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INTRODUCTION
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.
METHODS
Participant selection
Participants who visited our medical center between December 2021 and November 2023 with chronic rhinitis were prospectively enrolled. Chronic rhinitis was defined as having at least two symptoms (nasal obstruction, rhinorrhea, sneezing, and nasal itching) persisting for more than 3 months without other sinonasal diseases. Patients with chronic rhinosinusitis, concurrent sinusitis, recent sinus surgery, or antibiotic therapy within one month were excluded, as determined by patient history and endoscopic examination. Rhinitis questionnaires and nNO measurements were performed at baseline and after one month of treatment. Baseline assessments also included skin prick tests (SPT) and serological tests to determine atopic status. Treatment for chronic rhinitis consisted of INCS, intranasal antihistamine and corticosteroid sprays (INACS), oral antihistamines, and/or oral LTRAs. Regimens were based on symptom severity, endoscopic findings, and the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines [24]. All participants received intranasal steroid spray due to significant daily life impairments, such as difficulty sleeping or working. Additionally, INACS were prescribed for patients seeking rapid symptom relief or those dissatisfied with intranasal steroids alone.
To expedite therapeutic efficacy, all patients received concomitant oral antihistamines, with LTRA added for those with severe symptoms. Treatment adherence was assessed during outpatient visits at 2 and 4 weeks post-treatment initiation, and patients with poor adherence (<50%) were excluded. Written informed consent was obtained from all patients, and the study was approved by the Institutional Review Board (IRB No. 2021-09-002-029).
Measurement of nNO
Patients were thoroughly informed about the nNO measurement procedure prior to testing. Once their understanding was confirmed, nNO was measured using the NO analyzer (NIOX VERO, Circassia AB, Uppsala, Sweden) with the Tidal Breathing (TB-nNO) method, both before and after treatment. Following the NIOX VERO manual, the nasal olive was inserted into the selected nostril, and patients were instructed to inhale and exhale slowly through the mouth for 30 seconds. The nostril with the wider nasal cavity was chosen to ensure full insertion of the nasal olive; if no significant difference was noted between nostrils, the choice was made randomly.
Allergen sensitization and questionnaires
Before treatment, SPT and serological tests were performed, including measurements of serum total immunoglobulin E (IgE) and blood eosinophil percentages and counts. The allergens were categorized into seven families: house dust mites (Dermatophagoides pteronyssinus, Dermatophagoides farina), molds (mixture, Alternaria alternate, Aspergillus fumigatus, Aspergillus niger, Candida albicans, Chaetomium globosum, Cladosporium fumigatus, Helminthosporium sativum, Mucor mucedo, Penicillium chrysogenum), animal dander (hamster, dog, rabbit, cat, guinea pig, horse, cow, pig), cockroach, trees (mixture, alder, hazel, poplar, Japanese cedar, willow, birch, beech, oak, plane, elm, ash, box elder, olive), grass (mixture, Bermuda, meadow fescue, velvet, ryegrass, timothy, orchard), and weeds (white goosefoot, rye, wheat, mugwort, nettle, dandelion, plantain, ragweed). Normal saline and histamine were used as negative and positive controls, respectively. A maximum wheal diameter of 3 mm was considered positive; patients with at least one positive allergen result were classified as atopic. The monosensitized group comprised individuals sensitized to only one allergen family, while the polysensitized group included those sensitized to multiple families.
The Total Nasal Symptom Score (TNSS) and quality of life (QOL) questionnaires were administered on the same day as the nNO measurements, both before and after the one-month treatment. In the TNSS, each symptom—rhinorrhea, sneezing, nasal obstruction, and nasal itching—was scored from 0 to 3, yielding a total score range of 0 to 12. Ocular symptoms, including eye itching and frequent lacrimation, were also assessed; “TNSS eye” includes four nasal and two ocular symptoms. QOL was measured using the Korean version of the modified RQLQ [5,6], which comprises three sleep-related items, seven generalized symptoms, three practical issues, four nasal symptoms, four ocular symptoms, three activity limitations, and four emotional problems (Supplementary Table 1 in the online-only Data Supplement). Responses were graded on a scale from 1 to 7, and the overall RQLQ score was calculated as the mean across all domains.
Statistical analysis
Statistical analyses were conducted using R software v.3.6 (R Development Core Team). Data are presented as medians with interquartile ranges (IQR). Absolute changes from baseline (pre–post) in nNO levels, TNSS, TNSS eye, and RQLQ scores were calculated and analyzed using the Wilcoxon signed-rank test. Spearman’s test was used to assess correlations between changes in nNO levels and other parameters. Multiple linear regression analysis evaluated the relationship between nNO levels and TNSS, TNSS eye, and RQLQ scores while adjusting for age, sex, and atopic status. Subgroup analyses based on atopic status were performed using the Kruskal-Wallis rank sum test with Bonferroni correction for post-hoc analysis. A p-value of less than 0.05 was considered statistically significant.
