Effects of Endoscopic Sinus Surgery for Eosinophilic Chronic Rhinosinusitis on Respiratory Functions and FeNO Production in the Lower Respiratory Tract

Abstract

Objective:

To confirm the relevance of upper and lower airway inflammation in eosinophilic chronic rhinosinusitis (ECRS), the effects of endoscopic sinus surgery (ESS) on lower airway functions and inflammation need to be examined in ECRS patients.

Methods:

Chronic rhinosinusitis patients with nasal polyps (25 non-ECRS, 28 ECRS) were enrolled. The 12 patients in the ECRS group had comorbid asthma, in contrast to none in the non-ECRS group. We divided ECRS patients into 2 groups of ECRS with and without asthma. Clinical markers, including fraction of exhaled nitric oxide (FeNO), respiratory functions, and the Asthma Control Test (ACT) questionnaire, were investigated before and after ESS.

Results:

The FeNO levels in the ECRS with asthma group decreased after ESS. The mean FeNO levels in this group were 56.3 ppb before ESS and 24.9, 25.1, 25.0, and 15.5 ppb 1, 2, 3, and 4 months, respectively, after ESS. The mean forced expiratory rates in 1 second before and after ESS were 67.6% and 73.0%, respectively. The mean maximal expiratory flow rates at 50% of the vital capacity before and after ESS were 45.8% and 58.0%, respectively. Significant differences were observed in respiratory functions before and after ESS. The mean ACT scores in the ECRS with asthma group before and after ESS were 17.5 and 23.5, respectively. The ACT scores were significantly higher after than before ESS.

Conclusions:

The present results indicate that ECRS and bronchial asthma are common eosinophilic airway inflammatory diseases, and ESS for eosinophilic sinusitis may improve lower airway function.

Keywords

eosinophilic chronic rhinosinusitis endoscopic sinus surgery fractional exhaled nitric oxide asthma

Introduction

Eosinophilic chronic rhinosinusitis (ECRS) is a type of chronic rhinosinusitis with nasal polyps (CRSwNP); however, the clinical characteristics of ECRS differ from those of non-ECRS. Furthermore, ECRS is closely associated with bronchial asthma, a risk factor for refractory ECRS.^1
-3 Although ECRS and bronchial asthma are common eosinophilic airway inflammatory diseases, the effects of endoscopic sinus surgery (ESS) for ECRS on asthma, including respiratory functions and the fraction of exhaled nitric oxide (FeNO) produced in the lower respiratory tract, currently remain unclear.

Fraction of exhaled nitric oxide is a noninvasive and reliable marker of lower airway inflammation. Nitric oxide (NO) plays a number of roles in the upper and lower airway sites that are relevant to airway defense mechanisms and it is also an inflammatory mediator.^4,5 Several reports have suggested that eosinophilic inflammation is an important pathophysiological mechanism of both asthma and ECRS.^6
-8

The FeNO levels were previously shown to be elevated in patients with eosinophilic airway inflammation, such as bronchial asthma.⁹ In patients with asthma, FeNO levels increased after asthmatic reactions and decreased after the inhalation of corticosteroids.¹⁰ The FeNO levels may also be elevated in ECRS patients with and without asthma.

Through the examination whether ESS for the upper airways affects the lower airways, it might be able to consider the relationship between ECRS and asthma. In the present study, we examined oral FeNO levels in ECRS patients with and without asthma and in non-ECRS patients to investigate the effects of ESS on lower airway functions and inflammation.

Material and Methods

The present study was conducted in accordance with the Declaration of Helsinki and was approved by the IRB of Osaka Medical College.

Patients

This was a prospective case–control study in which 25 non-ECRS patients, 16 ECRS patients without asthma, and 12 ECRS patients with asthma were compared. All patients with chronic sinusitis were recruited from the Department of Otorhinolaryngology–Head and Neck Surgery, Osaka Medical and Pharmaceutical University, and were undergoing ESS for the first time. The diagnosis of CRS was based on clinical symptoms, endoscopic findings, and computed tomography scans.¹¹ The study protocol was approved by the ethical committee overseeing epidemiological research at Osaka Medical and Pharmaceutical University (1092-01).

