Allergic Rhinitis Aggravated by Air Pollutants: Review of International Expert Consensus and Clinical Essay on Fexofenadine

Allergic Rhinitis in India: Prevalence, Impact, and Risk Factors:

In India, AR holds considerable prevalence, constituting approximately 55% of all allergic conditions with documented occurrences falling within the range of 20% to 30% (2). AR has a detrimental impact on the quality of life. Indian studies have reaffirmed that AR unfavorably influenced behavior, work performance, and quality of life among afflicted individuals (3). Pollen, dust mites, molds, pet allergens, fungal spores, and air pollutants are some of the risk factors triggering AR (2). Among these, air pollution is one of the important risk factors for AR.

As per an International expert consensus on the management of allergic rhinitis (AR) aggravated by air pollutants, the sources and components of indoor and outdoor pollution have been systematically presented in Figure 1 (4)

Figure 1: Air Pollutants, indoor and outdoor sources. Adapted from Naclerio et al. World Allergy Organization Journal (2020) 13:100106. Abbreviations: CO: Carbon monoxide, DEP: Diesel extract particles, IAP: Indoor air pollution, NOx: Nitrogen oxides, O3: Ground level ozone, OAP: Outdoor air pollution, PM: Particulate matter, Sox: Sulphur oxides, VOC: Volatile organic compounds

Air Pollution in India: Impact and Pathophysiological Mechanisms Leading to Allergic Rhinitis

Air pollution was found to be responsible for 16% of global deaths, of which 92% were in low- and middle-income countries (5). Rapid urbanization is leading to an increased burden of air pollution in India. India experiences one of the highest concentrations of air pollution from biomass, fossil fuels, vehicular exhausts, and indoor sources like mosquito coils and incense. Approximately 77% of the population is exposed to PM2.5 (particulate matter) levels exceeding India's air quality standards (40 µg/m³), with the W.H.O recommending a threshold of <10 µg/m³. Exposure to ambient PM2.5 is linked to precipitating allergies, asthma exacerbations, cardiovascular events, and premature deaths, and contributes to 26.2% of global disability-adjusted life years (6). The pathophysiological mechanisms encompass: i) Pollutant-induced global warming releasing pollen allergens, ii) Air pollutants enhancing antigenic properties of biological aerosols, iii) Compromised mucociliary clearance increasing allergen penetration and airway sensitization, iv) Transport of free allergens to lower airways by binding to particulate pollutants, v) Respiratory epithelial structure and microflora changes through oxidative stress, vi) Co-localization of adjuvants and allergens creating multivalent epitopes, vii) Chemical modification and oligomerization of allergens by reactive oxygen and nitrogen species, viii) Epigenetic changes causing DNA methylation in the promoter region of immune effector genes by cigarette smoke (Fig 2) (5).

Figure 2: Pathophysiology of pollution causing AR. Adapted from K R Bharath Kumar et al. “Impact of Air Pollution on Allergic Rhinitis and Asthma: Consensus Statement by Indian Academy of Pediatrics.” Indian pediatrics vol. 58,8 (2021): 765-770. Abbreviations: UV-Ultraviolet, PM-Particulate matter, O3-Ozone, NO2-Nitrous oxide, Th2-Type 2 Helper cells, TTemperature, RH-Relative Humidity.

Optimizing AR Management: Guidelines and Treatment Approaches:

The cornerstone of allergic rhinitis management lies in an integrated approach; including patient education, self-monitoring, regular physician visits, and avoidance of triggers, with a particular emphasis on the pivotal role of pharmacotherapy, when indicated (7). ARIA has outlined specific guidelines for the management of AR, underscoring the importance of pharmacological interventions.

Pharmacological treatment for AR involves prescribing pharmacotherapy to manage the condition. Various treatment options are available, including oral and intranasal H1-antihistamines intranasal corticosteroids, and combination therapies (8). Within the array of diverse medications, fexofenadine seems to come out as a prominent consideration.

Fexofenadine: Approved, Accepted & Optimal Antihistamine:

• Fexofenadine stands out among the diverse antihistamines available, representing a newer second-generation treatment option that has garnered FDA approval for use in both children and adults, specifically for the treatment of allergic rhinitis. Derived from terfenadine, it selectively antagonizes H1(histamine) receptors on cell surfaces across various organ systems. Notably, Fexofenadine exhibits reduced affinity for cholinergic and alpha-adrenergic receptors, resulting in minimal anticholinergic effects and positioning it as one of the least sedating second-generation antihistamines (9).
• Fexofenadine's pharmacokinetics involve swift absorption, with oral tablets peaking at 1.5 hours. The maximum inhibition of histamine occurs 1-2 hours after administration. Notably, there is no receptor occupancy for central nervous system receptor distribution, and the elimination half-life is 14.4 hours (9).
• Fexofenadine is classified as a non-brain-penetrating antihistamine, primarily affecting H1 receptor occupancy. In terms of its pharmacodynamics, fexofenadine demonstrates minimal H1 receptor occupancy (-0.1%) and negligible affinity for H2/3 receptors. It has a Tmax (time to reach maximum concentration) of 1-3 hours and a T1/2 (half-life) ranging from 11 to 15 hours. Importantly, there is no need for dose adjustment in cases of renal or hepatic impairment (10,11).

