AR has often been trivialised as a ‘nuisance’ disease but is increasingly being recognised as a global health concern, which negatively impacts patients’ quality of life (QoL). In paediatric patients, AR not only negatively impacts QoL (eg sleep problems resulting in reduced school performance, family difficulties and decreased involvement in outdoor activities), but can affect contiguous organs such as the sinuses, ears, and chest.³

Diagnostic challenge

AR in paediatric patients is often difficult to evaluate and diagnose. Symptoms often overlap with those of upper respiratory infections such as the common cold (see Table 1).¹

According to Scadding et al, a positive family history (father or mother with AR) is the best predictor of AR in paediatric patients. The team add that very few infants and toddlers develop allergic-type symptoms before the age of three, but caution that this observation is based on anecdotal observations.³

Stanford University’s Lucile Packard Children’s Hospital (United States) recommends that the following symptoms be used to differentiate between a common cold and AR:⁵

Table 1: Common cold vs AR symptoms⁵

AR is largely a clinical diagnosis. A thorough history and physical examination are essential. History taking should include questions about the types of symptoms, the time, duration, and frequency of symptoms, suspected exposures, exacerbating/alleviating factors, and seasonality (about 20% of cases are seasonal, 40% perennial, and 40% with features of both).⁴

Patients with intermittent or seasonal AR generally present with symptoms such as sneezing, rhinorrhoea, and watery eyes, which may be caused by triggers such as pollens, animal dander, mould, or humidity. Patients with persistent disease complain about a postnasal drip, chronic nasal congestion, and obstruction.⁴

During the examination, take notice of how the patient breaths (paediatric patients with AR often breath through their mouths), and how often they sniffle or clear their throats. Paediatric patients also often have a transverse supra-tip nasal crease, and dark circles under the eyes (allergic shiners).⁴

Rhinoscopy typically reveals swelling of the nasal mucosa and thin, clear secretions. The inferior turbinates may take on a bluish hue, and cobble stoning of the nasal mucosa may be present. Whenever possible, an internal endoscopic examination of the nasal cavity should be conducted to assess for nasal polyps and structural abnormalities.⁴

Pneumatic otoscopy can be used to assess for eustachian tube dysfunction, which can be a common finding in patients with allergic rhinitis. Palpation of sinuses may elicit tenderness in patients with chronic symptoms.⁴

Where there is a clear history of symptoms in relation to known allergen exposure a trial of effective treatment, such as intranasal corticosteroids (INS) may be used as a diagnostic tool, with further investigation if unhelpful.³

Allergic sensitisation can be demonstrated by skin test or specific serum IgE antibody analysis. Skin prick test sensitivity ranges from 68% to 100% and specificity from 70% to 91%.³

Other tests such as evaluation of nasal nitric oxide and ciliary beat frequency, nasal allergen challenge, computed tomography scans, nasal smears, nasal cultures, and analysis of nasal fluid for β-transferrin may be required to include or exclude different forms of rhinitis.³

According to Scadding et al, another challenge is that parents/caregivers often rate patients’ symptom severity. They recommend using a visual analogue scale using emojis to ask paediatric patients to score their symptoms.³

Treatment challenges

International guidelines recommend antihistamines as first-line treatment for paediatric and adult patients. However, caution Scadding et al, there is a lack of well-controlled studies to determine the safety and efficacy of first-generation antihistamines in paediatric patients. These agents have known adverse effects such as psychomotor retardation and behaviour disturbance and so are not recommended in paediatric patients.³

Second-generation antihistamines are the agents of choice in adults and children >2-years with intermittent and persistent AR, regardless of disease severity.^1,6

Rupatadine is a novel dual acting second-generation antihistamine with data from a randomised, multicentre, double-blind clinical study using the Allergic Rhinitis and its Impact on Asthma (see Figure 1) classification of AR in paediatric patients aged six– to 11-years with persistent/chronic disease.^7,8

Figure 1: AR and its Impact on Asthma classification of AR

Potter et al (2013) conducted the first safety and efficacy study of rupatadine in paediatric patients (six- to 11-years) with persistent/chronic AR. Participants (n=360) were randomised in a 1:1 ratio to either rupatadine oral solution (1mg/ml) or placebo over six weeks. The primary efficacy endpoint was the change from baseline of the total nasal symptoms score (T4SS) after four weeks of treatment.⁸

