Nasal nitric oxide in relation to quality-of-life improvements after endoscopic sinus surgery DO NOT COPY. American Journal of Rhinology & Allergy

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1 Nasal nitric oxide in relation to quality-of-life improvements after endoscopic sinus surgery Chia-Hsiang Fu, M.D., 1,2 Chi-Che Huang, M.D., 1,2 Yi-Wei Chen, M.D., 1 Po-Hung Chang, M.D., 1,2 and Ta-Jen Lee, M.D. 1 ABSTRACT Background: The level of nasal nitric oxide (nno) in patients with chronic rhinosinusitis (CRS) has been proven to increase after surgical treatment. The relationship between nno and treatment outcome has not been documented to date. Objective: To evaluate the levels of and changes in nno after sinus surgery and its effects on quality-of-life improvements for patients with CRS after surgical treatment. Methods: By using a clinical cohort study design, we identified patients who were receiving bilateral endoscopic sinus surgery for CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) with a 1-year follow-up. We assessed the demographics, preoperative prognostic predictors, pre- and postoperative nno levels, and disease-related quality of life via a questionnaire. Results: Sixty-nine patients were enrolled, including 53 with CRSwNP and 16 with CRSsNP. The CRSwNP group had lower initial nno levels and higher endoscopic and image scores but similar demographics and questionnaire scores. In the patients with CRSwNP, nno levels recovered and reached a plateau at the third month after surgery. However, nno levels in the CRSsNP group continued to increase until 6 months after surgery before reaching a steady level. Higher preoperative nno levels were significantly related to better quality-of-life improvements at 3 months after surgery in both groups. Conclusion: The nno levels in patients with CRS increased and reached a plateau after sinus surgery for both groups. Under similar subjective disease severity, the CRSsNP group had higher preoperative nno levels and maintained a continuously longer rise before reaching a steady level after surgery. For both CRS groups, a higher initial nno level brought better quality-of-life improvements and could be provided as a preoperative prognostic indicator. (Am J Rhinol Allergy 29, e187 e191, 2015; doi: /ajra ) Chronic rhinosinusitis (CRS) is a multidisciplinary, frequently encountered disease, and functional endoscopic sinus surgery (FESS) remains a feasible, well-established solution for CRS refractory to maximal medical treatment. The relationship between FESS and its impact on quality of life (QOL) remains elusive and needs to be clarified. Several studies demonstrated a poor correlation among preoperative prognostic predictors, disease severity, and the subjective measurement of surgical outcomes for patients with CRS. Preoperative symptom scores and changes in symptom scores after surgery do not necessarily correlate well with radiologic findings. 1,2 Symptom-based surgical outcomes do not always correlate with the resolution of sinus diseases as judged by endoscopy or computed tomography (CT). 3,4 Nitric oxide (NO) in exhaled air is mainly produced in the upper airway, especially from the mucosal epithelium in the paranasal sinuses, where it is synthesized from L-arginine by inducible NO synthase (inos). NO has been proposed to play important roles in cell signaling, cell-mediated immune response, and cell apoptotic inhibition signals. 5 7 It has been used to monitor the status of local immunity and inflammation. Although the exact role of NO in the sinus still remains to be elucidated, previous studies led us to speculate that it is a consequence of increasing local host defenses in the sinus. 5 7 Nasal NO (nno) levels are affected by medical or surgical treatment for CRS, and they correlate well with cilia beat frequency Thus, nno has been used as a screening tool for primary ciliary dyskinesia and as a potential postoperative biomarker after sinus surgery for chronic sinusitis because NO levels correlated well with radiographic staging, 12 and symptom severity as well. 13 In comparison with image studies, such as CT or magnetic resonance imaging, nno is relatively noninvasive, and nno levels are feasible to determine the treatment outcomes for patients with sinusitis. To our knowledge, no long-term postoperative changes in nno levels have been reported and surgical outcomes estimated by the evaluation of preoperative nno levels or changes in nno levels have never been documented. It is increasingly important to not only determine the effectiveness of therapeutic interventions but also to predict treatment outcomes in advance. Patients, regardless of their disease severity, are concerned about their prognosis given their individual current conditions and wish to know the likelihood of major symptom-specific improvement, which is usually most patients major concern before surgery. We conducted this investigation in which we examined the correlation between changes in nno levels and the improvements in QOL. Our findings