According to the latest data from The Real Pollen Count (https://pollencount.co.za/) website, Johannesburg and Kimberley residents currently have a moderate risk (> 50 % will experience symptoms) of AR caused by pollens and may require acute treatments such as non-sedating antihistamines (AH).  

Although AR is often perceived as a nuisance condition, the reality is that it exacts a high toll on patients’ lives. If untreated or undertreated, AR causes a considerable symptomatic burden, negatively impacting the quality of life (QoL).    

Risk factors  

Allergens associated with AR include pollens (tree, grass and weed, including ragweed), moulds and indoor allergens (house dust mites and animal allergens) and have a large geographical variability within and between countries.   

Occupational AR includes both immunoglobulin E (IgE) and non-IgE mechanisms. IgE mechanisms include vegetal and animal proteins as well as certain chemicals, while non-IgE mechanism include isocyanates, persulfate salts and woods mechanisms.   

Risk factors for AR include antibiotic use, self-reported air pollution, exposure to farm animals, exposure to cats and/or dogs, maternal and paternal smoking, and vigorous physical activity in adolescents. Of note, many of these risk factors are shared with asthma and atopic dermatitis.  

Diagnosis, symptoms, and classification  

The diagnosis of AR is made by medical history and examination (physical examination and, if needed, nasal endoscopy) plus, in some patients, tests for allergen-specific IgE (skin prick tests or tests for serum-specific IgE).  

The diagnosis of AR is established if two or more of the following symptoms have been identified using appropriate tests: nasal obstruction, secretion sneezing, or nasal itching lasting for more than one hour per day for more than two weeks per year, as well as an allergen-mediated cause of these symptoms.  

In addition to nasal symptoms, patients with AR may also present with associated allergic conjunctivitis, non-productive cough, Eustachian tube dysfunction, and chronic sinusitis.   

AR is mediated by the inhalation of certain triggers:   

• Seasonal AR (SAR): Periodically triggered by outdoor allergens, in particular grass, tree or weed pollen
• Perennial AR: Last throughout the year in response to persistently present indoor allergens, such as house dust mite, animal dander, insects, and mould 

The Allergic Rhinitis and its Impact on Asthma Initiative (ARIA) classifies AR as intermittent or persistent, and mild or moderate/severe.

Complications  

Chronic rhinosinusitis, although distinct from AR, can be a complication of AR. It is characterised by nasal inflammation with symptoms of nasal congestion or discharge, ongoing for longer than three months.   

Chronic rhinosinusitis may also demonstrate findings of nasal polyps (nasal polyposis), which form as a result of chronic inflammation of the paranasal sinus mucosa.   

Nasal polyps are typically benign and present bilaterally. Unilateral nasal polyps should raise concern for malignancy. The incidence of nasal polyps in the general population is about 4% and more common in males.   

Sensitisation to allergens in AR can alter the immunological parameters of the adenoids, resulting in adenoid hypertrophy. Eustachian tube dysfunction commonly manifests in patients with AR and presents as ear fullness, otalgia, and ear-popping. About 10% to 40% of patients with AR also have concurrent asthma, and some studies suggest asthma is more common in moderate to severe persistent rhinitis.   

Many studies have shown that AR is an independent risk factor for asthma, especially in those diagnosed in infancy. Patients undergoing allergen desensitisation (allergy shots) can experience an acute exacerbation of rhinitis or asthma, or, in a worst-case scenario, can progress to anaphylaxis. Other suspected complications include otitis media with effusion, persistent cough, and eosinophilic esophagitis.  

Pathophysiological complexities 

The pathophysiology of AR is complex, comprising an early- and late-phase allergic response. The process is triggered by exposure to allergens mentioned that are recognised by antigen-specific IgE receptors on mast cells and basophils in pre-sensitised individuals. The early-phase reaction is characterised by mast cell degranulation.  

This phase is associated with the rapid onset (over a period of minutes) of acute nasal symptoms (eg sneezing and rhinorrhoea) and the emergence of ocular symptoms (eg itching, redness, and watering).  

These symptoms are caused by histamine release, particularly from mast cells in the nasal mucosa. This early-phase histamine release, together with the effects of other potent pro-inflammatory cytokines (eg leukotrienes) and eicosanoids (eg prostaglandins and kinins) also increases vascular permeability, leading to oedema formation. 

The late-phase reaction develops over a period of hours after exposure to an allergen. It is characterised by cellular recruitment of basophils, neutrophils, T-lymphocytes, monocytes, and eosinophils, and by the release of multiple mediators, including cytokines, prostaglandins, and leukotrienes, which perpetuate the inflammatory response.   

This late-phase inflammatory reaction is associated with tissue remodelling, further tissue oedema, and the development and perpetuation of nasal congestion, considered by patients to be one of the most troublesome symptoms of AR.   