Rupatadine showed statistically significant differences vs placebo for the T4SS reduction both at four weeks (-2.5±1.9 vs -3.1±2.1) and six weeks (-2.7±1.9 vs    -3.3±2.1). Rupatadine also showed a statistically better improvement in the children's quality of life compared with placebo. Adverse reactions were rare and non-serious in both treatment groups.⁸

In their study, Santamaría et al (2018) compared the efficacy of rupatadine oral solution (1mg/ml) before and after four weeks’ of use in two- to five-year-old children (n=44).¹

Additionally, evaluations of Total Five Symptoms Score (T5SS) including nasal congestion, sneezing, rhinorrhoea, itchy nose, mouth, throat, and/or ears, and itchy, watery, and red eyes) were analysed. Rupatadine was dosed according to body weight.¹

Only 15 adverse events were reported. All of them were of mild intensity and considered not related to the study treatment. No patient exceeded the standard parameter of >450ms in the last visit, for the QTc interval on their electrocardiograms.¹

From a maximum score value of 15, T5SS values at day 14 (6.35) and day 28 (5.42) were both statistically significant different from the baseline T5SS value (mean 8.65), with a reduction of 26.6% and 37.4%, respectively. All individual symptoms, including nasal congestion, also showed a decrease from baseline at both 14 and 28 days.¹

Rupatadine 1mg/mL oral solution was found to be safe in 2–5-year-old children, correlating with an improvement of AR symptoms, overall and each individually, after a daily dose administration.¹

Conclusions

Although histamine is the main mediator in the pathophysiology of AR, the role of platelet-activating factor(PAF) as a potent mediator involved in hypersensitivity-type allergic reactions, has emerged over the past few years. Rupatadine is the only agent that has demonstrated a capacity for an inhibition of PAF release in nasal airways. ^6,7,9

PAF is an endogenous phospholipid synthesized in inflammatory cells such as mast cells, eosinophils, basophils, neutrophils, macrophages, and platelets, which is released during allergic or inflammatory reactions. In allergic rhinitis, these reactions are associated with increased vascular permeability, eosinophil chemoattraction, and airway hyperresponsiveness.⁷

Rupatadine is a powerful and selective high-affinity inverse agonist of the histamine H1-receptor, which, unlike other H1-antihistamines such as desloratadine and levocetirizine, also produces specific and dose-dependent inhibition of potent PAF receptors. Another advantage of rupatadine is its rapid onset of action and long-lasting, showing a median Tmax of 0.8 h with a single daily dose, or 0.75–1 h with repeated doses.^6,7

Rupatadine, as a second-generation antihistamine, has a lower potential for H1-receptor occupancy in the brain compared to first-generation antihistamines and is less likely to produce sedation, somnolence, or drowsiness at recommended dosages.⁷

Rupatadine has several active metabolites that contribute to the drug’s overall efficacy. The most important route of elimination for the drug is via the bile.⁷

Systemic exposure to rupatadine after food intake increased by 23% compared with that under fasting conditions and Tmax was delayed by 1 hour, but exposure to its metabolites remained unaffected. These changes did not show clinical consequences, and therefore, rupatadine can be administered with or without food.⁷

REFERENCES:

1. Santamaría E, Izquierdo I, Valle M, et al. Rupatadine oral solution for 2-5-year-old children with allergic rhinitis: a safety, open-label, prospective study. J Asthma Allergy, 2018.
2. Doulaptsi M, Aoi N, Kawauchi H, et al. Differentiating Rhinitis in the Paediatric Population by Giving Focus on Medical History and Clinical Examination. Med Sci (Basel), 2019
3. Scadding GK, Smith PK, Blaiss M, et al. Allergic Rhinitis in Childhood and the New EUFOREA Algorithm. Front Allergy, 2021.
4. Akhouri S, House SA. Allergic Rhinitis. [Updated 2022 Jan 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538186/
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9. Muñoz-Cano RM, Casas-Saucedo R, Valero Santiago A, et al. Platelet-Activating Factor (PAF) in Allergic Rhinitis: Clinical and Therapeutic Implications. J Clin Med, 2019.