Twenty-eight patients fulfilled the criteria for ECRS, and the other 25 were diagnosed with non-ECRS. The 12 patients in the ECRS group had comorbid asthma, in contrast to none in the non-ECRS group. All ECRS and non-ECRS patients had nasal polyps. We divided ECRS patients into 2 groups of ECRS with and without asthma. Asthma was diagnosed by a respiratory physician based on the Global Initiative for Asthma definition, updated in 2015. We do not have nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease in this study.

Exclusion criteria were as follows: uncontrolled asthma before surgery, the oral and intravenous administration of steroids, and a history of other eosinophilic diseases, including eosinophilic granulomatosis with polyangiitis, eosinophilic pneumonia, and hypereosinophilic syndrome. Inhaled steroids were not restricted.

Fraction of Exhaled Nitric Oxide Measurement

The FeNO levels were measured in all patients before ESS and 1, 2, 3, and 4 months after ESS using NIOX MINO (Aerocrine AB) at a single expiratory flow rate of 50 mL/s according to the American Thoracic Society/European Respiratory Society guidelines.^12,13

Spirometry Analysis

We examined the forced expiratory rate in 1 second and maximal expiratory flow rate at 50% of the vital capacity (V50) in all patients before and 3 months after surgery.

Drug Treatment and Changes in FeNO Levels Before and After ESS

We assessed changes in FeNO levels before to 4 months after surgery. None of the patients were treated with systemic steroids before ESS and received nasal and/or inhaled steroids before and after ESS as needed.

After ESS, macrolide antibiotics and carbocisteine were administered to non-ECRS patients for approximately 4 months. Anti-LT antagonists (montelukast) and carbocisteine were administered to ECRS patients preoperatively and throughout the postoperative period. There are no alterations of treatments for asthma during the therapeutic period. However, the administration period varied according to the condition of each patient. Patients were monitored after surgery for at least once a month.

Asthma Control Test

The Asthma Control Test (ACT) questionnaire has been widely used and validated in various ethnic groups and correlates with physician assessments of asthma control.¹⁴ The ECRS with asthma group conducted ACT before and 3 months after ESS to assess asthma control.

Statistical Analysis

The Mann-Whitney U test or Wilcoxon test was used to assess differences between the 2 groups. Differences between preoperative and postoperative values were examined using the Steel-Dwass test. P < .05 was considered to be significant.

Results

The clinical characteristics of the study population are summarized in Table 1. A significant difference was observed in the baseline data of blood eosinophils between the ECRS with asthma group and the non-ECRS group (Table 1).

Table 1.

Clinical Characteristics of the Study Population.^a

	Non-ECRS (n = 25)	ECRS (asthma−) (n = 16)	ECRS (asthma+) (n = 12)	P
Male: female	15:10	14:2	10:2	NS
Age (years)	56 (28-72)	52 (29-68)	51 (34-63)	NS
Blood eosinophil count (number/μL)	234 (122-254)	440^b (350-480)	552^b (345-625)	<.05
Total IgE (IU/mL)	228	383	329	NS

Abbreviation: ECRS, eosinophilic chronic rhinosinusitis.

^a Data are shown as means with ranges in parentheses.

^b P < .05: significant difference from the other groups.

Comparison of Respiratory Function in Non-ECRS and ECRS Groups (With/Without Asthma) Before Surgery

FEV₁% was significantly lower in the ECRS with asthma group than in the non-ECRS group (P < .05). The mean FEV₁% values were 80.0 in the non-ECRS group, 77.5 in the ECRS without asthma group, and 67.6 in the ECRS with asthma group. %V50 was significantly lower in the ECRS with asthma group than in the non-ECRS group and ECRS without asthma group (P < .01). Mean %V₅₀ values were 72.7% in the non-ECRS group, 75.5% in the ECRS without asthma group, and 45.8% in the ECRS with asthma group (Figure 1).