should be helpful for the development of predicting surgical outcomes in advance. From the 1 Department of Otolaryngology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan and 2 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan This study was supported by a grant from Chang Gung University (CMRPG3A1001) The authors have no conflicts of interest to declare pertaining to this article Presented at the 2014 American Academy of Otolaryngology-Head and Neck Surgery Foundation annual meeting and OTO EXPO, September 24, 2014, Orlando, Florida Address correspondence to Ta-Jen Lee, M.D., Division of Rhinology, Department of Otolaryngology, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan address: entlee@adm.cgmh.org.tw Copyright 2015, OceanSide Publications, Inc., U.S.A. MATERIALS AND METHODS Study Design and Patient Selection This prospective study included patients who underwent bilateral endoscopic sinus surgery for CRS with nasal polyps (CRSwNP) or CRS without nasal polyps (CRSsNP), and were refractory to medication therapy for more than 12 weeks. Institutional review board approval (no B) was obtained from Chang Gung Memorial Hospital, Taoyuan, Taiwan. All the patients in this study were recruited from the Department of Otolaryngology Head and Neck Surgery over a 12-month recruitment period and were followed-up for 1 year after surgery. All the patients met the criteria of the Rhinosinusitis Task Force Committee for CRS. 14 Demographic information on patient age, sex, nasal allergies, asthma, or current smoking status of each individual was recorded as potential medical variables. Patients with the following characteristics and/or conditions were excluded from this study: 18 years of age, unilateral sinus diseases, e187

2 related previous sinonasal surgeries, sinonasal tumors, and current pregnancy. Subjective and Objective Measurements Subjective evaluation of specific symptoms for subjects was carried out via the Sino-nasal Outcome Test 22 (SNOT-22), with grades from 0 (no symptoms) to 5 (severe) for each symptom. A subjective questionnaire survey was conducted on the day before surgery and after surgery at 3, 6, and 12 months. This instrument was administered by an experienced research assistant blinded to the radiographic staging in this cohort. Preoperative CTs were evaluated by a surgeon (C.-H.F.) in a blinded fashion to record the severity of sinusitis by using the Lund- Mackay scoring system. For each patient, we also recorded the Lund- Kennedy endoscopy score, total nasal resistance by rhinomanometry, olfaction function test by the Sniffin Stick test, (Burghart, Wedel, Germany) allergy test results, and routine peripheral blood tests (eosinophil count, total immunoglobulin E level) before endoscopic sinus surgery was performed. Treatment after Surgery Immediately after FESS, all the patients were prescribed oral antibiotics (Augmentin [GlaxoSmithKline, London, UK] 1 g twice daily) for 2 weeks. One week after surgery, daily sinus cavity irrigation with normal saline solution and an intranasal spray of mometasone furoate 100 g (2 sprays) were applied over a 3-month period. In-clinic follow-ups with sinus cavity debridement were performed on a weekly basis during the first month after surgery, followed by visits every 2 weeks after 1 month, and extended to monthly visits after the second month and visits every 2 months after 6 months. Nasal Nitric Oxide Measurements Nasal nitric oxide (nno) measurements were done with an electrochemical analyzer (NIOX MINO; Phadia AB/Aerocrine AB, Uppsala, Sweden) by following The American Thoracic Society/European Respiratory Society recommendations. 15 An automatic measurement was set to 45 seconds, and the flow rate of aspiration was set to 5 ml/s. The first 15 seconds of sampling were for instrument dead space washout, and the air from the last 30 seconds of sampling was collected in the buffer chamber and run over the NIOX MINO sensor. The subject was asked to sit in a relaxed position, to exhale to tidal volume, and to insert a filtered mouthpiece in his or her mouth and a NIOX nasal olive into one nostril at a time. The subject then gently inhaled orally to total lung capacity through the mouthpiece (not holding the breath) while NO levels were continuously measured (Fig. 1). The olive was held tightly against the nostril during sampling to prevent leakage of air. After 45 seconds, the olive was removed from the subject s nostril, and the nasal NO values were analyzed within 2 minutes. The other side was then analyzed in the same manner. Postoperative nno levels were analyzed at 3, 6, and 12 months after surgery. Statistical Analyses With QOL improvement (SNOT-22) as the study end point, the minimum required sample size was calculated by using the statistical software PASS 2008 (NCSS, LLC, Kaysville, UT). 16 A minimum of 22 subjects were required in each study group to have statistic power at 0.9 to detect the QOL score change after FESS at a two-sided level of The smallest change in SNOT-22 score that can be detected by a patient has been reported to be 8.9 points. 