An estimated 44%–87% of patients with rhinitis may have a combination of AR and non-allergic rhinitis (NAR). AR is a chronic inflammatory disease of the upper airways, defined by a nasal eosinophilic inflammation arising from immunoglobulin E (IgE)-sensitisation to seasonal or perennial aero-allergens.3,4,5

Despite the high prevalence of AR in childhood, the disease is often underdiagnosed or undertreated.

AR vs NAR 

AR is considered a systemic illness and is often accompanied by constitutional symptoms such as fatigue, malaise, and headache. It also may be a comorbidity in patients with asthma, eczema, or chronic sinusitis.3,4 

AR is characterised by sneezing, rhinorrhea, nasal congestion and nasal pruritus, which are often accompanied by ocular pruritus/redness and or watery eyes in 60%–70% of patients.2 

As mentioned, AR has a significant impact on the QoL of patients as well as their care givers and is associated with a substantial economic burden. AR results in missed work and school days, impaired sleep, daytime somnolence and fatigue, irritability, decreased energy, reduced social and physical functioning and memory deficits.2  

The underlying mechanisms leading to NAR is heterogenic and less well understood compared to AR. AR and NAR share the same symptoms. Nasal symptoms can be triggered by environmental irritants such as smells and particulate materials, as well as changes in weather and barometric pressure. Some patients respond to emotional stress, hormonal changes, and other unidentified stimuli.3,4  

NAR has eight major subtypes which include:4  

  • Nonallergic rhinopathy (NAR) – previously known as vasomotor rhinitis  
  • NAR with eosinophilia  
  • Atrophic rhinitis 
  • Senile rhinitis  
  • Gustatory rhinitis  
  • Drug-induced rhinitis  
  • Hormonal-induced rhinitis 
  • Cerebral spinal fluid leak 

Types and classification of AR  

AR is the most common type of chronic rhinitis. The 2020 American Joint Task Force on Practice Parameters (JTFPP) practice update distinguishes between seasonal AR (SAR) and perennial AR (PAR). SAR is defined as symptoms present for a specific pollen-related season, while PAR is described as symptoms present year-round related to non-pollen allergens.6 

The AR and its Impact on Asthma or ARIA guideline distinguishes between:7  

  • Intermittent AR: Symptoms present for <4 days/week or persist for <4 consecutive weeks at a time 
  • Persistent AR: Symptoms present four or more days/week and persisting for >4 consecutive weeks. 

ARIA defines mild symptoms as the absence of all of the following: 

  • Sleep disturbance 
  • Impairment of daily activities 
  • Impairment of work or school 
  • Troublesome symptoms 

Moderate to severe AR is defined as the persistent presence of any of the above. 

Childhood versus adult AR 

AR usually develops at a young age (80% before 20 years of age) and about 40% of patients becoming symptomatic by age six. Although childhood and adult AR share similarities, there are also a number of differences. Several studies have examined the similarities and differences.2,3,5 

Table 1: Similarities and differences between childhood and adult AR 

  Children  Adults 
Prevalence  SAD is more prevalent (60.7%).   PAR is more prevalent (40%), followed by SAR (20%) and an additional 40% have PAR with seasonal flare-ups. 
Classification  About 60% of patients have intermittent, 52.1% moderate/severe intermittent, 37.6% persistent, 7.1% mild intermittent and 3.2% persistent AR.   

  • 51.5 % of patients have intermittent and 48.5% persistent, and 26 % severe AR. 

 

Symptoms 
  • Congestion is the most impactful symptom in children. 
  • Symptoms of moderate/severe AR include noisy breathing, repeated throat clearing, snoring, and a reduction in sense of smell 
  • Children may also have facial manifestations of obstructed breathing, including a gaping mouth, chapped lips, hypertrophied gingival mucosa, a long face, dental malocclusions, and allergic shiners  
  • They may also show signs of itching (eg an allergic salute or an allergic transverse nasal crease) or have malaise and disturbed nocturnal sleep with subsequent daytime fatigue. 
Symptoms are similar to those experienced by children, however, the frequency and severity of some symptoms may vary slightly.  
Comorbidities 
  • Co-morbidities associated with AR in children include asthma, atopic dermatitis/eczema, allergic conjunctivitis, chronic rhinosinusitis, and otitis media  
  • The most frequent comorbidities were conjunctivitis (53.6 %), asthma (49.5%), and atopic dermatitis (40 %), while the most frequent sensitising allergens were pollens (53.5 %) and house dust mites (43.5 %). 
  • In adults, co-morbidities and/or complications include conjunctivitis, chronic rhinosinusitis, nasal polyps, chronic cough, laryngitis, and gastro-oesophageal reflux 
  • In adulthood, the development of asthma is usually independent of allergy, whereas in childhood it is often associated with allergies. 
Differential diagnosis 
  • Infectious rhinitis (usually viral), foreign bodies, anatomical variations including unilateral choanal atresia, benign tumors including dermoid cysts and meningoencephalocele, cystic fibrosis and related diseases, mucociliary dyskinesia, or nasal obstruction induced by adenoid hypertrophy.  
  • In older children, facial trauma (septal hematoma, fractured nasal bones, and synechiae), cerebrospinal fluid rhinorrhoea, nasal glioma, and rhinitis medicamentosa due to an abuse of topical decongestants should also be consideredNasal polyps are uncommon in children and, if observed, the diagnosis of cystic fibrosis must be considered. 
Inflammatory or immunologic conditions (eg midline granuloma, nasal polyposis, Sjögren’s syndrome, systemic lupus erythematosus, relapsing polychondritisstructural or mechanical conditions (eg choanal atresia, deviated septum, enlarged adenoids or nasal tumours). 