Figure 1.

Respiratory functions in patients with chronic rhinosinusitis with nasal polyps. A, FEV₁% in patients with non- eosinophilic chronic rhinosinusitis (ECRS), ECRS without asthma, and ECRS with asthma. B, %V₅₀ in patients with non-ECRS, ECRS without asthma, and ECRS with asthma.

Comparison of FeNO Levels in Non-ECRS and ECRS Groups (With/Without Asthma) Before Surgery

The FeNO levels were significantly higher in the ECRS with asthma group than in the non-ECRS group (P < .05). The mean FeNO levels were 25.6 ppb in the non-ECRS group, 36.3 ppb in the ECRS without asthma group, and 39.8 ppb in the ECRS with asthma group (Figure 2).

Figure 2.

Fractional concentration of exhaled nitric oxide (FeNO) in patients with chronic rhinosinusitis with nasal polyps. The FeNO levels in patients with non-eosinophilic chronic rhinosinusitis (ECRS), ECRS without asthma, and ECRS with asthma.

Changes in FEV₁% and %V₅₀ in the ECRS With Asthma Group

Figure 3 shows changes in FEV1% before and after ESS in the ECRS with asthma group. FEV₁% were 67.6% and 73.0% before and after ESS, respectively. %V₅₀ were 45.8% and 58.0% before and after ESS, respectively, and were significantly different. These results indicated that ESS improved respiratory functions in the lower airway (Figure 3). There were no significant changes in FEV₁% and %V₅₀ in the non-ECRS group and ECRS without asthma group (data not shown).

Figure 3.

Respiratory functions in patients with eosinophilic chronic rhinosinusitis (ECRS) with asthma. A, FEV₁%. B, %V₅₀ measured before and after endoscopic sinus surgery (ESS).

Changes in FeNO Levels From Before to 4 Months After ESS in the ECRS With Asthma Group

Figure 4 shows changes in FeNO levels from before to 4 months after ESS in the ECRS with asthma group. Patients were followed up after surgery for at least 4 months; therefore, postoperative treatments were controlled. Three out of the 12 patients in this group used systemic and local steroids for 1 week after surgery. Furthermore, FeNO levels slightly decreased after ESS.

Figure 4.

Time course of the fractional concentration of exhaled nitric oxide (FeNO) with eosinophilic chronic rhinosinusitis (ECRS) with asthma measured before and after endoscopic sinus surgery (ESS).

The mean FeNO levels were 56.3 ppb before ESS, 24.9 ppb at 1 month, 25.1 ppb at 2 months, 25.0 ppb at 3 months, 15.5 ppb at 4 months after ESS in the ECRS with asthma group (Figure 4). There were no significant changes in FeNO levels in the non-ECRS group and ECRS without asthma group (data not shown).

Changes in ACT Scores Before and 3 Months After ESS in the ECRS With Asthma Group

The mean ACT scores in the ECRS with asthma group before and after ESS were 17.5 and 23.5, respectively. The ACT scores were significantly higher after than before ESS. These results indicated that ESS on the upper airway contributed to asthma control in the lower airways (Figure 5).

Figure 5.

Asthma Control Test (ACT) scores in patients with eosinophilic chronic rhinosinusitis (ECRS) with asthma before and after endoscopic sinus surgery (ESS).

Discussion

In the present study, FeNO levels were significantly higher in the ECRS with asthma group than in the non-ECRS group; however, no significant difference was observed between the non-ECRS group and ECRS without asthma group. Furthermore, FeNO levels decreased after ESS in the ECRS with asthma group. These results suggested that ESS for ECRS, an upper respiratory tract disease, decreased FeNO levels in the lower respiratory tract, thereby improving lower respiratory functions.

