Chronic rhinitis is a common inflammatory condition of the nasal mucosa, characterized by rhinorrhea, nasal obstruction, sneezing, and itching of the nose and eyes. It is classified into allergic rhinitis (AR) and non-allergic rhinitis (NAR), regardless of whether specific allergens trigger the symptoms. AR represents a substantial proportion of rhinitis cases and affects up to 40% of the world’s population, with its prevalence continuing to increase annually [1,2]. Management includes topical medications such as intranasal corticosteroid sprays (INCS) and intranasal antihistamine sprays, as well as systemic medications like oral antihistamines, oral leukotriene receptor antagonists (LTRA), or oral steroids.

Evaluation of treatment effects on chronic rhinitis employs various methods, including visual analog scales and questionnaires such as the Control of Allergic Rhinitis and Asthma Test 10, the International Study of Asthma and Allergies in Childhood core questions, or the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). These subjective tools assess rhinitis symptoms [3-6]. However, groups such as young children, elderly individuals, and those with cognitive impairments may struggle to report symptoms and cooperate during assessments. Thus, an objective and easily applicable tool for evaluating treatment response would benefit these patients.

Nitric oxide (NO) is produced by airway epithelial cells and eosinophils in response to signaling by proinflammatory cytokines [7]. Fractional exhaled NO has been used in asthma patients to assess eosinophilic inflammation in the lower respiratory tract [8]. Likewise, nasal NO (nNO) can be utilized to measure eosinophilic inflammation within the nasal cavity [9-14]. Previous studies have demonstrated that nNO levels are higher in patients with AR than in those with NAR or without rhinitis [7,9,15-21]. Several studies have attempted to elucidate the association between nNO levels and symptom severity [18-20,22,23]. However, because nNO levels vary with symptom severity, ostiomeatal unit obstruction, comorbidities, and anatomical alterations, no standardized normal range has been established [9,14-16,19-21]. Consequently, assessing the treatment response of chronic rhinitis based solely on absolute nNO values is challenging. Measuring the relative change in nNO from pre- to post-treatment may yield more consistent results. This study aimed to objectively evaluate the treatment response in rhinitis by employing nNO as an easily applicable method for most patients.

This study investigated the potential of nNO as an objective and easily applicable biomarker for evaluating treatment response in chronic rhinitis. We observed positive correlations between changes in nNO levels and subjective measures of chronic rhinitis symptoms, as represented by the TNSS, TNSS eye, and RQLQ scores after treatment. Although chronic rhinitis is primarily a symptomatic disease, certain patient populations—such as young children and individuals with cognitive impairments—may have difficulty consistently and accurately reporting symptom changes. In addition, symptom questionnaires based on patient-reported outcomes can be influenced by factors such as emotional state or stress, thereby increasing variability. In this context, an objective tool such as nNO could complement subjective evaluations by providing reliable measures of treatment response. Our findings indicate that nNO holds promise as a noninvasive and supportive biomarker in clinical practice.

NO is produced by NO synthase and plays a role in various physiological processes, including microbial growth, vasodilation, mucociliary functions, and type 2 inflammation [9,14]. Because NO is involved in T-cell growth and inflammatory responses, measuring nNO can serve as a tool for evaluating type 2 inflammation in the nasal cavity and paranasal sinuses. Accordingly, previous studies have investigated nNO as an indicator of eosinophilic inflammation in these regions, with some reporting higher nNO levels in patients with AR than in those with NAR or without rhinitis [7,9,15-21]. Several studies have also attempted to use the absolute nNO level to assess symptom severity [18-20,22,23]. However, the absolute normal range of nNO remains unstandardized because of inconsistencies caused by ostiomeatal unit obstruction, comorbidities, or anatomical variations [9,14-16,19-21]. Moreover, absolute nNO values might not accurately reflect symptomatic changes in chronic rhinitis. We hypothesized that the relative change in nNO levels from baseline to post-treatment would be less influenced by these inconsistencies and could more reliably reflect treatment response. In addition, we employed the TBnNO method, which does not require velum closure, thereby enabling children, older adults, and patients with cognitive impairments to cooperate easily.

A significant reduction in TNSS, TNSS eye, and RQLQ scores after treatment indicated an improvement in patients’ subjective discomfort. Notably, nNO levels also decreased significantly after treatment, mirroring the trends observed in the symptom questionnaires and suggesting that nNO changes may represent the treatment response in chronic rhinitis. Statistical analyses of the relative values revealed significant positive correlations between the objective nNO changes and the subjective improvements measured by TNSS, TNSS eye, and RQLQ scores. These results support the potential role of nNO as an objective and supportive indicator of treatment response in chronic rhinitis. Furthermore, the stronger correlations between nNO changes and RQLQ scores compared to those with TNSS and TNSS eye may be attributed to the more detailed and comprehensive nature of the RQLQ.