As a result of mucosal inflammation, tissues become primed and react more vigorously to allergen exposure. These late-phase reactions and modifications in tissue responsiveness contribute to bronchial hyper-responsiveness.   

Treatment complexities  

Patients with AR often turn to over-the-counter medications for relief but often find themselves dissatisfied with the results. As mentioned above, the correct diagnosis of AR according to characteristics are extremely important because it will guide the initiation of the most effective treatment.   

AR can be challenging to treat. Most patients presenting to their physician have moderate/severe disease, while others experience persistent symptoms and are polysensitised.   

Phenotypes that are difficult to treat include mixed rhinitis (both AR and non-AR), severe chronic upper airway disease (eg uncontrolled disease despite guideline-directed care), and local AR (eg localised nasal allergic response in the absence of systemic atopy).   

Current ARIA guidelines (2019) recommend the following treatment:  

Step 1: Nonsedating H1-AH (INAH) (oral, intranasal, ocular), leukotriene receptor antagonists, or cromones (intranasal, ocular) for mild symptoms 

Step 2:  Intranasal corticosteroid (INCS) for moderate-to-severe symptoms and/or persistent AR  

Step 3: INCS plus intranasal azelastine for patients with uncontrolled symptoms at step 2 (current or historical). Combination of INCS and INAH (depending on the physician’s experience, other therapeutic strategies could be used). Free combination of INAH)/oral AH plus INCS. Fixed combination of INCS plus INAH 

Step 4: Oral CS as a short course and an add-on treatment  

Step 5: Consider referral to a specialist and allergen immunotherapy. 

The 2020 American Academy of Otolaryngology-Head and Neck Surgery guideline recommend the following: 

Intranasal corticosteroids 

• INS should be prescribed for patients with AR whose symptoms affect QoL. With potent anti-inflammatory properties, INS directly modulate the pathophysiology of AR. In nasal allergen challenge models, pre-treatment with INS results in significant reduction in mediator and cytokine release along with a significant inhibition in the recruitment of basophils, eosinophils, neutrophils, and mononuclear cells to nasal secretions. Moreover, use of these agents in seasonal disease leads to a reduction in inflammatory cells and cytokines within the nasal mucosa and secretions of patients with AR. INS also reduce the antigen-induced hyperresponsiveness of the nasal mucosa to subsequent challenge by antigen and histamine release.  

• Placebo-controlled clinical trials demonstrate the effectiveness of INS in the reduction of nasal symptoms including sneezing, itching, rhinorrhoea, and congestion in adults and children with AR. By reducing nasal symptoms, INS significantly improve the QoL and sleep of patients with AR.  
• As far as duration of therapy before INS are considered ineffective, onset of action starts at time points ranging from three to five hours to 36 hours after the first dose. Once efficacy is reached after the first dose, it is maintained for the duration of these trials. Although there seems to be more reduction in some of these parameters over the length of therapy, these changes are not statistically significant compared with the time points when active ingredients reached statistically significant benefit. Therefore, based on the above data, it is reasonable to assume that efficacy would be reached after one week of therapy at the most and, if none is observed, the treatment might be considered ineffective. 
• Along with diminished nasal symptoms, INS have beneficial effects on allergic eye symptoms including itching, tearing, redness, and puffiness. These symptoms are thought to occur from the direct effects of allergen on the conjunctiva and reflexes originating in the nose after allergen exposure. The reflex response is reduced by INS. Some studies have also suggested that INS improve asthma control in patients suffering from both AR and asthma. Hypertrophic adenoids can also be reduced in size with INS use. 
• Comparative studies have shown that INS are superior to oral H1 antihistamines in controlling nasal symptoms, including nasal congestion, with no significant difference in the relief of ocular symptoms. INS are more effective than leukotriene receptor antagonists across the range of allergy symptoms.   
• Short courses of systemic corticosteroids are often used clinically for patients with severe AR but have not been shown to be superior to INS. In nasal challenge studies, systemic steroids are effective in reducing AR symptoms, mediator release, and eosinophil influx during the late-phase response.  

• INS are strongly recommended for the treatment of AR because of their superior efficacy in controlling nasal congestion and other symptoms of this inflammatory condition. Prophylactic treatment with INS is best initiated several days before the pollen season in subjects with known seasonal AR. Starting treatment at the recommended dose is suggested followed by evaluation of the patient’s response on follow-up. During this visit, the nose should be examined for signs of local irritation due to the drug or mechanical trauma from the applicator itself, and the treatment regimen should be modified according to the patient’s response. 

Antihistamines 

• Oral AHs, which block the action of histamine on the H1 receptor, have numerous anti-inflammatory effects and can be broadly categorised as first- or second-generation agents. Older first-generation agents, which are lipophilic and cross the blood-brain barrier, also have antimuscarinic effects. Newer second-generation agents are highly selective for the H1 receptor and have limited penetration of the central nervous system. Oral second-generation AH that are less sedating should be prescribed for patients with AR and primary complaints of sneezing and itching. 

