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Expert analysis: The importance of confirming allergic triggers in rhinitis

Rhinitis is an inflammatory disorder of the nasal mucosa clinically defined by two or more symptoms of nasal itching, sneezing, anterior or posterior rhinorrhoea, and nasal blockage.1
Rhinitis is considered chronic when the symptoms are present for at least one hour daily and last longer than two weeks.2 The lifetime prevalence rates of acute rhinitis and chronic rhinitis are 100% and >20%, respectively, which explains the considerable financial burden that the condition imposes to health care systems, in terms of consultations and medications prescribed.3 Moreover, chronic rhinitis negatively affects work and school performance and has been related to learning disabilities in children,4 and to an impairment in quality of life greater than that of chronic conditions such as arterial hypertension.5 Chronic rhinitis is often associated to other inflammatory disorders of the mucous membranes such as sinusitis, conjunctivitis and asthma, which further amplifies its impact.6 Nevertheless, the condition has been historically trivialised and has been regarded as a relevant health problem only in recent years.
Several classifications have been proposed for chronic rhinitis based on different parameters such as pathophysiology, frequency and pattern of symptoms or trigger(s) eliciting rhinitis.2 One easy classification divides the disorder into allergic rhinitis (AR) and non-allergic rhinitis (NAR). AR is the most frequent form of chronic rhinitis,7 and constitutes a relatively homogenous phenotype with known pathophysiology defined by IgE-sensitisation to environmental allergens.6 Conversely, NAR comprises a highly heterogeneous group of diseases where immune-mediated inflammation is not always apparent.8 NAR patients are defined by rhinitis symptoms and negativity of classical IgE-sensitisation tests, namely the skin prick test (SPT) and serum allergen-specific IgE7 (Figure 1).
Figure 1: Diagnostic biomarkers
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Figure 1: Diagnostic biomarkers in the allergic phenotypes of rhinitis. Allergic rhinitis (AR) is characterised by the positivity of skin prick (SPT) test and serum specific (s)IgE. These two biomarkers are sufficient for diagnosis in many cases of AR. In AR individuals, the clinical relevance of an IgE-sensitisation can be accurately established by a nasal allergen challenge (NAC). The basophil activation test (BAT) and the nasal sIgE are positive in most cases of AR, even though they do not use to be necessary for diagnostic purposes. By definition local allergic rhinitis (LAR) patients test negative for both SPT and serum sIgE. The diagnosis of LAR is routinely established by the positivity of the NAC. Some LAR individuals have detectable nasal sIgE or positive BAT responses, and these tests can assist to reach the diagnosis.
Symptoms of AR are driven by re-exposure to seasonal or perennial allergens in IgE-sensitised individuals,1 and AR patients are by definition positive for at least one of the two tests to measure IgE sensitisation: SPT and/or serum allergen-specific IgE.6 Nevertheless, a significant proportion of healthy subjects also display positivity for either test, demonstrating that the correlation of symptoms with allergen exposure is crucial for the interpretation of IgE-sensitisation tests.9 A nasal allergen challenge (NAC) can help determine the clinical relevance of IgE-sensitisation in this setting10 (Figure 2). Interestingly, some patients with seasonal or perennial rhinitis symptoms display positive NAC with negative SPT and serum allergen-specific IgE. Our group and others have studied this disease phenotype, which is usually termed local allergic rhinitis (LAR).11,12 This disorder does not properly fit into the above mentioned AR/NAR dichotomy. Similar to AR, LAR patients have a type 2-dominated nasal inflammation, including activation of resident mast cells and recruitment and activation of eosinophils.13,14 Moreover, LAR patients share many clinical features and in vitrofindings with AR individuals, importantly the positivity of the NAC,15 and the presence of allergen-specific IgE in the nasal secretions.16 Epidemiological studies have demonstrated that LAR is a moderate-to-severe condition that might affect up to 25% of non-atopic patients with rhinitis, and that tends to worsen over time,17 with associated onset of asthma and conjunctivitis.18 LAR is not an initial state of AR, as studies from our group show that the long-term conversion rate to systemic atopy is comparable between LAR subjects and the general population.17
Figure 2: Diagnostic algorithm of the allergic forms of rhinitis
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Figure 2: Diagnostic algorithm of the allergic forms of rhinitis. BAT: basophil activation test; NAC: nasal allergen challenge; NsIgE: allergen-specific IgE in the nasal secretions.
Identification of triggers is crucial
Identification of the allergic triggers of rhinitis is crucial in order to implement adequate avoidance measures in both atopic and non-atopic patients. Moreover, this identification can help administer specific therapies, such as allergen immunotherapy (AIT). Several controlled trials from different groups have demonstrated the capacity of AIT (with house dust mites, grass and tree pollens) to control the symptoms, reduce the need for rescue medication, improve quality of life and increase the nasal tolerance to the allergen in LAR individuals19–21 (Table 1).
Table 1: Studies that have investigated the performance of AIT in LAR patients
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Table 1: Studies that have investigated the performance of AIT in LAR patients. In all cases similar results and conclusions were obtained: AIT is able to control the symptoms of LAR patients, to reduce the need for rescue medication, to improve quality of life, and to increase the amount of allergen tolerated in the NAC. The red square highlights the three randomised, double-blind, placebo-controlled clinical trials (RDBPCCT) published to date. 
In AR patients, AIT is able to prevent the progression of the disease, especially the onset of asthma.22 It is currently under investigation whether AIT has the same capacity in the LAR phenotype. Importantly, there is a rapid evolution towards the clinical worsening during the first five years after LAR onset,17 implying that this initial period represents a window of opportunity to establish specific therapies aiming to prevent the progression of the disease.     
All the above mentioned aspects highlight the relevance of identifying the allergic triggers of nasal reactivity, regardless of the atopic status of the rhinitis patient. In this regard, the NAC is the key tool for the diagnosis of LAR and it can confirm the clinical relevance of IgE-sensitisations in AR individuals.23 Moreover, the NAC can help design the composition of AIT in patients with multiple sensitisations, or monitor its effect.23 The NAC displays the optimal features for an in vivo test, as it is very safe and reproducible.24 The NAC for LAR diagnosis significantly outperforms the detection of nasal allergen-specific IgE and the basophil activation test in terms of both sensitivity and specificity.23,24 
In summary, there is a significant proportion of non-atopic rhinitis patients who display nasal reactivity to environmental allergens. Therefore, the inclusion of the NAC in the diagnostic algorithm is necessary to accurately identify the allergic triggers of rhinitis. This identification is crucial for the early prescription of specific therapies such as AIT which has the potential to prevent the progression of the disease, including the onset of asthma.      
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