33, 35). Diagnosis is based on presence of nasal specific IgE and/or a positive nasal provocation test in absence of any systemic atopy (36).


4. Epidemiology of allergic rhinitis


4.1. Global epidemiology of allergic rhinitis

AR is frequent both in adults and children all around the world. It is the 16th more frequently diagnosed disorder in the outpatient clinics in the USA. It ranks as the 5th most frequent chronic disease in the adults, and the first most frequent chronic disease in the children in the USA (37). It has been estimated that AR affects more than 500 million individuals worldwide. AR is most frequently seen in the adolescents, and secondly in the first decade of life (38). AR prevalence has been reported as 10-30% in the adults, and 40% in the children (39).

A study performed on 7398 volunteers (older than the age of 6 years) in the USA revealed presence of AR symptoms in one of three individuals in the previous year, independent of an upper respiratory tract infection. There was hypersensitivity for at least one allergen in 52.7% of the participants. Global prevalence of AR has been estimated as 10-20% (40).

AR prevalence shows regional differences. The prevalence in adults has been reported as 16.3% in the Switzerland while it has been reported as 23.5% in the USA (39). “The International Study of Asthma and Allergies in Childhood” report indicates regional differences in childhood, too: AR prevalence is the smallest in Iran, affecting only 1.5%, and the highest in Nigeria, affecting 39.7% of the children. The prevalence of AR has been estimated as 13-19% in children younger than 14 years of age in the USA (27).


4.2. Specification of the epidemiological studies and data in Turkey, and questioning their accuracy

There are only a few studies on AR prevalence in our country, and further studies on larger populations are needed. A multi-center study on 4125 individuals (age range 16-54 years, mean age 30.5 years) from every geographical region of Turkey was conducted in 44 centers. AR prevalence was found as 22.3% in adult men, and as 23.8% in adult women (41). Another study on university students reported AR prevalence as 21.8%, and the diagnosis was based on a physician report in 12.1%. AR prevalence was 17% in males, and 25.2% in females, with a statistically significant difference in between (42). A study that included 12-15-year-old students in Trabzon reported AR prevalence as 14.5%. The prevalence was higher in the girls. In addition, parental smoking, living in an apartment, and presence of a pet in the house increased AR prevalence significantly (43).

Although the data are insufficient, the results of the Turkish studies indicate various differences between Turkish population and the populations of other countries. Further studies on larger populations are needed in Turkey.


4.2.1. Comparison of epidemiological data in Turkey with other regions of the world

AR prevalence demonstrates regional differences in the world. The prevalence has been reported as 25% in Europe, however there are differences among the European countries. AR prevalence was reported as 28.5% in Belgium, 24.5% in France, 20.6% in Germany, 16.9% in Italy, and 26% in the United Kingdom (44). A study reported AR prevalence in Japan as 29.8% in 1998, and as 39.4% in 2008 (45). A large Middle-East study including Bahrain, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Oman, Palestine, Qatar, Saudi Arabia, Syria, United Arab Emirates and Yemen reported AR prevalence as 9-38% in all age groups (46). The data for Turkey are unsatisfactory, however AR prevalence has been estimated as 20-25%, with regional differences (41). The AR prevalence in Turkish adults is similar to the prevalences in other regions of the world.

Pediatric AR prevalence has been reported as 13-19% in the USA (27). A large Korean study reported childhood AR prevalence as 20.8% (47). A study compared prevelances of AR in Turkey in 2002 and 2008. Prevalence of physician-diagnosed AR was reported as 4.3% in 2002, and as 7% in 2008 (48). There are no recent studies that investigated AR prevalence in children in our country. Further studies are needed.


4.2.2. Specification of the regional differences in Turkey (diet, seasonal differences)

AR prevalence shows differences in our country in accordance with geographical regions, diet and lifestyle. A study that included 11,483 participants in İstanbul investigated AR prevalence in 6-7 -year-old schoolchildren, and reported once-in-a-lifetime AR prevalence as 44.3%, active AR prevalence as 29.2% and physician-diagnosed AR prevalence as 8.1% (49). A study that investigated prevalences of allergic disorders in Bolu in 30-49-year-olds reported AR prevalence as 16.5%, and noted that the prevalence was higher in individuals with low socioeconomic status (50). Other researchers investigated the influence of diet on AR prevalence in 6-7-year-old children in our country. They reported that AR prevalence was lower in children that ate grains, rice or chocolate more than three times a week. The authors did not find any influence of Mediterranean diet on AR prevalence (51). AR prevalence may show differences in accordance with geographical regions, seasonal factors and diet. Further large-scale studies are needed on this topic both in our country and in the world.