17 The Mann Whitney U test was applied for comparing continuous variables, and the two-sided Fisher s exact test was applied for categorical variables between CRSwNP and CRSsNP. The pre- and postoperative status of nno levels and QOL scores were compared by the Wilcoxon signed rank test. Correlation analyses were applied for Figure 1. Illustration of nasal nitric oxide (nno) sampling. Slow oral breath against a mouthpiece closes the velum to isolate nno from lower airway gases and avoids contamination of ambient nitric oxide (NO) during sampling. studying the relationship between the nno levels, SNOT-22 scores, and other variables in each group. To compare the differences between patients with allergy and patients without allergy, the Mann- Whitney U test and the two-sided Fisher s exact test were used for comparing continuous variables and categorical variables, respectively. We also compared pre- and postoperative nno levels by using the Wilcoxon signed rank test for both patients with allergy and patients without allergy. The change in nno level was defined as the absolute difference between the pre- and postoperative nno levels. In an attempt to determine the prognostic power of nno, the initial level and the postoperative change in nno at 3, 6, and 12 months were analyzed together with SNOT-22 scores via correlation analysis. Data were analyzed by using a statistical software package (SPSS Version 16.0 for Windows; SPSS Inc., Chicago, IL). All the p values were twotailed, and p 0.05 was considered statistically significant. RESULTS Demography and Preoperative Parameters in the Two Groups Eighty-two consecutive patients received bilateral FESS and were initially enrolled in this cohort study, including 57 with CRSwNP and 25 with CRSsNP. Of whom, 53 patients with CRSwNP and 16 patients with CRSsNP completed the postoperative survey. The mean SNOT-22 score improvements after surgery for CRSwNP and CRSsNP were 24.2 and 25.2, respectively, and the statistical power was 1.0 ( 0.05, two-tailed). Patients in the CRSwNP group had better willingness to receive surgical treatment and complied with a 1-year follow-up for the concept that nasal polyp is generally thought as a more complicated inflammatory disease compared with CRSsNP. Hence, the compliance to postoperative visits in the patients with CRSsNP was lower in comparison with that of the patients with CRSwNP. The demographic data and clinical factors are shown in Table 1. There was no significant difference in the basic background between these two groups. Potential related medical variables were analyzed, and the results revealed that patients in the CRSwNP group had higher endoscopy scores (9.3 versus 5.8; p 0.001) and CT scores (16.4 e188 November December 2015, Vol. 29, No. 6

3 Table 1 groups Demographic data and clinical parameters of the two CRSwNP (n 53) versus 11.8; p 0.004), as predicted. Patients in the CRSsNP group had significantly higher preoperative nno levels (255.4 versus 165.2; p 0.032). Preoperative nno levels negatively correlated with endoscopy and CT scores in both groups, although statistical significance was reached only in the CRSwNP group (p 0.001) but not in the CRSsNP group (p 0.119) (Fig. 2). Among other medical factors and backgrounds, no significant differences were detected in age, allergy status, SNOT-22 scores, or other variables in preoperative status between the two groups. Postoperative nno Level All the patients completed postoperative 3-, 6-, and 12-month evaluations. The nno levels were significantly elevated and reached a plateau at 3 months after sinus surgery in the CRSwNP group (Fig. 3). However, for patients with CRSsNP, postoperative nno levels did not significantly rise and reach a plateau until 6 months after surgery. Elevated postoperative nno levels persisted until 12 months after surgery and were significantly higher than the preoperative levels in both groups (p 0.01 for both groups). Sphenoid sinuses were not opened in 11 patients with CRSwNP and in 8 patients with CRSsNP. All other sinuses were opened during bilateral endoscopic sinus surgery. There was no significant difference in postoperative nno levels whether or not they had their sphenoid sinuses opened in either group (p for CRSwNP and p for CRSsNP group). Postoperative Improvements in QOL CRSsNP (n 16) p Value Age, mean (SD), y Sex, men:women 36:17 9: AR, no. (%) 10 (18.9) 4 (25.0) Asthma, no. (%) 11 (20.8) 2 (12.5) Smoker, no. (%) CT score, mean (SD) * Endoscopy score, mean (SD) * Nasal resistance, mean (SD), Pa Olfaction test score, mean (SD) Total IgE, mean (SD), ku/l Eosinophil count, mean (SD), % Preoperative nno, mean * (SD), ppb SNOT-22 score, mean (SD) CRSwNP chronic rhinosinusitis with nasal polyps; CRSsNP CRS without nasal polyps; SD standard deviation; AR allergic rhinitis; CT computed tomography; IgE immunoglobulin E; nno nasal nitric oxide; SNOT-22 Sino-nasal Outcome Test 22. *Statistically significant. The total SNOT-22 scores decreased significantly in the 3 