The Role of Upper and Lower Airway Patency in Chronic Rhinosinusitis With Nasal Polyps and Asthma

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1 The Laryngoscope VC 2012 The American Laryngological, Rhinological and Otological Society, Inc. The Role of Upper and Lower Airway Patency in Chronic Rhinosinusitis With Nasal Polyps and Asthma Zhenxiao Huang, MD; Bing Zhou, MD; Qi Zhang, MD; Qian Huang, MD; Yan Sun, MD; Mingjie Wang, MD, PhD; Xiangdong Wang, MD; Chengshuo Wang, MD; Yunchuan Li, MD; Shunjiu Cui, MD Objectives/Hypothesis: To investigate the role of airway patency and factors associated with airway patency in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma. Study Design: Retrospective study. Methods: The upper and lower airway patency of 140 patients with CRSwNP and asthma (asthma group) and 42 patients with CRSwNP without asthma (nonasthma control group) was measured using acoustic rhinometry, rhinomanometry, and spirometry. Total serum immunoglobulin E and eosinophil counts were also compared. The severity of nasal diseases in these patients was assessed via the Lund Mackay score (LMS) and Lund Kennedy score (LKS). Results: There was no difference between the asthma and nonasthma groups in terms of total nasal resistance at 75 Pa (R 75T ), bilateral minimum cross-sectional area (MCA RþL ), or bilateral nasal cavity volume between 0 and 7.0 cm 3 (V7 RþL ). Forced expiratory volume in 1 second (FEV 1 ) and forced expiratory flow between 25% and 75% of forced vital capacity (FEF ) of the asthma group were significantly lower than those of the nonasthma group. FEV 1 and FEF were not correlated with R 75T, MCA RþL,V7 RþL, or severity of nasal disease. For the patients with asthma, LMS and serum eosinophil counts were independent predictors of MCA RþL. Conclusions: The presence of asthma may not influence upper airway patency in CRSwNP patients. In CRSwNP patients with asthma, impairment of upper airway patency was associated with changes in LMS and eosinophilia, and in these patients lower airway patency was significantly lower than that of the control group (without asthma). In CRSwNP patients with asthma, there was little or no association between upper and lower airway patency. Key Words: Chronic rhinosinusitis, asthma, airway patency, lung function. Level of Evidence: Level of Evidence: 3b. Laryngoscope, 123: , 2013 INTRODUCTION Chronic rhinosinusitis (CRS) and allergic rhinitis are the most common comorbidities among patients with asthma, 1,2 and they share similar inflammatory responses and histopathology. A large body of evidence from clinical epidemiology, pathophysiology, histology, and treatment outcomes supports the concept of a unified airway in which signs of disease in one part of the respiratory tract should be considered a disease of the whole. This concept is sometimes expressed as one way, one disease. 2 4 From the Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital and Key Laboratory of Otolaryngology Head and Neck Surgery, Capital Medical University, Ministry of Education, Beijing, China. Editor s Note: This Manuscript was accepted for publication July 17, This study was supported by grants from the Beijing Municipal Health Bureau (No ) and the National Natural Science Foundation of China (No ). The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Bing Zhou, MD, Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, No. 1 Dong Jiao Min Xiang, Dongcheng District, Beijing, , P. R. China. entzhou@263.net DOI: /lary The prevalence of CRS in the general population is 5% to 16%, 5 8 and among CRS patients the prevalence of asthma is 20%. Yet it was found that in patients with asthma, the prevalence of nasal symptoms and CRS was 85% to 95%. 3 Furthermore, recent studies showed that patients with chronic obstructive pulmonary disease (COPD), nonallergic asthma, or bronchiectasis had increased nasal symptoms and more nasal inflammation Associations between upper and lower airway inflammatory diseases, asthma development, and other lung diseases are not fully understood. Complete airway patency, or open, clear nasal and tracheobronchial passages for air exchange, is dependent on the dimension of the airway, airflow volume, and resistance in both the upper and lower airways The degree of airway patency is commonly measured using rhinometry, rhinomanometry, and spirometry. 