4.2.3. Specification of the epidemiological data in relation to age, gender, region, method of diagnosis, occupation, allergens, classification, urban/rural areas, diet (breast milk, lactose, gluten)

A number of factors may affect AR prevalence. A study that investigated AR prevalence in accordance with the age groups designated the age groups as 20-44, 45-64 and 65-84 years, and found the prevalence as 26.2% in females and 28.6% in males in 20-44-year group, as 21.3% in females and 19.8% in males in 45-64-year group, and as 17.8% in females and 17.1% in males in 65- 84-year group. The authors also reported lower AR prevalence in smoking individuals, and higher prevalence as level of education increases and socio-economic status gets better (21). A study from South Korea investigated AR incidence, and grouped the participants into 1-6, 7-12, 13-18, 19-64 and >65-year age groups. The authors found out that AR incidence increased from 2003 to 2011 (52). A meta-analysis on gender and AR epidemiology reported that AR was significantly more frequent in girls younger than 11 years of age, however it was more frequent in boys in 11-18-year-old age group. The prevalence was similar in adult women and men. Those data included the individuals from all continents except Asia (53). AR prevalence changes in accordance with gender and age.

A large-scale study from China reported AR prevalence as 13.5% in rural, and as 19.1% in urban areas. The AR prevalence was significantly higher in the urban areas (54). A study on the geriatric population investigated house dust mite hypersensitivity in the individuals living in urban, semi-urban and rural areas, and reported sensitization rates as 17.2%, 9.8% and 6%, respectively (55). A study from Poland reported prevalence of allergic diseases (bronchial asthma, AR and atopic dermatitis) twice higher in the ones living in the cities compared to the ones living in rural areas (56). A study investigated AR prevalence in 19-25-year-old female university students, and reported higher AR prevalence in the ones with high socioeconomic status. The AR prevalence was higher in individuals that had spent their childhood in urban areas. There was no correlation between estrogen levels and AR prevalence (57).

A total of 304 individuals were tested for house dust mite allergens, and AR was found in 46%, non-allergic rhinitis was found in 50%, and LAR was seen in 4% (58). An Australian study investigated food allergy epidemiology, and reported the prevalence as 11% in children aged 1 year, and as 3.8% in children aged 4 years. Specific food allergy prevalences were as follows in 4-year-old children: Peanut allergy 1.9%, egg allergy 1.2%, and sesame allergy 0.4%. AR and food allergy was simultaneously evident in 8.3% of 4-year-old children (59). A study on European and American women reported that consuming seafood during pregnancy did not increase AR incidence in the offspring. It was reported that consuming seafood during pregnancy did not increase AR prevalence (60). AR prevalence was higher in 1-4-year-olds that consumed cow milk three times a day (61). The effect of dietary habits on AR prevalence was investigated in children. The authors reported that a fat-rich, carbohydrate-poor diet increased AR incidence (62). A study on correlation of obesity with AR prevalence reported that AR prevalence increased in direct proportion to body mass index (63). High omega-3 poly-unsaturated fatty acid level in the colostrum was correlated with high AR prevalence in adolescence, however there was no correlation with high omega-6 content in the colostrum (64). It is evident that dietary habits are correlated with AR prevalence.

The children exposed to air pollution and high carbon monoxide in the city in their first year of life were reported to have higher AR prevalence at 6-7 years of age (65). A study from Sweden reported that smoking increased rhinosinusitis prevalence both in males and females, but decreased AR prevalence in males (66). Another study on AR prevalence and smoking reported that smoking did not affect AR prevalence in smoking individuals, however AR was more frequent among passive smokers (67). Although studies on smoking and AR prevalence are scarce, one may say that smoking does not increase AR prevalence.

