Intranasal budesonide for rhinitis during a high airborne pollution period: a randomized controlled trial

This study aimed to assess the efficacy of intranasal budesonide in adults with self-reported rhinitis symptoms triggered/worsened by high airborne pollution. The results showed that budesonide resulted in a statistically significant higher reduction in 24-h rTNSS over the first 10 days of treatment compared with placebo. The results were consistent between the FAS and PPS, confirming the reliability of the result for the primary endpoint.

This is the first Phase IV study to provide direct evidence on the efficacy of an intranasal corticosteroid for rhinitis symptom relief during high airborne pollution. A prior 4-week, Phase IIa, randomized, double-blind, multicenter trial showed no significant difference in treatment effect between fluticasone furoate (FF) nasal spray 110 µg once daily, and placebo in patients with irritant (non-allergic) rhinitis triggered predominately by air pollution [17]. The authors analyzed that the lack of a treatment effect may be in part due to the overall good air quality present throughout the study or an insufficient dose or duration of FF. Unlike the smaller FF pilot study (n = 102), this multicenter, large-scale, budesonide study was sufficiently powered to test for a treatment difference between groups. In addition, the AQI in our study reached levels that were defined as unhealthy. Thus, our study adds to the evidence that budesonide significantly improves nasal symptom severity in subjects with rhinitis triggered or exacerbated by air pollution.

As outlined in the statistical analysis plan, power estimations were made only for the primary endpoint. Here budesonide produced a significantly greater reduction in rTNSS over the treatment period compared with placebo (LS Mean: − 2.20 vs − 1.72, respectively; P = 0.0107). Such relatively small but statistically significant difference between active and placebo therapies may be partly due to the placebo effect. Actually, previous studies on AR also showed a relatively large placebo effect and a less than 1.00 difference on nasal index score or rTNSS between active and placebo [16, 18]. Of course, it’s still better to conduct further studies with larger sample size population to confirm the conclusions here in the future.

Since statistical significance was not achieved in the SGIC as a secondary endpoint, subsequent endpoints became exploratory. Statistical significance is not consistent across these exploratory endpoints. Compared with placebo, budesonide significantly improved the exploratory endpoints of itching/sneezing averaged over 10 days (P = 0.001) as well as the combined scores of nasal obstruction + itching/sneezing (P = 0.006) and secretion/runny nose + itching/sneezing (P = 0.006). The improvement in the remainder of the individual and combined nasal symptom scores were not significantly different between the budesonide and placebo groups. There were also no significant differences in individual non-nasal symptoms between the budesonide and placebo groups. Taken together, these results may suggest that improvements in itching/sneezing are major contributors to the overall efficacy of budesonide during the 10-day treatment period. In addition, no significant difference was observed between treatment groups in the averaged change of nasal obstruction during the first 10 days, the statistical significance noted for congestion on Days 10 and 12 suggests that improvement in nasal obstruction may take a longer timeframe. A higher proportion of subjects in the budesonide group reported total control of symptoms (7.8% vs 3.9% for budesonide vs placebo, respectively), whereas a higher proportion of subjects in the placebo group reported no control over symptoms (9.7% vs 18.4%, budesonide vs placebo, respectively). These results were consistent with the PGIC results, but no significant difference in averaged SGIC or PGIC was observed between treatment groups.

Studies have shown that the changes in dispersion patterns and increased allergenicity of pollens and spores may be linked with climate change and air pollution. It poses a greater risk in sensitized people of developing allergic respiratory disease and aggravation of symptoms to those who are already affected [19, 20]. For patients with NAR, ambient physical or chemical stimuli alone irritate the nasal mucosa6. Even, rhinitis people without allergic sensitization are more likely to report more severe nasal symptoms when live in areas with higher levels of pollution compared with those with allergy [9] Nasal hyperreactivity is a common feature in both AR and NAR, generally regarded as nonspecific in NAR and phenotypic in AR [21, 22]. In present study, the participants were only asked to provide information about their previous allergy history (14.6%), confirmation of diagnosis was not performed primarily because the study is intended to target a real-world population of rhinitis sufferers from rhinitis symptoms triggered or worsened by airborne pollution regardless of the presence of underlying allergies. It is necessary to carry out in-depth research in a larger population with clear allergen information in order to specially analyze the impact of allergy on the conclusion of efficiency in the future.

Several explanations on the potential mechanisms of airborne pollution-induced rhinitis have been proposed. In-vitro culture of noninflammatory nasal mucosal tissue showed that exposure to PM2.5 might lead to loss of barrier function in human nasal epithelium through decreased expression of tight junction (TJ) proteins and increased release of proinflammatory cytokines [23]. The destructive effects of chronic airborne particulate matter exposure brought about by sinonasal airway barrier disruption and non-allergic eosinophilic inflammation have also been demonstrated in mice [24]. Even short-term haze exposure may lead to nasal inflammation and hypersensitivity, predominantly by Th2 cytokine-mediated immune responses, as demonstrated in a 5-day observational study involving healthy human volunteers [25]. One study was able to observe that concomitant exposure to environmental pollutants, such as diesel exhaust particles, and house dust mites may result to enhanced allergic airway inflammation characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of innate lymphoid cells (ILCs) and Th2 cells, type 2 cytokine production and airway hyperresponsiveness as compared to sole exposure with either of these two. This observed phenomenon appears to be relevant for this study as this was conducted during the winter season when pollution levels and predominance of perennial AR tend to be higher. Intranasal steroids are generally recommended as first-line treatment of rhinitis [26, 27] and have been proven to affect the restoration of the epithelial barrier function while resisting eosinophil-dominant inflammation. One study showed that early phase steroid-induced resolution involves inhibition of eosinophilia in total nasal tissue and lamina propria and CCL5-dependent recruitment of cells in the nasal mucosa in AR [28].

The decision to conduct this study in cities in northern China was based on historical air quality data. According to the 2019 Report on the State of the Ecology and Environment in China [29], the average proportion of days in the year that the northern Chinese cities of Beijing, Tianjin, Hebei, and their surrounding areas exceed the air quality standard (AQI ≤ 100) was 46.9% compared to that of the Yangtze River Delta at 23.5%. Additionally, air pollution is most serious and concentrated during the winter season, while seasonal allergen levels are very low. In this study, the average daily AQI exposure across all sites for each treatment group (110.2 for budesonide; 111.6 for placebo) suggests that the average air quality reached unhealthy levels for sensitive people [30, 31] during the study.

When the study enrollment was halted by the COVID-19 pandemic, the results of an interim analysis conducted by a third party demonstrated that the results were sufficiently powered to demonstrate efficacy for the primary endpoint. However, while early study cessation did not limit the results of this multicenter, randomized, placebo-controlled, double-blind study, it could have affected the turnout for the other secondary and exploratory efficacy measures. Another limitation is that the follow-up periods were short. It could limit the generalizability of the results since patients might require treatment for the entire pollution season, which lasts about 6 months.

Last but not least, although this study was carried out in Chinese population, to our knowledge, there is no evidence suggesting that the topical use of budesonide or other corticosteroids would have a different impact due to ethnicities. Moreover, pollution is a growing global problem, so the conclusions here are also likely to benefit patients with rhinitis caused by air pollution all over the world. Further studies are needed to investigate the effect of relevant atopic history and other comorbidities that may contribute to NAR as well as the local eosinophilic inflammatory status on the outcome of intranasal budesonide towards airborne pollution induced rhinitis.

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