Atopic allergic sensitization is defined by the production of immunoglobulin E (IgE)-mediated immune response toward allergens. Allergic rhinitis (AR) is a common disorder that afflicts 400 million people worldwide and it represents a global concern as its prevalence has increased over the years (1). AR usually comorbids with other diseases such as asthma (2), leading to impaired quality of life, school or work performance, and significant financial impact. AR is shown to be caused by aberrantly high Th2 cytokines, and recent findings on the cause of AR are directed toward impairment of the nasal epithelial barrier integrity (3–8). In this review, we summarize the well-established yet important concepts of AR including the epidemiology, clinical and laboratory diagnostic criteria, pathophysiology of AR including allergens as well as Th2 responses in AR.

Allergic rhinitis prevalence has increased significantly since the 1990s (9–11). It is reported to affect approximately 25 and 40% of children and adult globally, respectively. Approximately 80% of AR symptoms develop before the age of 20 years (12) and peak at age 20–40 years before gradually declining (13). The incidence rate of AR in children over the first 5 years of life was reported to be 17.2%, with a peak age at diagnosis between 24 and 29 months (2.5%) (14). Meta-analysis studies have shown the sex-specific differences in the prevalence of AR with male predominance in childhood and a female predominance in adolescents (15, 16).

Prevalence of AR has increased with years due to several risk factors including global urbanization as shown by several studies comparing AR prevalence in urban settings with rural areas (17, 18). This is mainly caused by increased levels of pollutants [e.g., traffic-related pollutants and particulate matter 2.5 (PM2.5)] that can exacerbate pollen-sensitized AR (19–21). It has been reported that AR is more prevalent in urban areas compared with rural areas (18). Climate changes also prolong pollen season as reported in Europe over the last three decades along with more frequent seasonal allergies (22).

Smoking, however, did not show a significant association with the severity of nasal symptoms in AR but usually impacted patients with chronic rhinitis (23, 24). Conversely, maternal smoking conferred the greatest risk in pediatric AR (25). Novel tobacco products such as electronic cigarette and heated tobacco products increase the risk of AR in adolescents compared with traditional smoking (26).

The economic impact of AR is significant where the total annual cost of self-reported AR in Sweden is estimated at €1.3 billion (27) and up to $20.9 billion in United States (1). In addition, AR is a systemic inflammatory disease and often comorbids with other disease such as asthma, atopic disease, sinusitis, conjunctivitis, and otitis media (9), complicating the treatment and management of AR patients.

AR is characterized by the presence of nasal and non-nasal symptoms. Nasal symptoms include anterior or posterior rhinorrhea, sneezing, nasal blockage and/or itching of the nose (9). These symptoms may persist for hours after allergic reaction upon the exposure of allergens that cause mucosal inflammation (13). In consequences, the mucosa is rendered more reactive to the triggering allergen as well as to other allergens and to non-allergenic stimuli (e.g., strong odors and other irritants). Non-nasal symptoms are characterized by ocular symptoms such as allergic rhinoconjunctivitis (i.e., itching and redness of the eyes and tearing) which frequently occurs in AR patients (10). Other symptoms include itching of the palate, postnasal drip and cough.

Hypersensitivity reactions can be observed in AR, bronchial asthma, allergic conjunctivitis, allergic dermatitis, food allergy and anaphylactic shock (28). Over 30% of AR patients suffer debilitating allergic symptoms that can lead to severe disability and life-threatening conditions such as anaphylaxis (29). In severe cases, intense bronchospasm, laryngeal edema, cyanosis, hypotension and shock may occur (28).

In terms of AR severity, it can be classified as mild and moderate/severe based on the AR and its Impact on Asthma (ARIA) guidelines (9). It is measured based on four aspects including sleep abnormality, impairment in daily activities, impairment in school or work performance, and troublesome symptoms. Patients without the aforementioned problems are considered as mild AR while patients suffering from one or more of the items are considered as moderate/severe AR. The ARIA guidelines also classify AR symptoms into intermittent and persistent based on the duration of symptoms present in AR patient. For intermittent symptoms, the symptoms occur in less than 4 days per week or less than 4 consecutive weeks while for persistent symptoms, they occur in more than 4 days per week and more than 4 consecutive weeks.

To determine the specific allergen that causes the production of IgE antibodies in AR, multiple tests can be conducted such as in vivo skin tests including skin prick test (SPT; percutaneous) and intradermal (intracutaneous) skin tests (IDST), and in vitro serum allergen-specific IgE (ssIgE) immunoassay. SPT and ssIgE immunoassay are the most common laboratory tests to determine the causative allergen(s) (30, 31). However, there is no “gold standard” laboratory test in diagnosing AR but SPT represents the first-line approach in the assessment of allergic sensitivities (9, 32). SPT is a quick and cost-effective methodology in diagnosing any allergic sensitization (33).

ssIgE immunoassay utilizes commercially available test panels which are more costly (33). It is also less sensitive for the diagnosis of allergy due to inhalant allergens compared with SPT. However, ssIgE immunoassay can be useful when skin testing is not available or cannot be performed due to patients have extensive skin disease, unable to discontinue antihistamines or other interfering medications, dermatographic, or other issues that complicate skin testing (34, 35). A novel non-invasive local diagnosis is through dried blood spot (DBS)-based diagnosis to detect IgE reactivity which can test up to more than 170 allergen molecules (36, 37).