15,16 Currently, total nasal resistance, minimum cross-sectional area (MCA), nasal cavity volume, forced expiratory volume in 1 second (FEV 1 ), and forced expiratory flow between 25% and 75% of forced vital capacity (FEF ) are the most frequently used parameters to assess upper and lower airway patency. 12,13 Studies have shown an association between the patency of the upper and lower airways in young children and patients with COPD. 17,18 However, there is little information about upper and lower airway patency in patients with both CRS with nasal polyps (CRSwNP) and asthma. 569

2 TABLE I. Demographic and Clinical Characteristics of CRSwNP Patients With or Without Asthma. Characteristic CRSwNP þ Asthma, n ¼ 140 CRSwNP Only, n ¼ 42 P Age, yr (range) 47 (18 67) 48 (24 70).12 Gender, M:F 78:62 29:13.12 Body mass index Duration of CRS, yr (range) 6 (0.5 40) 6.5 (0.3 52).54 Nonsmokers:smokers 109:31 30:12.39 Atopy, No. [%] 22 [15.7] 7 [16.6].88 LMS (range) 19 (4 24) 15.5 (2 24) <.001* LKS (range) 10 (4 16) 7.2 (2 14).001* R 75T,Pacm 3 s 1 (range) 0.24 (0 18.7) 0.24 (0 1.8).96 V7 RþL,cm 3 (range) 13.7 ( ) 13 ( ).85 MCA RþL,cm 2 (range) 1.03 ( 0.77 to 2.41) 1.04 ( 0.89 to 4.84).72 FEV 1, % of predicted <.001 * FEF 25 75, % of predicted <.001* Total serum IgE, ku/l 115 (2 1,856) 61 (2 591).004* Serum eosinophils, cells/l 0.5 ( ) 0.3 ( ) <.001* *P <.01. CRSwNP ¼ chronic rhinosinusitis with nasal polyps; M ¼ male; F ¼ female; CRS ¼ chronic rhinosinusitis; LMS ¼ Lund Mackay score; LKS ¼ Lund Kennedy endoscopic score; R 75T ¼ total nasal resistance at 75 Pa; V7 RþL ¼ bilateral nasal cavity volume between 0 and 7.0 cm 3 ; MCA RþL ¼ bilateral minimum cross-sectional area; FEV 1 ¼ forced expiratory volume in 1 second; FEF ¼ forced expiratory flow between 25% and 75% of forced vital capacity; IgE ¼ immunoglobulin E. Thus, the aim of this study was to test the role of airway patency in CRSwNP with asthma, and investigate the potential factors that affect upper and lower airway patency in CRSwNP with asthma. MATERIALS AND METHODS Subjects and Study Design This study was a retrospective analysis of CRSwNP patients with and without asthma who underwent endoscopic sinus surgery at the Department of Otorhinolaryngology of Beijing Tongren Hospital between April 2008 and August CRSwNP was diagnosed in these patients based on: 1) the presence of symptoms for 12 weeks, including nasal obstruction, nasal discharges, facial pressure, or decreased sense of smell; 2) either endoscopic signs or computed tomographic (CT) images showing mucosal changes within the ostiomeatal complex, sinuses, or both 19 ; and 3) a postoperative histopathology diagnosis of nasal polyps or chronic inflammation of the sinus mucosa. CRSwNP patients with bronchial asthma were diagnosed and managed by respiratory physicians. A diagnosis of asthma was made either via a positive methacholine challenge test result or bronchodilator response. The study included 182 CRSwNP patients in two groups: those with asthma (n ¼ 140; the asthma group), and those without asthma (n ¼ 42; the nonasthma control group). All subjects were between the ages of 18 and 70 years. Their CRSwNP was refractory to medical management. None of the patients had acute upper respiratory infections, COPD, bronchiectasis, pregnancy, cystic fibrosis, primary ciliary dysfunction, or Kartagener syndrome. Objective Measurements Upper airway patency. Three important variables for upper (i.e., nasal) airway patency were measured: bilateral MCA (in cm 2 ), bilateral nasal cavity volume between 0 and 7.0 cm 3 (V7; in cm 3 ), and total nasal resistance at 75 Pa (R 75T ;in Pacm 3 s 1 ). Eccovision acoustic rhinometry (Hood Laboratories, Pembroke, MA) was used to measure MCA and V7. Bilateral MCA and V7 volume were obtained with the formulas: MCA RþL ¼ MCA L þ MCA R, and V7 RþL ¼ V7 L þ V7 R, respectively, where L represents left, and R represents right. An ATMOS 300 anterior active rhinomanometer (ATMOS