RESULTS
Demographics and clinical features of the patients
A total of 46 patients were included in the study. Ages ranged from 12 to 71 years, with a median age of 29.0 (IQR, 17.0–46.8) years. Twenty patients (43.5%) were female, and 26 (56.5%) were male. Based on SPT results, 39 patients (84.8%) were diagnosed with AR, while 7 (15.2%) were diagnosed with NAR. Table 1 summarizes the demographic features and clinical parameters. Treatment strategies were determined based on subjective symptoms and endoscopic findings. Seventeen patients were treated with INCS, and 29 received INACS. All patients received oral antihistamines, and 26 (56.5%) additionally received oral LTRA.
Subjective symptom scores and nNO levels
TNSS, TNSS eye, and RQLQ scores significantly decreased after treatment (all p<0.001) (Fig. 1). Specifically, TNSS changed from 9.0 (IQR, 6.0–11.0) to 4.0 (IQR, 2.0–5.8), TNSS eye from 11.0 (IQR, 9.0–14.8) to 5.0 (IQR, 3.0–7.0), and RQLQ from 3.5 (IQR, 2.3–4.5) to 1.5 (IQR, 1.2–2.1). Additionally, nNO levels significantly decreased from 545.5 parts per billion (ppb) (IQR, 342.0–754.3) at baseline to 425.5 ppb (IQR, 314.5–627.0) post-treatment (p=0.036) (Fig. 2). Baseline nNO levels did not correlate with pre-treatment eosinophil percentages or serum total IgE levels (p=0.642 and p=0.883, respectively), although initial nNO levels exhibited non-significant correlations with pre-treatment TNSS, TNSS eye, and RQLQ scores (p=0.070, p=0.071, and p=0.060, respectively). These results are presented in Supplementary Fig. 1 (in the online-only Data Supplement).
Correlations between rhinitis symptom scores and nNO changes
Changes in nNO levels after treatment were significantly correlated with changes in TNSS and TNSS eye (p=0.047, r=0.294; and p=0.021, r=0.340, respectively) (Fig. 3A and B). Supplementary Fig. 2 (in the online-only Data Supplement) illustrates the correlations between changes in nasal and ocular symptoms and nNO levels. Among individual symptoms, only nasal itching showed a significant correlation with changes in nNO (p=0.004, r=0.412). Although not statistically significant, changes in rhinorrhea and eye itching tended to correlate with nNO changes (p=0.102, r=0.244; and p=0.055, r=0.285, respectively).
Furthermore, changes in nNO levels were significantly correlated with changes in RQLQ scores (p=0.004, r=0.419) (Fig. 3C). Supplementary Fig. 3 (in the online-only Data Supplement) demonstrates that changes in the RQLQ categories—including sleep disturbances (p=0.019, r=0.346), generalized symptoms (p=0.022, r=0.336), practical problems (p=0.004, r=0.421), nasal symptoms (p=0.004, r=0.419), ocular symptoms (p=0.037, r=0.308), and activity limitations (p=0.002, r=0.343)—were significantly correlated with nNO changes, while the emotional problems category was not (p=0.265). Multivariate analysis adjusted for age, sex, and atopic status confirmed significant correlations between nNO changes and TNSS, TNSS eye, and RQLQ score changes (β=0.349, p=0.025; β=0.361, p=0.020; and β=0.402, p=0.009, respectively) (Table 2).
Subgroup analysis according to atopic status
A subgroup analysis based on atopic status classified patients into three groups: monosensitized AR patients (sensitized to only one allergen family, n=7), polysensitized AR patients (sensitized to multiple allergen families, n=32), and NAR patients (no allergic sensitization, n=7). Changes in nNO levels were not statistically significant among these groups (p= 0.107). Although the overall difference was not significant, the nNO change in monosensitized patients was higher than that in NAR patients (p=0.052) (Fig. 4). Supplementary Fig. 4 (in the online-only Data Supplement) shows the correlations between changes in nNO levels and rhinitis symptom/RQLQ scores stratified by atopic status. Subgroup analysis revealed significant correlations between nNO changes and changes in TNSS, TNSS eye, and RQLQ scores in the polysensitized group (p=0.049, p=0.048, and p=0.017, respectively). In the NAR group, significant correlations were observed between nNO changes and RQLQ scores (p=0.003, r=0.964), whereas no significant correlations were identified in the monosensitized group.
DISCUSSION
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.
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