Allergic rhinitis (AR) can be defined as intermittent or seasonal allergic rhinitis and persistent or perennial allergic rhinitis. Symptoms of AR include sneezing, itching of the eyes, nose, and throat, nasal discharge, nasal congestion, and a positive immunoglobulin E (IgE) test result after inhalation of specific allergens (eg, pollen, dust mites, cat or dog hair). Currently, AR has affected approximately 500 million people worldwide and is significantly associated with comorbidities including asthma, eczema, chronic or recurrent sinusitis, cough, and tension and migraine.
Recently, the well-known medical journal JAMA published a review on AR, which summarizes the precautions for the diagnosis and treatment of AR. Based on this article, the mechanism, differential diagnosis, risk factors, diagnostic evaluation, and treatment options of AR are summarized.
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mechanism
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When an allergen enters the nasal mucosal epithelial barrier and is processed by antigen-presenting cells (e.g., dendritic cells), resulting in the differentiation of naïve T cells into type 2 helper T cells that release cytokines, a process known as sensitization. This process promotes the production of allergen-specific IgE by B cells. At the same time, IgE can bind to the allergens and the IgE receptors of mast cells, Langerhans cells, monocytes, and basophils, causing mast cell activation and the release of bioactive mediators, including histamine, leukotrienes, and platelet-activating factor, when the patient is reexposed to the allergen (Figure 1).
Fig. 1 Mechanism of allergic sensitization
Disruption of epithelial cells also releases alarm cytokines (eg, thymic stromal lymphopoietin, IL-25, IL-33) that further promote the inflammatory response. Eosinophils are type 2 inflammatory cells that enter the nasal mucosa in response to IL-4 and IL-5 and release cytokines, chemokines, leukotrienes, prostaglandins, and toxic proteins or enzymes that perpetuate inflammation (Figure 2). In addition, the trigeminal nerve can also be activated by the above-mentioned substances, which can exacerbate the severity of rhinitis.
Fig.2 Allergic reactions
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differential diagnosis
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The differential diagnosis of AR includes localized AR, non-AR rhinitis, occupational rhinitis, infectious rhinitis, and drug-associated rhinitis. It is important to note that patients with AR have a positive skin prick test or IgE test for inhaled allergens, and non-AR rhinitis does not have the above. Non-AR rhinitis is associated with exposure to chemicals (such as detergents) or irritants (tobacco or perfume) and sudden changes in temperature.
Currently, the most common symptoms of AR include rhinorrhea (90.38%) and nasal congestion (94.23%). Localized rhinitis has similar clinical symptoms to AR and responds to some AR treatments, but its IgE test is negative. Therefore, one of the key points of AR examination is IgE examination. It is important to note that approximately 71% of non-AR rhinitis is classified as drug-induced rhinitis, so the patient's medication history and current prescription should also be reviewed when differentiating AR.
Occupational rhinitis is IgE-positive rhinitis caused by a specific work environment, and the most common working environment includes various chemical cleaners, sterilizers, and other chemical agents, but usually wearing an N95 mask or wearing corresponding protective equipment as prescribed can eliminate or improve the symptoms.
Infectious rhinitis is rhinitis caused by upper respiratory tract infections, such as COVID, influenza virus, etc. Usually after the infection is gone, infectious rhinitis gradually disappears.
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Risk factors
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Risk factors for AR include AR, a family history of asthma or atonic dermatitis, and the presence of other allergic diseases such as asthma or atopic dermatitis. In addition, neonates are susceptible to type 2 inflammation, which can increase the risk of AR. A normal gut microbiota can reduce the risk of sex 2 inflammation and AR. Methods to maintain a normal gut microbiome include vaginal delivery, gestational age at term, breastfeeding, early exposure to domestic pets, and the presence of siblings. Factors that disrupt the normal gut microbiota include (1) early exposure to antibiotics, (2) living in an urban area, (3) cesarean section, (4) premature birth, and (5) an only child.
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Diagnostic evaluation
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Certain clinical features can help clinicians distinguish AR from mixed rhinitis, and a questionnaire has shown that the following features are associated with nonAR:
Non-AR-related features
No seasonal rhinitis
Parents have no history of allergies
Dogs and cats are asymptomatic when present
Reactions to perfumes
Rhinitis symptoms do not appear until ≥ age of 35 years.
In addition, up to 50% of patients with chronic rhinitis may have mixed rhinitis, with symptoms precipitated by allergic and non-allergic factors.