Medizin Technik, Lenzkirch, Germany) was used to measure R 75T. All patients were seated calmly with mouth closed. A pressure sensor was placed in the contralateral nostril to record data by air flow sensor. R 75T was obtained with the formula: R 75T ¼ left nasal resistance right nasal resistance/(left nasal resistance þ right nasal resistance). Lower airway patency. FEV 1 and FEF were tested in patients using a computerized, pneumotachograph spirometer (Ecoscreen; Jaeger, Hoechberg, Germany). FEV 1 and FEF <80% of predicated value were considered an indication of impairment of lung function. CT and endoscopic scoring. The Lund Mackay score (LMS) was use to rank the subjective appearance of the CT scan. 20 The sinus groups included the maxillary, anterior ethmoidal, posterior ethmoidal, sphenoidal, and frontal sinuses. The possible score for each side ranged from 0 to 12, and the total score from 0 to 24. The Lund Kennedy endoscopic score (LKS) was used to rank the subjective appearance of the sinus endoscopy. 20 The items for measurement included polyp, edema, discharge, scarring, and crusting. The possible scores for each side were 0 to 10, and the total ranged from 0 to 20. Two investigators who were blinded to the patient groups evaluated all the LKS scores. Total serum immunoglobulin E levels and serum eosinophil counts. The levels of total serum immunoglobulin E (IgE), and IgEs specific for common inhalants and food allergens, were measured using a UniCAP system (Phadia, Uppsala, Sweden). The concentrations of specific IgE antibodies 0.35 ku/l were considered atopic. Serum eosinophil counts were 570

3 Fig. 1. Forced expiratory volume in 1 second (FEV 1 ) and forced expiratory flow between 25% and 75% of forced vital capacity (FEF ) in the asthma and nonasthma groups. FEV 1 and FEF were measured in patients using a computerized, pneumotachograph spirometer (Jaeger). FEV 1 and FEF <80% of predicted was considered an indication of impaired lung function. The average FEV 1 and FEF of the asthma group were significantly lower than those of the nonasthma controls. Bar graphs represent mean and standard deviation. P <.001 indicates significant difference between the two groups. examined with a hematology system (XE-2100; Sysmex, Kobe, Japan). Statistical Analysis Statistical analyses were performed using SPSS for Windows 17.0 (SPSS Inc, Chicago, IL). The Kolmogorov Smirnov test was used to assess the normality of distributions. The paired t test, Mann Whitney U test, and v 2 tests were used to evaluate the degree of differences between the two groups. Correlations were analyzed with Spearman correlation coefficient test. Multiple regressions were used to examine associations between predictors and rhinomanometric, acoustic rhinometric, and spirometric variables. A P value <.05 was considered a significant difference. RESULTS Patients Characteristics There was no difference between the asthma and control groups in terms of age, gender, body mass index, duration of CRS, or smoking and atopic status. Neither were there differences in R 75T, V7 RþL, or MCA RþL between the two groups (Table I). Total serum IgE levels and serum eosinophils were significantly higher in the asthma group compared with the nonasthma group (P ¼.004 and P <.001, respectively). In addition, the LMS and LKS of the asthma group were significantly higher than those of the nonasthma group (P <.01 and P ¼ 0.001, respectively). The V7 RþL, and MCA RþL of the two CRSwNP groups of this study were significantly lower compared with these parameters in healthy individuals (unpublished data not shown). FEV 1 and FEF were significantly lower in the asthma group compared with the nonasthma group (both P <.001; Table I and Fig. 1). Correlation Analyses Relatedness of upper and lower airway patency. There were no significant correlations found among FEV 1, FEF 25 75, MCA RþL,V7 RþL, and R 75T in the asthma group. Relatedness of airway patency and other variables. There were no significant correlations found among FEV 1, FEF 25 75, duration of CRS, total serum IgE, serum eosinophils, LMS, and LKS in the asthma group (Table II). However, MCA RþL and V7 RþL