Further analyses of nasal and ocular symptoms revealed that only nasal itching was significantly correlated with changes in nNO, while rhinorrhea and eye itching showed a tendency toward correlation. This finding suggests that nNO changes may be particularly sensitive to improvements in the itching sensation following treatment. Additionally, nasal obstruction was the most prominent symptom both before and after treatment, indicating that patients experience greater discomfort from nasal obstruction compared to other rhinitis symptoms; this finding is consistent with previous research [25]. In AR, nasal obstruction results from a combination of early- and late-phase inflammatory responses. In the early phase, allergens bind to IgE receptors on mast cells, triggering the release of histamine and other proinflammatory mediators such as leukotrienes, prostaglandins, tumor necrosis factor-α, and interleukin (IL)-4. In the late phase, persistent mucosal swelling and early-phase mediators promote the infiltration of inflammatory cells, including eosinophils. Eosinophils release various proinflammatory mediators—such as eosinophil cationic protein and eosinophil peroxidase—that subsequently lead to the production of IL-3, IL-5, and IL-13, which play critical roles in the chronic inflammatory response. This cascade exacerbates mucosal swelling, leading to mucus retention, infection, and ultimately chronic nasal obstruction [26]. Therefore, because inflammatory cell infiltration drives chronic nasal obstruction, this condition may not be fully alleviated within a one-month treatment period, potentially explaining the weak correlation observed in this study. In contrast, nasal itching is primarily mediated by neurogenic inflammation, in which sensory neurons in the nasal mucosa are activated upon allergen exposure. These nociceptive neurons release neuropeptides such as substance P and calcitonin gene-related peptide, which in turn activate inducible NO synthase in epithelial cells, resulting in increased NO production [27,28]. Elevated nNO levels are thus a direct outcome of neurogenic inflammation in AR. Unlike nasal obstruction or rhinorrhea—which involve complex mechanisms such as mucosal edema or mucus hypersecretion—nasal itching is more directly linked to neurogenic pathways and NO production. Moreover, the overall score for watery eyes was the lowest among the symptom categories both before and after treatment, suggesting that the relatively low level of discomfort associated with this symptom may hinder accurate assessment. This observation aligns with the lack of correlation between changes in watery eyes and nNO levels in our study.

When evaluating changes in each RQLQ category relative to nNO alterations, almost all categories—except the emotional problems category—demonstrated significant correlations. Given that the pre-treatment emotional problems score was the lowest among all RQLQ categories, and considering that its changes did not correlate with nNO alterations, these findings suggest that patients experience more significant discomfort from physical symptoms and daily life limitations due to rhinitis than from emotional distress.

Regarding allergic sensitization, no difference in initial nNO levels was observed between patients with AR and those with NAR, which contrasts with findings from some previous studies [7,15-21]. However, our NAR group (n=7) was considerably smaller than the AR group (n=39), which limits our analysis and prevents definitive conclusions about baseline nNO differences between the two groups. Furthermore, changes in nNO levels after treatment were not statistically different among the monosensitized, polysensitized, and NAR groups, suggesting that treatment effects on rhinitis may not be strongly influenced by atopic status. Although the numbers of patients in the monosensitized and NAR groups were small, the nNO change in the monosensitized group tended to be higher than that in the NAR group. In the polysensitized group, significant correlations between changes in nNO levels and changes in TNSS, TNSS eye, and RQLQ scores indicate that reductions in nNO may be associated with decreased type 2 inflammation. Conversely, the absence of significant correlations in the monosensitized group may be attributable to the small sample size, which limits statistical power. Notably, the strong correlation between nNO changes and RQLQ scores in the NAR group suggests that nNO alterations are not exclusively associated with type 2 inflammation. Further studies involving larger populations are warranted.

Several factors contributed to the small number of patients in the monosensitized and NAR groups. First, patients with AR account for 70%–80% of chronic rhinitis cases [29]. Second, among AR patients, 70%–80% are polysensitized [30]. Third, monosensitized patients with AR and those with NAR generally experience less severe symptoms than polysensitized AR patients [30-32]. Consequently, patients who visit a university hospital are more likely to present with severe symptoms and be polysensitized. Further studies with larger populations of NAR and monosensitized patients are needed to enable robust subgroup analyses of atopic status.

This study has several limitations. First, the follow-up period consisted of only a single assessment per patient over a consistent treatment duration. Sequential, long-term follow-ups to evaluate the correlation between nNO changes and subjective symptom improvements could strengthen the evidence for nNO as an objective evaluation tool for chronic rhinitis. Second, the small sample sizes of monosensitized patients and those with NAR limited the statistical significance of our findings. In addition, the small sample size hindered our ability to assess the degree of symptom improvement and nNO changes across different treatment strategies. With a larger sample, the impact of treatment methods on nNO changes could be more thoroughly examined. Lastly, the correlation coefficients between changes in TNSS, TNSS eye, and RQLQ scores and nNO alterations were low. Nonetheless, we consider that changes in nNO, as an objective measure of rhinitis symptoms, may serve as a supportive tool to complement overall evaluations of treatment efficacy rather than as a standalone indicator. Despite these limitations, this study is, to our knowledge, the first to investigate nNO changes as potential biomarkers of treatment response in chronic rhinitis. This approach may be particularly useful for patients who have difficulty self-reporting symptom changes, such as young children, older individuals, and those with cognitive impairments.

In summary, this study demonstrated significant correlations between nNO changes and improvements in subjective symptoms, as measured by TNSS, TNSS eye, and RQLQ scores after treatment. Our findings suggest that nNO may serve as an objective biomarker to complement subjective evaluation tools and contribute to a comprehensive assessment of chronic rhinitis. Future research involving larger, more diverse patient populations and long-term follow-ups is warranted to validate these findings further.