• Intranasal AHs (IAHs) may be prescribed for patients with seasonal, perennial, or episodic AR. One of the benefits of intranasal application is targeted delivery and increased dosage to nasal tissues while limiting systemic effects.  IAHs show benefit even in patients who fail oral AH treatment.  

• Specifically with regard to nasal congestion, IAHs are more efficacious than oral preparations. IAHs also have the advantage of rapid onset of action in the range of 15 to 30 minutes, which is much faster than in the oral route (average onset 150 minutes).  
• Olopatadine is approved for treatment of seasonal AR in adults and in children six years and older. Immunotherapy should be prescribed for patients with AR who have inadequate response to pharmacologic therapy. 

Combination therapy 

Combination pharmacologic therapy may be prescribed for patients with AR who have inadequate response to monotherapy. The most effective combination therapy is an INS and an INAH. 

A 2019 meta-analysis, which included the findings of 12 randomised controlled trials (n=7675) looked at the efficacy and safety of monotherapy versus combination therapy. The authors focused on improvements in total ocular symptom scores（TOSS, daytime eye symptom scores（DESS）and incidence of adverse events（AE）between monotherapy group and combination therapy group.  

The authors found that the efficacy of combination therapy group was superior to the monotherapy group in TNSS with significant difference. Compared with monotherapy group, individual nasal symptom scores in combination group were significantly decreased. There were no significant differences in the incidence of AE (headache, dysgeusia, epistaxis) between two groups. They strongly recommended combination therapy for AR. 

A more recent study (2020) study evaluated the efficacy and safety of fixed-dose combination nasal spray of olopatadine hydrochloride and mometasone furoate in patients with SAR. 

In this phase 2, double-blind, parallel-group study, patients (≥12 years of age) with SAR were equally randomised to twice-daily olopatadine 665μg and mometasone 25μg, once-daily olopatadine 665μg and mometasone 50μg, twice-daily or once-daily olopatadine monotherapy (665μg), mometasone monotherapy (twice-daily 25μg or once-daily 50μg), or placebo for 14 days.  

The primary endpoint-mean change from baseline in morning and evening reflective TNSS was analysed. Average morning and evening 12-hour instantaneous TNSS, ocular symptoms, individual symptoms, onset of action, QoL, and AEs were also assessed. 

Twice-daily combination therapy provided statistically significant and clinically meaningful reflective TNSS improvements versus placebo, twice-daily olopatadine, and mometasone. Similar significant improvements in instantaneous TNSS were observed with twice-daily combination therapy vs placebo and twice-daily mometasone. Improvements were not significant versus olopatadine.  

Treatment-emergent AEs rates were 10.8%, 9.5%, and 8.2%, with twice-daily combination therapy, once-daily combination therapy, and placebo, respectively. 

Helping your patient to manage AR 

To help patients manage their symptoms, ARIA developed Mask-air, an app that makes provision for the daily recording of symptoms, their impact on QoL, and medications taken. According to ARIA, this will help the patient and healthcare professionals to determine the diagnosis and effective treatment for AR.  

REFERENCES:   

Akhouri S and House SA. Allergic Rhinitis. StratPearls [Internet] 2021. https://www.ncbi.nlm.nih.gov/books/NBK538186/. 

American Academy of Family Physicians. Clinical Practice Guideline: 

Allergic Rhinitis. 

https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical-recommendations/allergic-rhinitis.html 

Andrews CP, Mohar D, Salhi Y, and Tantry SK. Efficacy and safety of twice-daily and once-daily olopatadine-mometasone combination nasal spray for seasonal allergic rhinitis. Ann Allergy Asthma Immunol, 2020. 

Bousquet J, Anto JM, Bachert, C et al. Allergic rhinitis. Nature Reviews Disease Primers, 2020. 

Crisci CD and Ardusso LRF. A Precision Medicine Approach to Rhinitis Evaluation and Management. Curr Treat Options Allergy, 2020. 

Dayal AK and Sinha V. Trend of Allergic Rhinitis Post COVID-19 Pandemic: A Retrospective Observational Study. Indian Journal of Otolaryngology and Head & Neck Surgery, 2020. 

Drazdauskaite G, Layhadi JA and Shamji MH. Rhinitis, Conjunctivitis, and Sinusitis. Current Allergy and Asthma Reports, 2021.  

Klimek L, Bachert C, Pfaar O et al. ARIA guideline 2019: treatment of allergic rhinitis in the German health system. Allergol Select, 2019. 

Li J, Shen Y and Zou QY. Efficacy and safety of monotherapy versus combination therapy in treatment of allergic rhinitis: a Meta-analysis. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, 2019.