It was reported that children with 25-OH levels greater than 75 had lower AR prevalence compared to children that had 25-OH levels lower than 50 (27). A large study from Italy also investigated correlation of vitamin D levels and AR prevalence. Although higher AR rate was present in individuals with low vitamin D levels, the result did not reach statistical significance (68). It may be concluded that vitamin D deficiency increases AR prevalence.


5. The influence of allergic rhinitis on quality of life

AR classification is based on clinical subjective symptoms. In ARIA classification, AR is classified as “intermittent” if the duration of the symptoms is less than 4 days/week, or less than 4 consecutive weeks/year, and as “persistent” in presence of symptoms more than 4 days/week and more than 4 consecutive weeks/year. AR is classified as “mild” or “moderate/severe” in relation of the symptoms’ influence on the quality of life (1). Since the clinical definition is based on the patient history, and it is impossible to have epidemiological data in ARIA classification, there is need for standardized questions to ask the patients (38).

Acoustic rhinometry and rhinomanometry that measures nasal obstruction, nasal nitric oxide determination to assess inflammation, and visual analog scale (VAS) that defines symptom severity are used to determine the clinical severity of AR symptoms. It has been claimed that VAS was comparable with the quality of life scales designed for AR for quantitative measurement of severity of AR (69). VAS has been used for a number of disorders. The patients are asked to mark the severity of their symptoms on a line, one end marked with 0, and the other end marked with 10. A number of studies agreed that VAS was successful for quantitating rhinitis symptoms, and it is suggested for quantitative measurement of symptom severity in AR (70-72).

Although quantitative data collection by visualization through VAS helps the clinicians for the analysis of the symptom scores, this inventory is not sufficient to determine the comorbidities of the disease and to convert them into data. In this context, quality of life scales provide a standardized and numerical summary of the symptoms of the patient, and functional and psychosocial results of the disease and its treatment, and epidemiological analysis of the data is made possible. General quality of life scales provide data for an overall functional disability and disturbance, therefore they can be used for all segments of the population, for all diseases and disorders, and for various medical interventions. Disease-specific quality of life scales are specific scales for the disease under research, and may detect small variations (73).


5.1. Quality of life scales frequently used for allergic rhinitis


5.1.1. Medical Outcome Study, Short-Form 36 (SF-36), Short Form-12 (SF-12), Short Form-20 (SF-20)

This is an overall health questionnaire used for detecting the effects of chronic conditions on functional heath status (74). The overall scale estimates physical and mental wellbeing of the individual. In case of AR, this scale was proven to differentiate healthy individuals from the patients, and it could be used successfully in the follow up of treatment (75). It is the most frequently used general quality of scale in the literature for investigation of AR patients.


5.1.2. Glasgow Benefit Inventory

This is a frequently used 18-item questionnaire directed to overall, physical and social benefits of the treatment employed. It is mostly used in studies on hearing surgery and hearing aids (76).


5.1.3. Sinonasal Outcome Test 20 and Sinonasal Outcome Test 22 (SNOT-22)

This scale consists of the questions on nasal symptoms. It measures the severity of the symptoms as well as the emotional and mental significance of these symptoms for the patients. Symptom-related comorbidities are also included. SNOT-22 includes additional symptoms, it is proven to be reliable and valid, and it is an easy-to-use, popular scale used frequently in studies on rhinitis symptoms in order to obtain quantitative data (77).


5.1.4. Rhinoconjunctivitis Quality of Life Questionnaire

It is the most frequently used rhinitis-specific quality of life scale (78). It measures not only the rhinitis symptoms, but also selection of the activities that rhinitis influences, and the disability regarding those activities. This scale is employed for various rhinitis groups, and it has modifications for different symptoms.


5.1.5. Rhinasthma Quality of Life Questionnaire

The target population of this questionnaire is the asthma patients with comorbid AR. It has been proven to be reliable in patients with simple rhinitis and comorbid allergic asthma (79). Since those two disorders co-exist most of the time, Rhinasthma Quality of Life Questionnaire is frequently used in studies on those disorders.