Nitric oxide is produced by resident cells (eg, airway epithelial cells, airway and circulatory endothelial cells, and trafficking inflammatory cells) in the main and peripheral airways and alveoli. It exerts various effects, and the enzyme nitric oxide synthase (NOS) is the most potent enzyme for NO synthesis. Nitric oxide synthase has 3 isoforms: neural NOS (nNOS), induced NOS (iNOS), and endothelial NOS (eNOS). Both nNOS and eNOS are constantly expressed and exert physiological and vasodilator effects, such as neurotransmission and vasodilation. On the other hand, iNOS is induced by inflammatory cytokines and produces a large amount of NO, which is a major factor in the production of NO and has been shown to contribute to tissue damage in the human nasal sinuses.¹² Human nasal sinus mucosa is physiologically important for NO production, and changes in NO may be useful for the diagnosis of nasal allergy and sinusitis and the evaluation of treatment effects.

Fraction of exhaled nitric oxide is regarded as a noninvasive and reliable marker of lower airway inflammation and is particularly useful for assessing the clinical status of patients with asthma and predicting their responsiveness to steroids.^12,15 Previous studies demonstrated that FeNO is an important biomarker of eosinophilic inflammation in lower airway diseases, such as asthma.¹⁶

We herein showed that FeNO levels were significantly higher in the ECRS with asthma group than in the non-ECRS group, suggesting that the lower airway is involved in inflammation in ECRS patients with asthma. Although FeNO may be elevated in ECRS patients with concomitant asthma, it is important to note that its levels may also be increased in those without asthma. In the present study, mean FeNO levels were slightly higher in the ECRS without asthma group than in the non-ECRS group. In addition, FeNO levels in the ECRS without asthma group were as high as 36.3 ppb, which is higher than the normal range (>25 ppb). Consistent with the previous findings,^17,18 the present results suggested that ECRS, but not non-ECRS, patients had lower airway inflammation.

Eosinophilic chronic rhinosinusitis is regarded as a common eosinophilic inflammatory disease of the upper and lower respiratory tracts rather than an eosinophilic inflammatory disease of the upper airway only. Eosinophilic chronic rhinosinusitis patients with previously undiagnosed asthma may not have exhibited significant symptoms. Some ECRS patients were found to have occult lower airway inflammation with elevated FeNO levels.¹⁹ Therefore, elevated FeNO levels in ECRS patients may be an indicator of occult asthma.

In the present study, the effects of ESS were evaluated using NO as an inflammatory biomarker of the lower airways, respiratory function tests to assess lower airway functions, and ACT as a measure of asthma symptom control. Significant improvements were observed in respiratory functions and ACT scores, suggesting that ESS, a treatment for upper airway inflammation, had a positive impact on lower respiratory functions and the clinical asthma control status. In this study, 3 of the 12 ECRS patients were treated with oral prednisolone 10 mg for 7 days after ESS, and systemic steroid administration had effects on lower airway function, asthma symptoms, and FeNO levels. Respiratory function and ACT assessments were performed 3 months after ESS, and FeNO measurements were performed monthly until 4 months after ESS. Therefore, we speculated that the administration of oral steroids did not have a significant impact on these evaluations.

Although ECRS and non-ECRS have not yet been classified, previous studies reported the effects of ESS for CRSwNP on asthma.^20
-22 Galli et al demonstrated that the removal of nasal polys by ESS reduced FeNO levels.²³ The principle for performing ESS for ECRS is to open all sinuses, making each sinus a single large cavity.

Eosinophilic chronic rhinosinusitis as an upper respiratory tract inflammatory disease and asthma as a lower respiratory tract inflammatory disease may be regarded as common upper and lower respiratory tract inflammatory diseases, and each may be involved with the other. The present results indicated that ESS for ECRS inhibited the production of FeNO, which is an inflammatory biomarker in the lower airways, contributing to improvements in respiratory functions and the asthma control status.