were negatively correlated with serum eosinophils in the asthma group (r ¼ and 0.221; P ¼.008 and.009, respectively; Fig. 2 and Table III). In addition, MCA RþL was negatively correlated with LMS in the asthma group (r ¼ 0.22; P ¼.009; Table III). A multiple regression analysis model was constructed of MCA RþL, and it was found that LMS and serum eosinophils were independent variables predicting changes in MCA RþL (P ¼.023 and P ¼.039, respectively; Table IV). DISCUSSION This study found that among these CRSwNP patients, both the asthma and nonasthma groups had TABLE II. Spearman Correlation Coefficients for Lower Airway Patency and Variables in the Asthma Group* Age, r CRS, r IgE, r LMS, r LKS, r R 75T, r MCA RþL, r V7 RþL, r EC, r FEV 1 FEF *No significant correlation between lower airway patency and other variables was observed. Duration. Percentage of predicted. CRS ¼ chronic rhinosinusitis; IgE ¼ immunoglobulin E; LMS ¼ Lund Mackay score; LKS ¼ Lund Kennedy endoscopic score; R 75T ¼ total nasal resistance at 75 Pa; MCA RþL ¼ bilateral minimum cross-sectional area; V7 RþL ¼ bilateral nasal cavity volume between 0 and 7.0 cm 3 ;EC¼eosinophil cell; FEV 1 ¼ forced expiratory volume in 1 second; FEF ¼ forced expiratory flow between 25% and 75% of forced vital capacity. 571

4 TABLE IV. Bilateral Minimum Cross-Sectional Area Linear Regression Model Summary of the Asthma Group (R ). B SD b P Constant Age Gender Duration of CRS LKS LMS* Total serum IgE Serum eosinophils* Fig. 2. Association between upper airway patency and serum eosinophil counts in the asthma group. The figure illustrates the correlation between bilateral nasal cavity volume between 0 and 7.0 cm 3 (V7 RþL ) and serum eosinophil counts in 140 patients in the asthma group as determined by Spearman correlation coefficient test (r ¼ 0.221, P ¼.009). similar upper airway patency, and that in the asthma group impairment of upper airway patency was related to serum eosinophils and radiological severity of nasal disease. The correlation was supported by multiple linear regression analysis. After taking age, gender, duration of CRS, and LKS into consideration, the independent predictors of MCA RþL were serum eosinophils and LMS. The model (r 2 ¼ 0.11) showed that 11% of the change in MCA RþL could be explained by changes in serum eosinophils and LMS in our cohort study. Nasal patency has been reported to correlate with changes in nasal lavage and systemic eosinophilic inflammatory markers. 17,21 Consistent with this, our study provides the new finding that systemic eosinophilic inflammatory response could also be correlated with changes in nasal patency. Another recent study reported that impaired nasal patency might be a marker of upper airway inflammation in patients with rhinitis and asthma. 22 Hellgren et al. 23 found that nasal patency in patients with asthma without CRS was significantly lower than that of healthy controls, and indicated that reduced nasal patency was driven by lower airway disease. However, our results suggest that impairment of TABLE III. Spearman Correlation Coefficients for Upper Airway Patency and Variables in the Asthma Group. Age, r CRS, r* IgE, r LMS, r LKS, r EC, r R 75T MCA RþL V7 RþL *Duration. P <.01. CRS ¼ chronic rhinosinusitis; IgE ¼ immunoglobulin E; LMS ¼ Lund Mackay score; LKS ¼ Lund Kennedy endoscopic score; EC ¼ eosinophil cell; R 75T ¼ total nasal resistance at 75 Pa; MCA RþL ¼ bilateral minimum cross-sectional area; V7 RþL ¼ bilateral nasal cavity volume between 0 and 7.0 cm *P <.05. SD ¼ standard deviation; CRS ¼ chronic rhinosinusitis; LKS ¼ Lund Kennedy endoscopic score; LMS ¼ Lund Mackay score; IgE ¼ immunoglobulin E. nasal patency driven by asthma is less significant in the presence of sinonasal diseases. Our study showed that the asthma group had a significantly lower airway patency than the nonasthma group, although the two groups had been matched according to gender, age, body mass index, duration of disease, and smoking status. This result suggests that the asthma group had more severe impairment in lung function than did the nonasthma group. Note that FEV 1 and FEF in the asthma group were not correlated with duration of nasal disease, LMS, LKS, or serum eosinophils. These findings were consistent with reports by Dixon et al. 1 and Williamson et al., 24 in which a disassociation was shown between duration and severity of nasal disease, and lung functions in patients with asthma. Also, both upper and lower airways were considered to be related to nasobronchial reflex, postnasal drainage inflammatory mediators, common mucosal susceptibility, and systemic amplification. 