Role of histamine 

As mentioned, AR is caused by an IgE-mediated reaction, which in turn leads to nasal inflammation of varying intensity. Allergens include pollens, moulds, animal dander, and dust mites.6  

Two phases of responses are triggered by an IgE/allergen:6 

  • Early phase: Immediate response, which is experienced by more than 90% of AR patients. Includes the products of degranulation (preformed mediators such as histamine), and de novo inflammatory mediators such as prostaglandin D2 or cysteinyl leukotriene E4 
  • The late-phase: Occurs two to five hours after exposure to allergen and peaks at six to eight hours after exposure and is experienced by up to 50% of AR patients. During the late-phase reaction, an exaggerated non-specific nasal hyperreactivity occurs simultaneously with the heightened response to the initial allergen stimulus. Preventing or suppressing both the early-phase and late-phase allergen-induced inflammatory reactions is crucial for the successful AR treatment. 

The role of histamine as the primary mediator in the pathophysiology of allergic diseases was first identified in1910. During the release of mediators in response to an allergic reaction, a key molecule, platelet-activating factor (PAF), is released.8,9  

PAF is a potent molecule of phospholipid origin derived from cell membranes of platelets, basophils, mast cells, neutrophils, macrophages, and endothelial cells.9  

PAF contributes to the inflammatory response by increasing the oxidative burst in neutrophils following phagocytosis of bacteria and enhances the synthesis of eicosanoids by leukocytes.9  

During IgE-mediated hypersensitivity reaction in the lung, PAF induces mast cell release of serotonin and histamine, as well as platelet aggregation. Thus platelet aggregation can increase vascular permeability in acquired immunologic responses and result in inflammation.9 

Histamine is a biogenic amine synthesised and stored mainly in mast cells and basophils. Histamine interacts with the histamine H1receptor, leading to various classical pathophysiological effects.8  

These include for example vascular permeability, smooth muscle contraction, vasodilatation and flushing, mucus secretion and pruritus, which either singly or in conjunction with one another lead to bronchial obstruction in asthma, nasal blockage, sneezing, itching and discharge in rhinitis and itchy skin wheals/flares in urticaria. In AR patients, nasal challenges with histamine have shown that it increases nasal secretions, causing nasal blockage, sneezing and rhinorrhea.8  

Apart from the classical activities of histamine, increasing evidence shows that histamine also elicits proinflammatory and immunemodulatory effects. Several studies have shown that histamine receptors are expressed on the cell surface of basophils, mast cells, neutrophils, lymphocytes, macrophages, epithelial cells, and endothelial cells, and therefore is likely to modulate the function of these cells.8  

It is therefore likely that antihistamines (AHs) have a wider impact on allergic inflammation, and that effects on immune cells, which have been linked to nonreceptor mediated pathways so far, may actually be receptordependent.8  

Based on these findings, researchers hypothesise that the antiinflammatory effects reported for newer second-generation AH (sgAH) might derive from their interaction with the H1 receptor, rather than with other non-histamine receptors.8  

Safety and efficacy of oral anti-histamines 

Oral sgAHs are recommended as the first line of defence against intermittent and persistent AR. These agents are effective in blocking the release of histamine that is present in high concentrations during an allergic reaction. Oral sgAHs have been shown to be safe and effective for the suppression of nasal pruritus, sneezing, rhinorrhea, and accompanying ocular symptoms in adults with AR.4 

 But are they effective and in paediatric patients 

Few safety and efficacy studies have been done in children. Most of these studies focused on children between six- and 11years old. The only study done in children between the ages of two- and five-years evaluated the efficacy of rupatadine for the treatment of SAR. No studies have been undertaken in children with intermittent AR based on the ARIA classification.9  