Although difficulties are associated with assessing the long-term effects of surgery without drug therapy, we investigated the effects of ESS on the production of FeNO by the lower airway for 4 months, and the results obtained indicated the continuous inhibition by ESS of inflammation-induced NO. The effective treatment of ECRS, including ESS, may prevent the future development of asthma in ECRS patients who do not have comorbid asthma.

The present results demonstrated that lower airway functions and NO-related inflammation were both improved by ESS. Significant improvements were also observed in ACT scores. Hamada et al reported that the relationship between the inhibition in FeNO and asthma improvement was correlated significantly.²⁴ Furthermore, a functional link was suggested between the upper and lower airway functions. As one explanation for the upper airway effect on the lower airway, cysteinyl leukotriene (Cys-LT) concentrations in ECRS patients with asthma are elevated in nasal polyps, while urinary LTD4 concentrations decreased after ESS.^19,25 Endoscopic sinus surgery may inhibit the production of Cys-LT in nasal polyps, resulting in reductions in systemic circulating Cys-LT, which suppresses eosinophilic inflammation in the lower respiratory tract.

As another explanation for nasal effects on the lower airway, the production and maturation of eosinophils in the bone marrow were accelerated by type 2 cytokines, such as interleukin 5 (IL-5), which have been linked to nasal and paranasal inflammation.²⁶ Endoscopic sinus surgery may reduce the production of IL-5 from the pathological nasal or sinus mucosa, resulting in a decrease in eosinophil numbers in peripheral blood and the attenuation of eosinophilic inflammation in the lower airways.¹⁹ Assuming that ESS controls the lower respiratory inflammation through the control of pathological mucosa in the nasal sinuses, it is important to objectively demonstrate the effects of ESS on nasal symptoms. Although we confirmed that there was no recurrence of nasal polyp in all cases during the study periods, we did not evaluate nasal symptoms, and we consider this to be one limitation of the present study.

Since ECRS often recurs after ESS, combination therapy with ESS and medical treatment, including steroids, need to be considered for its prevention.^27,28 Eosinophilic chronic rhinosinusitis is a refractory sinus disease, and the recurrence of nasal polyps is often observed after ESS surgery. Bachert et al demonstrated the efficacy and safety of dupilumab, a fully human monoclonal antibody that inhibits signaling of IL-4 and IL-13, key drivers of type 2 inflammation, in patients with ECRS despite previous treatment with systemic corticosteroids, surgery, or both.²⁹ Combination therapy with ESS and several new biologic therapies, including dupilumab, may need to be considered as a cure therapy.

In addition to the management of recurrent nasal polyps, the establishment of biomarkers that predict the early recurrence of nasal polyps is needed to prevent the recurrence of ECRS. Fraction of exhaled nitric oxide might have potential as biomarker for this purpose.

Conclusion

In the present study, we examined the effects of ESS for ECRS on the production of FeNO as well as respiratory functions and the control of asthma symptoms. Eosinophilic chronic rhinosinusitis patients, even those without asthma, had occult lower airway inflammation, as indicated by elevated FeNO levels. Endoscopic sinus surgery reduced the production of NO from the lower airway and also improved respiratory functions and asthma symptoms.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Tetsuya Terada

References

Yoshimura

Kawata

Haruna

, et al. Clinical epidemiological study of 553 patients with chronic rhinosinusitis in Japan. Allergol Int. 2011;60(4):491–496.

Tanaka

Hirota

Kamijo

, et al. Lung functions of Japanese patients with chronic rhinosinusitis who underwent endoscopic sinus surgery. Allergol Int. 2014;63(1):27–35.

Fokkens

Lund

Mullol

, et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. a summary for otorhinolaryngologists. Rhinology. 2012;50(1):1–12.

Lundberg

Weitzberg

. Nasal nitric oxide in man. Thorax. 1999;54(10):947–952.

Scadding

. Nitric oxide in the airways. Curr Opin Otolaryngol Head Neck Surg. 2007;15(4):258–263.