3 The lack of connection between severity of nasal lesion and lung function might suggest that impairment in lower airway patency could be mediated through mechanisms other than the postnasal drainage of inflammatory mediators. CRSwNP with asthma exists as part of a systemic inflammatory disease. However, airway tissue remodeling in the nose appears to be far less severe than in the lungs. 25 This may account for the difference by some measures of severity between the upper and lower airways. A previous report showed that inflammation in the paranasal sinus might cause lung disease, or vice versa, via the release of eosinophils from bone marrow and inflammatory progenitors. 26 Disease severity in the nose and sinuses was also similar to that of the lung in asthmatics. 1 Two studies found an association between upper and lower airway patency in normal children 6 years old and those with COPD. 17,18 However, this association has not been reported in patients with CRSwNP and asthma. Our study found that in patients with CRSwNP and asthma, upper airway patency was not correlated with lower airway patency. This lack of association between upper and lower airway diseases makes it

5 difficult to reach the conclusion that severity of nasal disease has a profound effect on lower airway dysfunction. Thus, more studies are needed to elucidate this. There is growing evidence that asthmatic CRS patients have more severe nasal lesions than nonasthmatic CRS patients. 27,28 Pearlman et al. 29 found that in CRS patients, the mean LMS was higher in those with asthma and nasal polyps (regardless of atopic status) than in those without asthma. Our study showed that both the LMS and LKS of the asthma group were higher than those of the nonasthma group. The close similarities in physiology between CRSwNP and asthma have been noted. 30,31 Consistent with other studies, 24,32 our results showed that total serum IgE and eosinophils were significantly elevated in the asthma group compared with the nonasthma group, and high levels of IgE could be considered a risk factor for rhinitis and asthma development. 33 Together, these results suggest that systemic eosinophilic inflammation in patients with asthma might affect the mucosal status and nasal volume, and worsen the severity of CRSwNP. We should point out that our study was limited by its retrospective nature, in that we were not able to establish a pathophysiological connection between upper and lower airflow with the acoustic rhinometry, rhinomanometry, and spirometry data available to us. A histological study on nasal and bronchial tissue biopsy would be desirable, especially after nasal and bronchial provocation. CONCLUSION The present study found that CRSwNP causes impairment of upper airway patency that is independent of asthma. However, lower airway patency in patients with both CRSwNP and asthma was significantly lower than in CRSwNP patients without asthma. In CRSwNP patients with asthma, upper airway patency was reversely correlated with inflammatory responses and radiological severity of nasal diseases. This correlation was not true of lower airway patency in these patients. We found no association between upper and lower airway patency in patients with CRSwNP and asthma. Furthermore, the severity of disease as assessed through radiologic and endoscopic procedures was more severe in CRSwNP patients with asthma than in those without asthma. BIBLIOGRAPHY 1. Dixon AE, Kaminsky DA, Holbrook JT, Wise RA, Shade DM, Irvin CG. Allergic rhinitis and sinusitis in asthma. Chest 2006;130: Bachert C, Vignola AM, Gevaert P, Leynaert B, Van Cauwenberge P, Bousquet J. 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