Another uncommon diagnostic test for AR includes intradermal skin testing (IDST) in which tiny quantity of allergen is injected into the dermis with a hypodermic needle for the diagnosis of IgE-mediated allergic conditions (38). Other alternative or supporting tests include eosinophil cationic protein (ECP) and the percentage of eosinophils (39, 40), tryptase (marker of mast cell activation) (41), leukotriene B4 (40) and basophil activation test (through flow cytometry) to determine the causative allergen in local AR (42, 43). These tests are usually conducted in research settings and not routinely used for AR diagnosis.

Diagnostic criteria are generally broad and must reflect the different features of a disease (i.e., heterogeneity), with a view to accurately identify as many patients with the condition as possible (44). Due to the lack of gold standards in diagnosing AR, definitive diagnostic criteria have been challenging to establish. The choice of confirmatory test is a matter of clinical judgment and the results obtained must be considered together with additional risk factors, rather than definitive indicators of disease (45).

However, for patients to be diagnosed with AR, they must have clinical symptoms and possess laboratory characteristics as discussed in the previous section. AR patients must encounter two or more of the following clinical symptoms for more than 1 h on most days: (1) Watery rhinorrhea; (2) Sneezing, especially paroxysmal; (3) Nasal obstruction; (4) Nasal pruritis; (5) With or without conjunctivitis. When individuals present with clinical symptoms of AR, allergy laboratory tests are conducted for confirmation.

In skin tests, positive result is considered when the wheal-and-flare reaction occurs on the skin test site after 20 min of exposure to allergens. For SPT, positive result must demonstrate wheal (i.e., a red and itchy raised bump with surrounding inflammation that indicates the presence of allergic antibodies) size in diameter of ≥4 mm (46, 47). Figure 1 shows a positive SPT on house dust mite (HDM) allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae and Blomia tropicalis) tested on an AR patient who attended the ORL-HNS clinic of Hospital Universiti Sains Malaysia, and each wheal size was greater than 4 mm. The SPT protocols were approved by the Human Research Ethics Committee of Universiti Sains Malaysia (JEPeM; approved ethics code: USM/JEPeM/18060273).

The performance of any diagnostic criteria is dependent on the prevalence of the disease in a given geographical area or clinical setting (e.g., community clinic vs. tertiary care facility). AR diagnostic criteria are summarized in Table 1.

Allergic rhinitis represents a common pediatric problem where approximately 40% of pediatric AR patients develop symptoms as early as age 6 years old and increase with age (48–50). Symptoms of pediatric AR are similar with adolescents; however, young children may frequently exhibit sniffing, snorting, throat-clearing, and coughing (51). Comorbidities in pediatric AR are often combination of several conditions which indicate AR is a disease manifestation that involves systemic inflammation including conjunctivitis, atopic dermatitis, asthma, rhinosinusitis, otitis media with effusion, or food allergies (51, 52). The MeDALL (Mechanisms of the Development of ALLergy) project that involved more than 12,000 children from 12 ongoing longitudinal cohort studies showed the co-existence of asthma, rhinitis and eczema prevalence in the same child (53). In addition, findings from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC₂₀₁₀) have shown higher prevalence of AR, asthma and aeroallergen sensitization in children exposed to urban environment in their early age compared with those exposed to rural environment (54).

Diagnosis of AR in pediatrics includes complete history taking, physical examinations (e.g., nose, oropharynx, tympanic membranes, and eyes) as well as differential diagnosis based on the clinical symptoms suggestive of AR but not evidence of systemic atopy (55). A very young child with persistent nasal symptoms should be considered as having other disorders that can mimic AR (56). For children under 2 years of age, other disorders include adenoidal hypertrophy, acute or chronic sinusitis, congenital abnormalities (choanal atresia), foreign bodies and nasal polyps will be taken into consideration during diagnosis. On the other hand, older children may present with other disorders including acute infectious rhinitis, chronic non-allergic rhinitis, chronic rhinosinusitis, rhinitis medicamentosa, rhinitis due to systemic medications, atrophic rhinitis, rhinitis associated with hormonal changes, unilateral rhinitis or nasal polyps and rhinitis with immunologic disorders. Descriptions on each of these specific disorders (56) and differential diagnosis based on age (57) have been discussed in the cited references.

Increased prevalence of AR and that it is an incurable disease pose major unmet needs to alleviate these issues. AR comorbidities also confer increased health and socioeconomic burden on AR patients. Moreover, diagnosing AR is more challenging in patients with dual AR (DAR), a recently defined AR phenotype in which the DAR patients display perennial and seasonal allergies-related nasal symptoms, and only allergic to seasonal allergies. This indicates the importance of measuring inflammation at local allergic sites which might be different from peripheral inflammation in DAR patients (114–116). Thus, future studies warrant a better understanding of allergen-mediated cellular mechanisms at local sites of AR patients, in conjunction with further research on its pathogenic mechanisms such as breakdown of nasal epithelial barrier integrity that may lead to the discovery of novel therapeutic agents for the disease.

SMNH, HTT, NSMA, and KKW conceived the manuscript. SMNH and KKW designed the manuscript, performed literature search, wrote and revised the manuscript. SMNH prepared the figures and table. HTT, NSMA, and NMS revised the manuscript. All authors have read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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