5.1.6. General Nasal Patient Inventory

This is a 30-item questionnaire for all rhinology patients. It measures quality of life in patients with any nasal disorder (80).


5.1.7. Sinonasal-5 Quality of Life Survey

It is a specific scale for children with persistent sinonasal symptoms. It has been used in treatment and follow up of pediatric sinonasal disorders.


5.1.8. Rhinitis Control Assessment Test (RCAT)

This scale is used to follow up the rhinitis symptoms after treatment. Higher scores in follow up has a significant correlation with disease control.


5.1.9. Nasal Obstruction Symptom Evaluation Scale

This is a nasal symptom assessment questionnaire used in adults. It is a reliable and valid 5-item nasal symptom scale that assesses nasal obstruction (81). Its validity has been proven in the follow up of the patients after surgery. It may be used in studies on sinusitis and rhinitis.


5.1.10. Rhinosinusitis Disability Index

This is a disease-specific questionnaire that measures the impact of the symptoms on daily activities, and their functional and emotional effects. It has been found beneficial in AR patients as well as rhinosinusitis patients (82).


5.1.11. Rhinosinusitis Symptom Inventory

This scale includes major and minor symptoms of rhinosinusitis.

Rhinoconjunctivitis quality of life questionnaire has been regarded as the main reliable and valid distinguishing scale for rhinitis-related quality of life (77). Other than this scale, SNOT-22 has been proven to differentiate rhinitis patients from the symptom-free individuals, and it has been suggested for the patients that had surgery. This scale has now been used by many researchers for rhinitis patients since it takes all nasal symptoms into account. It has been suggested that SNOT-22 is the most easy-to-use, specific and reliable scale (83). Turkish validation of SNOT-22 was done in 2015 (84).

The studies on the impact of AR on quality of life usually employ the aforementioned scales. A meta-analysis compared house dust mite-related perennial AR and pollen-related seasonal AR in 2016 (85). Included studies were the ones that measured health-related quality of life with generic indices such as SF-12 and SF-36, or disease-specific indices. It was reported that perennial AR due to house dust mite had a more negative impact on quality of life when compared to seasonal AR due to pollen (85). Another study on 990 AR patients found that nasal congestion and ocular symptoms influenced negatively the quality of life the most, as measured with VAS symptom scores and RQLQ, compared to other symptoms of AR. Nasal airflow measurements before and after treatment showed a significant positive correlation with total nasal symptom scores of RQLQ, even the change was minimal (86). Similarly, SF-36 provided similar results with RQLQ in AR patients after control of the symptoms with treatment (87). Both scales were found useful in the follow up, and to distinguish the patients that were actively treated with fluticasone or administered placebo. SF-36 was claimed to be as specific as RQLQ, which enclosed AR- specific items (87). RCAT, a 6-item easy-to-use scale addressing AR-related symptoms in the previous week and has been created for the follow up of AR patients was also reported to provide sufficient data in the follow up period (88).


6. Diagnosis of allergic rhinitis


6.1 History

A detailed history is crucial in AR since nasal inflammation may occur in a number of disorders. Rhinitis symptoms are similar in allergic and non-allergic rhinitis. Therefore, the specific points for AR in the history may help the physician in the diagnosis of AR.


6.1.1. Symptoms


6.1.1.1. Nasal symptoms

Rhinorrhea, nasal itching, sneezing and nasal congestion are the main symptoms of AR. Rhinitis is accompanied by eye, ear and throat symptoms. Rhinorrhea is usually copious and serous in character. Sinusitis may be evident in some patients. In this case, the patients may complain of purulent nasal and postnasal discharge, pressure on face, anosmia, headache and halitosis (89). Nasal itching is usually a characteristic of AR. Paroxysmal sneezing episodes are the most characteristic symptoms of AR, and may be accompanied by nasal itching and irritation.

Most of the AR patients complain of nasal congestion that worsens at night. Rhinorrhea, nasal itching and sneezing are mostly seen in seasonal AR, however nasal congestion is frequently evident in perennial AR. Nasal congestion may result in mouth-breathing and snoring (38). There are a number of disorders causing nasal congestion, therefore simultaneous symptoms should be questioned. The patient should be questioned whether nasal congestion