Walford

Doherty

. Diagnosis and management of eosinophilic asthma: a US perspective. J Asthma Allergy. 2014;7:53–65.

Lötvall

Akdis

Bacharier

, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355–360.

Meltzer

Hamilos

Hadley

, et al. Rhinosinusitis: establishing definitions for clinical research and patient care. J Allergy Clin Immunol. 2004;114(6 suppl):S156–S212.

Majid

Kao

. Utility of exhaled nitric oxide in the diagnosis and management of asthma. Curr Opin Pulm Med. 2010;16(1):42–47.

10.

Saito

Inoue

Sugawara

, et al. Exhaled nitric oxide as a marker of airway inflammation for an epidemiologic study in schoolchildren. J Allergy Clin Immunol. 2004;114(3):512–516.

11.

Takeno

Hirakawa

Ishino

. Pathological mechanisms and clinical features of eosinophilic chronic rhinosinusitis in the Japanese population. Allergol Int. 2010;59(3):247-256.

12.

Barnes

Dweik

Gelb

, et al. Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest. 2010;138(3):682–692.

13.

American Thoracic Society; European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171(8):912–930.

14.

Nathan

Sorkness

Kosinski

, et al. Development of the Asthma Control Test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113(1):59–65.

15.

Strunk

Szefler

Phillips

, et al. Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children. J Allergy Clin Immunol. 2003;112(5):883–892.

16.

Lee

Choi

. Exhaled nitric oxide measurement is useful for the exclusion of nonasthmatic eosinophilic bronchitis in patients with chronic cough. Chest. 2008;134(5):990–995.

17.

Takeno

Taruya

Ueda

Noda

Hirakawa

. Increased exhaled nitric oxide and its oxidation metabolism in eosinophilic chronic rhinosinusitis. Auris Nasus Larynx. 2013;40(5):458–464.

18.

Guida

Rolla

Badiu

, et al. Determinants of exhaled nitric oxide in chronic rhinosinusitis. Chest. 2010;137(3):658–664.

19.

Kambara

Minami

Akazawa

, et al. Lower airway inflammation in eosinophilic chronic rhinosinusitis as determined by exhaled nitric oxide. Int Arch Allergy Immunol. 2017;173(4):225-232.

20.

Batra

Kern

Tripathi

, et al. Outcome analysis of endoscopic sinus surgery in patients with nasal polyps and asthma. Laryngoscope. 2003;113(10):1703–1706.

21.

Ragab

Scadding

Lund

Saleh

. Treatment of chronic rhinosinusitis and its effects on asthma. Eur Respir J. 2006;28(1):68–74.

22.

Uri

Cohen-Kerem

Barzilai

Greenberg

Doweck

Weiler-Ravell

. Functional endoscopic sinus surgery in the treatment of massive polyposis in asthmatic patients. J Laryngol Otol. 2002;116(3):185–189.

23.

Galli

Montuschi

Passàli

Laruffa

Parrilla

Paludetti

. Exhaled nitric oxide measurement in patients affected by nasal polyposis. Otolaryngol Head Neck Surg. 2012;147(2):351–356.

24.

Hamada

Oishi

Chikumoto

, et al. Impact of sinus surgery on type 2 airway and systemic inflammation in asthma. J Asthma. 2021;58(6):750–758.

25.

Higashi

Taniguchi

Mita

, et al. Clinical features of asthmatic patients with increased urinary leukotriene E4 excretion (hyperleukotrienuria): involvement of chronic hyperplastic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol. 2004;113(2):277–283.

26.

Passalacqua

Canonica

. Impact of rhinitis on airway inflammation: biological and therapeutic implications. Respir Res. 2001;2(6):320–323.

27.

Para

Clayton

Peters

. Management of rhinosinusitis: an evidence based approach. Curr Opin Allergy Clin Immunol. 2016;16(4):383–389.

28.

Bachert

Mannent

Naclerio

, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA. 2016;315(5):469–479.

29.