Because treatment may vary between subtypes of rhinitis, otolaryngologists should have skin prick testing or serologic testing in patients with suspected AR. To confirm the diagnosis of AR, a positive test related to symptoms caused by exposure to allergens is required. A meta-analysis of seven studies with a total of 430 patients from Health Canada (using allergen-specific nasal challenge as the gold standard) showed that skin prick testing had a sensitivity of 85% and a specificity of 77% for confirming AR. In addition, meta-analysis showed that the sensitivity and specificity of the intradermal test were 60%~79% and 68%~69%, respectively.
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treat
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Environmental interventions
First-line treatment for AR is to remove the environmental factors that precipitate symptoms, and the patient's home and work environment needs to be investigated to identify potential allergens. Common indoor allergens include dust mites, pets, mold spores, cockroaches, and rodents such as mice. People with pollen allergies should close windows. Air conditioning can reduce patient exposure to indoor and outdoor inhaled allergens.
Effective environmental control measures can be costly, requiring multiple interventions and maintenance methods. However, placing air filtration systems in the living and working environments where most people with AR and asthma live and work can reduce the risk of allergen exposure and improve indoor air quality.
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drug therapy
First-line treatment options for intermittent AR include oral second-generation antihistamines, including cetirizine, levocetirizine, and desloratadine. In addition, guidelines recommend that patients with AR can be treated with leukotriene modifiers such as montelukast. Other drug regimens include intranasal antihistamines (azelastine or olopatadine) and corticosteroids (triamcinolone acetonide, budesonide, or mometasone).
Treatment of persistent AR includes a combination of intranasal antihistamines and corticosteroids, with or without systemic antihistamines. Intranasal corticosteroids can significantly improve patients' symptoms, so most consensus recommends them as first-line therapy for improving moderate to severe AR. The most common adverse reaction of intranasal corticosteroids is epistaxis, and the risk of epistaxis caused by corticosteroids is 4%~8% in the short term (2~12 weeks), and 20% and 28% in long-term use. In less common cases, they can also cause septal erosions and ulcers.
Second-generation antihistamines are well tolerated for both intranasal and systemic use. It is important to note that some patients have a low response to treatment, which may be due to three reasons: (1) the patient is not AR, (2) the drug is not used in the right way, and (3) there is an anatomical abnormality such as a deviated septum or turbinate hypertrophy. CT and other methods can be used to determine whether the patient has anatomical abnormalities to guide treatment. In general, children ≥ 6 years of age can also be treated with second-generation antihistamines, but the dose needs to be adjusted.
Finally, intramuscular corticosteroids are not indicated for the treatment of seasonal or perennial AR because of their low benefit-risk. For severe, acute, and seasonal AR patients, a short course of high-dose corticosteroids (35~40mg, 5~7d) can be used for intervention. In addition, before the allergy season, preventive medication can be administered.
In addition, high-volume or isotonic saline irrigation of the nasal cavity may reduce symptoms in patients with AR. A series of meta-analyses showed that saline irrigation was associated with a significant benefit compared with placebo (standardised mean difference: -1.44 [95% CI, -2.39~-0.48]).
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immunotherapy
Immunotherapy can make the patient gradually tolerate the allergen. Currently, the U.S. Food and Drug Administration (FDA) has approved subcutaneous immunotherapy and sublingual immunotherapy for the treatment of allergic diseases, including AR. Immunotherapy works by modulating the innate immune system by decreasing local mast cells, basophils, eosinophils, and type 2 inherriatic lymphoid cells. Immunotherapy may affect the adaptive immune system by inducing specific IgG-blocking antibodies, immunosuppressive cytokines, etc.
Immunotherapy requires collaboration with a rheumatologist and immunologist and, if a systemic reaction occurs, emergency treatment with drugs (e.g., epinephrine). The usual course of treatment is longer, up to 6 months. However, there are also short-term treatment options, which inject allergens multiple times each time for 3~4 days, which can greatly shorten the course of treatment.
Patients receiving immunotherapy must have been preceded with other medications, such as antihistamines, which can prevent local or systemic reactions. If the patient reports that immunotherapy is effective, then it should be continued for 3~5 years.
In contrast to subcutaneous immunotherapy, sublingual immunotherapy can be used at home, but patients need to have an epinephrine syringe on hand to prevent systemic reactions. In addition, about 50% of patients experience oral palate itching, which can cause discomfort and anxiety, but this adverse effect does not induce laryngeal angioedema or systemic reactions.
Bibliography:
1. Bernstein JA, Bernstein JS, Makol R, Ward S. Allergic Rhinitis: A Review. JAMA. 2024 Mar 12; 331(10):866-877. doi: 10.1001/jama.2024.0530. PMID: 38470381.
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