Fexofenadine for Allergic Rhinitis: Place in Various Guidelines

• Fexofenadine is efficacious for pollution-induced AR (FEXPOLSAR Trial): In a double-blind, randomized phase 3 study conducted at a single center, researchers investigated the efficacy and safety of fexofenadine HCl 180 mg compared to a placebo in mitigating the effects of diesel exhaust particles (DEP) on seasonal AR symptoms induced by ragweed. The study included 251 patients and consisted of three periods: Period 1 (ragweed pollen alone), Period 2 (ragweed pollen + DEP), and Period 3 (ragweed pollen + DEP + a single dose of fexofenadine HCl 180 mg or placebo). The findings revealed that the Total Nasal Symptoms score (The TNSS was determined by summing the scores for rhinorrhea, sneezing, and nasal itching) for Period 3 was -0.24, while for Period 2, it was 0.13. The researchers concluded that a single dose of fexofenadine HCl 180 mg was effective and significantly reduced all analyzed symptoms compared to the placebo (16). Table 1 records the primary clinical advantages observed in the study with most benefits reported effect within 12 hours

Table 1: Clinical Benefits reported in the FEXPOLSAR Trial

Figure 3: Summary of the average area under the curve for individual symptom scores, comparing the placebo and fexofenadine groups. Adapted from Ellis, Anne K et al. “Effect of fexofenadine hydrochloride on allergic rhinitis aggravated by air pollutants.” ERJ open research vol. 7,2 00806-2020. 6 Apr. 202.

• Fexofenadine modulates genes when added to AR Treatment Regimen: A recent study assessed T helper-9 (Th9), a newly identified T cell subset implicated in AR pathogenesis. Focusing on the impact of fexofenadine (120mg/day, 2 tablets) and fluticasone propionate (100μg/day, one puff/nostril), the research examined their effects on key transcription factors in Th9 cell differentiation among 26 AR patients (average age 32.8 ± 9.1 years ). After one month of treatment, a significant decrease in Interferon regulatory factor 4 (IRF-4) and B cell-activating transcription factor-like (BATF) gene expression was observed (P < 0.001 and P < 0.01, respectively), suggesting the regimen's potential to impact AR patients positively. Fexofenadine and fluticasone propionate treatment for one month effectively reduces IRF4 and BATF gene expression, potentially ameliorating allergic rhinitis clinical signs by modulating Th9 cells and enhancing AR-controlling cell activity (17).

• Fexofenadine safety and efficacy: A meta-analysis was carried out of various randomized controlled clinical trials to evaluate the efficacy and safety of fexofenadine in managing AR. Despite the absence of corroborative meta-analyses, the longstanding use of fexofenadine prompted this comprehensive examination. Analyzing a meticulously selected cohort of 8 studies from an initial pool of 20, the investigation elucidates a notable reduction in daily reflective total symptom scores, favorable outcomes in morning instantaneous scores, and individual nasal symptom scores. The safety analysis reveals a negligible disparity in reported adverse events. This study, characterized by methodological rigor and encouraging findings, advocates for the inclusion of fexofenadine in AR treatment protocols. (18)

• Allergic rhinitis is a widespread inflammatory condition, reportedly accounting for approximately 55% of all allergic conditions in India, significantly impacting the quality of life.
• Air pollution, responsible for 16% of global deaths, is a significant risk factor, contributing to AR. The pathophysiological mechanisms involved include pollutant-induced global warming, enhanced antigenic properties of biological aerosols, compromised mucociliary clearance, and epigenetic changes caused by cigarette smoke.
• Fexofenadine emerges as a standout among antihistamines, being a newer second-generation option approved by the US FDA for treating allergic rhinitis in both children and adults.
• Its distinct pharmacological profile, includes selective antagonism of H1 receptors with minimal anticholinergic effects, positioning it as one of the least sedating options in its class.
• It is a safe, efficacious, and widely accepted antihistamine; backed by scientific evidence and multiple national and international guideline recommendations.