Potter et al (2013) conducted the first, large, multi-centre, randomised controlled study on the efficacy of a sgAH (rupatadine) in children (n=360) with persistent AR in both symptoms and quality of life. Children in the study were aged between six- and 11-years.10  

The primary efficacy endpoint was the change from baseline in the Total Nasal Symptoms Score (T4SS nasal congestion, sneezing, rhinorrhea, itchy nose, mouth, throat, and/or ears) after 28 days of therapy. Rupatadine showed statistically significant differences compared with placebo, both at four weeks (−3.1 ± 2.1 vs. −2.5 ± 1.9) and six weeks (−3.3 ± 2.1 vs. −2.7 ± 1.9) in the baseline reduction in T4SS.10  

Santamaría et al (2018) conducted a multicenter open-label study in twoto five-year-old children with AR (n=40). Evaluations of Total Five Symptoms Score (T5SS nasal congestion, sneezing, rhinorrhea, itchy nose, mouth, throat, and/or ears and itchy, watery, and red eyes).11  

Symptoms were assessed by parents/legal guardian before and after four weeks of rupatadine 1mg/mL oral solution administration, dosed according to body weight.11  

All individual symptoms of T5SS, including nasal congestion, showed a decrease from baseline at both 14 and 28 day. Only 15 adverse events were reported, all of them were of mild intensity, and were considered not related to the study treatment.11 

Rupatadine demonstrated an improvement of AR symptoms after a daily dose administration and proved to be safe in two to five-year-old children, a population in which there is a general lack of clinical evidence, concluded the authors.11 

Gonzalez-Nuñez et al conducted a database search of the preclinical and clinical global safety data from rupatadine studies in patients over two-years old. The assessment confirmed a safety profile for rupatadine which is similar for sgAH in patients with allergic rhinitis or urticaria. The study confirmed that rupatadine is a safe and well tolerated drug, the same as placebo, in patients over two-years old, with no central nervous system or cardiovascular effects.12 

Conclusion 

Children are mostly affected by AR. AR negatively affects their QoL, resulting in missed school days, impaired sleep, daytime somnolence and fatigue, irritability, decreased energy, reduced social and physical functioning and memory deficits. Oral sgAHs have been shown to be safe and effective for the suppression of nasal pruritus, sneezing, rhinorrhea, and accompanying ocular symptoms in adults with AR. Few efficacy and safety of oral sgAHs in the treatment of AR in paediatric patients, have been published – especially in the two- to five-year age group. A recent study showed that rupatadine improves symptoms and general QoL in this patient population. 

References 

  • Sultesz M, Horvath A, Molnar D et al. Prevalence of allergic rhinitis, related comorbidities and risk factors in schoolchildren. Allergy, Asthma & Clinical Immunology, 2020.  
  • Izquierdo-Dominguez A, Te Terrassa CS, Valero A et al. Comparative Analysis of Allergic Rhinitis in Children and Adults. Current Allergy and Asthma Reports, 2012. 
  • Quillen DA and Feller DB. Diagnosing Rhinitis: Allergic vs. Nonallergic. Am Fam Physician, 2006.  
  • Meltzer EO, Blaiss MS, Derebery J et al. Burden of allergic rhinitis: Results from the Pediatric Allergies in America survey. American Academy of Allergy, Asthma & Immunology, 2009. 
  • Dykewicz MS, Wallance DV, Amrol D et al. Rhinitis 2020: A Practice Parameter. American Academy of Allergy, Asthma, and Immunology, 2020.  
  • Klimek L, Bachert C, Pfaar O et al. ARIA guideline 2019: treatment of allergic rhinitis in the German health system. Allergol Select, 2019. 
  • Alvaro V. Role of histamine and platelet-activating factor in allergic rhinitis. Journal of Physiology and Biochemistry, 2004. 
  • Nieto A, Nieto M and Mazon A. The clinical evidence of second-generation H1-antihistamines in the treatment of allergic rhinitis and urticaria in children over 2 years with a special focus on rupatadine. Expert Opinion on Pharmacotherapy, 2021. 
  • Potter P, Maspero JF, Vermeulen J et al. Rupatadine oral solution in children with persistent allergic rhinitis: A randomized, double-blind, placebo-controlled study. Pediatr Allergy Immunol, 2013. 
  • 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. 
  • González-Núñez V, Bachert C, Mullol J et al. Rupatadine: global safety evaluation in allergic rhinitis and urticaria. Expert Opin Drug Saf, 2016.