months after surgery until 12 months after surgery in both the CRSwNP and CRSsNP groups, which demonstrated that the treatment of FESS for patients with CRS had provided effective long-term relief of subjective symptoms. The top three preoperative symptom scores of the patients greatest concerns for both groups were nasal obstruction (3.53 and 3.54, respectively), need to blow nose (2.87 and 2.86, respectively), and postnasal discharge (2.76 and 2.82, respectively). Postoperative scores of these top three symptoms all improved significantly in the 3 months after surgery, and these improvements remained significant until 12 months after surgery for both the CRSwNP (p 0.01) and CRSsNP (p 0.05) groups. Effect of Allergy Status Overall, 20 patients had a positive allergy test results, and the remaining 49 patients had negative results. The significant difference between the patients with allergy and those without allergy was the total immunoglobulin E level (369.9 versus 57.8, p.001), whereas no significant differences were illustrated in preoperative nno levels, existence of nasal polyps, endoscopy scores, CT scores, SNOT-22 scores, or other parameters. Postoperative nno levels elevated significantly in both patients with allergy and patients without allergy (Fig. 4), and the postoperative nno levels seemed to keep continuously increasing at 12 months in the allergy group. The improvements in postoperative QOL had no significant differences between the allergic and nonallergic groups at 3, 6, and 12 months after surgery. Correlation between nno and Improvements in QOL The correlation between preoperative nno levels or postoperative nno change and subjective improvements of SNOT-22 total scores or individual scores of the top three symptoms was evaluated by the Spearman correlation. We observed that a higher preoperative nno level induced a more significant decrease in postoperative SNOT-22 total scores at 3 months in both the CRSwNP and CRSsNP groups (p and 0.034, respectively) (Fig. 5). Although neither preoperative nno levels nor postoperative nno changes had a statistically significant correlation with total or individual items of SNOT-22 score improvements at 6 or 12 months after surgery in either group, a trend toward a similar positive correlation between preoperative nno levels and postoperative QOL improvements was observed. DISCUSSION Most of the literature reports that patients with CRS have lower nno levels when compared with normal controls 13,18,19 and that these nno levels increase after medical or surgical treatment. 10 Collection of nno has been provided as a fast, safe, and valuable objective measurement to monitor the responses of CRS to therapeutic interventions. Several techniques for measuring nno have been proposed. 20,21 We followed the standardized procedure for the measurement of airway NO established by the American Thoracic Society/ European Respiratory Society. 15 Velum closure is required to isolate nno, which prevents the contamination of NO from lower airway gases. Slow oral exhalation against a mouthpiece not only reliably closes the velum but also avoids contamination of ambient NO during sampling. While air is aspirated continuously via one nasal olive at a constant low rate of 5 ml/s, the subjects can orally breathe and inhale to total lung capacity. Some confounding factors can be avoided by this method, and those patients who cannot hold their breath for 45 seconds or perform a standard humming do not need to be excluded. As generally thought, patients with CRS and with more advanced disease severity had higher CT scores or subjective symptom scores, although these two scores are not necessarily compatible. In this investigation, patients with CRSwNP and patients with CRSsNP had similar preoperative SNOT-22 scores. Most other demographic data showed no differences between the two groups, except for higher endoscopy and CT scores in the CRSwNP group as predicted. The CRSwNP group had a lower mean preoperative nno level in agreement with previous literature reports. 19 In this cohort study, postoperative nno levels were elevated in both the CRSwNP and CRSsNP groups, as previously reported. 10 However, to our knowledge, follow-up of nno change after FESS has not been documented in the medical literature. We found that the progress of nno elevation was not exactly the same for the two groups. The nno level increased e189

4 Figure 2. Correlation analysis between preoperative nasal nitric oxide (nno) levels and computed tomography (CT) scores in (A) the chronic rhinosinusitis with nasal polyps (CRSwNP) group and (B) the chronic rhinosinusitis without nasal polyps (CRSsNP) group. Figure 3. Comparison of the nasal nitric oxide (nno) levels among pre- and postoperative 3, 6, and 12 months in (A) the chronic rhinosinusitis with nasal polyps (CRSwNP) group and (B) the chronic rhinosinusitis without nasal polyps (CRSsNP) group. *p 0.05, **p Figure 4. Comparison of the nasal nitric oxide (nno) level among pre- and postoperative 3, 6, and 12 months in (A) the patients with allergy and (B) the patients without allergy. *p 0.05, **p Figure 5. Correlation analysis between preoperative nasal nitric oxide (nno) levels and postoperative improvements of Sino-nasal Outcome Test 22 (SNOT-22) scores at the third month in (A) the chronic rhinosinusitis with nasal polyps (CRSwNP) group and (B) the chronic rhinosinusitis without nasal polyps (CRSsNP) group. significantly and reached a plateau at the third month after surgery for the CRSwNP group. It was generally acknowledged that the mucociliary function of the sinonasal tract tended to recover 3 months after surgery 22 ; however, in the CRSsNP group, the nno level did not increase significantly until 6 months after surgery. It seemed that nno levels recovered sooner in the CRSwNP group once the blockage of the sinonasal pathways by nasal polyps was eradicated and ventilation of sinuses was restored. Because inos in sinus mucosa has been reported to synthesize nno, the results of this study indicated that the function of inos may not completely recover from an inflammatory state in patients with CRSsNP until 6 months after surgery, despite ventilation of the sinus passage and the mucociliary clearance function being restored. However, postoperative biopsy should be obtained, and a longer follow-up period would be necessary to prove this hypothesis and provide a more definitive conclusion on the postoperative nno change. Subjective measurements (QOL questionnaires) had a poor correlation with objective measurements (endoscopy scores, CT scores) in our patients with CRS as reported in the literature. 1 4 The finding was similar when there was poor correlation between the subjective measurement (SNOT-22 scores) and the objective measurement (nno level), both before and after surgery. There was a trend, however, for the SNOT-22 scores and nno levels in both the CRSwNP and CRSsNP groups to reach a plateau at a certain period after surgery (at 3 and 6 months, respectively), and the initial nno levels were found to significantly correlate with short-term surgical outcomes, which indicated that higher initial nno levels produce more symptom score improvements at the third postoperative month for both groups. e190 November December 2015, Vol. 29, No. 6

5 Although no statistically significant correlation was found between the plateau of postoperative QOL and the nno levels 6 months after surgery, we could still see a similar trend that indicated higher preoperative nno levels in relation to better SNOT-22 score improvements for both the CRSwNP and CRSsNP groups. Because there are no other strong prognostic preoperative factors available, our study results indicated the potential role of the preoperative nno levels in patients with CRS before endoscopic sinus surgery in predicting postoperative QOL improvement. In addition, the negative correlation between nno and CT scores that was found before surgery may further indicate the potential role of using nno level during follow-up in place of CT, which reduces patients exposure to radiation after surgery. Postoperative long-term QOL improvements for patients with CRS still remain complex. A multidisciplinary approach with more patients should be used to obtain a more definite conclusion for long-term outcomes. Nasal allergies theoretically cause an elevation of nno, which thus has an adverse effect on patients with CRS. 18 The correlation between allergy-related eosinophilic inflammation and surgical outcomes of FESS remain uncertain. 23,24 In this study cohort, the presence of nasal allergy did not play a critical role in preoperative nno, SNOT-22 scores, or postoperative improvements in QOL. Nevertheless, in contrast to the steady postoperative nno levels of patients without allergy since the third month, the allergy group in this investigation had continuously rising nno levels until 12 months after surgery. The supposed role of allergy in elevating nno levels was revealed only after the sinus surgery and became more obvious with time. Thus, we may presume that the function of inos in the sinus mucosa was restored after postoperative sinus function recovery and that this phenomenon was more apparent and lasting for patients with allergy. CONCLUSION We concluded that the noninvasive measurements for nno could be an alternative prognostic factor for disease severity in patients with CRS in both groups. In the long term, after sinus surgery, nno levels increased and then remained at a steady level in both groups. Nevertheless, under similar subjective disease severity, as observed in the CRSwNP group, the CRSsNP group had higher preoperative nno levels. Postoperative nno levels in the CRSsNP group took more time to reach a plateau. Initial nno levels detected before endoscopic sinus surgery were related to postoperative improvements in the QOL for both groups. Further studies may clarify the correlation of nno levels, other potential prognostic parameters, and multidimensional surgical outcomes. REFERENCES 1. 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