Chronic rhinosinusitis (CRS) is an inflammatory disease

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1 Original Research Sinonasal Disorders Association between Asthma and Chronic Rhinosinusitis Severity in the Context of Asthma Control Otolaryngology Head and Neck Surgery 2018, Vol. 158(2) Ó American Academy of Otolaryngology Head and Neck Surgery Foundation 2017 Reprints and permission: sagepub.com/journalspermissions.nav DOI: / Adam P. Campbell, MD 1,2, Katie M. Phillips, MD 1,2, Lloyd P. Hoehle 1,2, Robert A. Gaudin, MD 3, David S. Caradonna, MD, DMD 1,4, Stacey T. Gray, MD 1,2, and Ahmad R. Sedaghat, MD, PhD 1,2,4,5 No sponsorships or competing interests have been disclosed for this article. Abstract Objective. Comorbid asthma is associated with decreased quality of life (QOL) in chronic rhinosinusitis (CRS). It is unclear whether this association is independent of the patients clinical asthma status. We therefore sought to determine if asthma is associated with lower QOL in CRS, independent of asthma control. Study Design. Cross-sectional cohort study of 350 patients with CRS. Setting. Tertiary academic rhinology clinic. Subjects and Methods. In total, 350 participants with CRS were recruited and 28.3% were asthmatic. CRS-specific QOL was measured using the 22-item Sinonasal Outcome Test (SNOT-22). Asthma control was assessed with the Asthma Control Test (ACT). General health-related QOL was assessed with the EuroQoL 5-dimensional general health-related quality of life survey visual analog scale (EQ- 5D VAS). Associations were sought between SNOT-22 and EQ-5D VAS (dependent variables) and asthma (independent variable), while controlling for ACT. ACT score for patients with CRS without asthma was set at 25 (indicating completely controlled, asymptomatic asthma). Results. Comorbid asthma was associated with SNOT-22 (b = 11.8; 95% confidence interval [CI], ; P \.001) and EQ-5D VAS (b = 26.2; 95% CI, to 21.3; P =.014). After controlling for ACT, asthma was no longer associated with SNOT-22 (P =.147) or EQ-5D VAS (P =.994). Instead, ACT score was associated with SNOT-22 (b = 22.1; 95% CI, 23.2 to 21.1; P \.001) and EQ-5D VAS (b = 2.1; 95% CI, 1.1 to 3.0; P \.001). ACT score completely drove the association between asthma and worse QOL. Conclusion. Comorbid asthma is not necessarily reflective of decreased QOL in CRS. The association of comorbid asthma with lower QOL in CRS is related to the clinical status (eg, control) of asthma. Keywords chronic rhinosinusitis, CRS, sinonasal symptoms, asthma, asthma control test, ACT, SNOT-22, EQ5D-VAS Received May 24, 2017; revised July 11, 2017; accepted August 9, Chronic rhinosinusitis (CRS) is an inflammatory disease of the sinonasal mucosa that causes a significant decrease in patients quality of life (QOL). This decrease in QOL is typically due to chronic sinonasal symptomatology, acute CRS exacerbations, and comorbid pulmonary conditions. 1-3 Previous studies have highlighted the heterogeneous nature of this disease by identifying multiple inflammatory mechanisms 4-6 as potential etiologic agents of CRS, which may all lead to the chronic airway inflammation and clinical phenotype that define the disease. 7 As inflammatory disorders of airway mucosa, asthma and CRS are commonly comorbid. Over 40% of patients diagnosed with asthma have comorbid CRS, 8 and 50% of patients with CRS with nasal polyps also have asthma. 9 The epidemiologic relationship between CRS and asthma forms the basis of the unified airway theory, which is supported by evidence that antigenic stimulation of one site can trigger an inflammatory reaction in the other and that their 1 Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA 2 Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA 3 Department of Oral and Maxillofacial Surgery, Charité University Medical Center Berlin, Berlin, Germany 4 Division of Otolaryngology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA 5 Department of Otolaryngology and Communications Enhancement, Boston Children s Hospital, Boston, Massachusetts, USA Corresponding Author: Ahmad R. Sedaghat, MD, PhD, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA. ahmad_sedaghat@meei.harvard.edu

2 Campbell et al 387 development may be related In addition, prior studies have shown that medical treatment of rhinitis or rhinosinusitis can lead to improved pulmonary outcomes in asthmatic patients Previous studies have linked the diagnosis of asthma to greater severity of CRS disease. In particular, asthmatic patients have been shown to have worse radiographic CRS disease severity based on Lund-MacKay scores, 22 and those with worse asthma severity have higher Lund-MacKay scores. 23 CRS has also been associated with increased frequency of asthma exacerbations, 24,25 and increasing sinonasal symptom severity has been associated with decreased asthma control in patients with CRS and asthma. 2,26 Despite this prior work, the nature of the exact associative relationship between comorbid asthma and the severity of sinonasal symptomatology in CRS remains unclear. In this study, we sought to characterize the association between asthma and patient-reported outcome measures (PROMs) of CRS, including sinonasal symptomatology and general health-related QOL. Since the specific impact of asthma on asthmatics may be highly variable depending on the clinical status of the asthma, 27 we also sought to determine how any association between asthma and CRS-related PROMs might be affected by the degree of asthma control. Asthma control is a well-established and measurable outcome measure for asthma that encompasses the frequency of symptom exacerbations, the need for rescue medications, and the overall impact of the disease on a patient s day-today activities. 27 We hypothesized that asthma would be associated with more severe sinonasal symptoms and decreased general health-related QOL and that this association would be modified by the degree of asthma control experienced by asthmatic patients with CRS. Methods Study Participants The Massachusetts Eye and Ear Infirmary Human Studies Committee approved this study. We prospectively recruited adult patients aged 18 years or older who met established consensus guideline criteria for CRS. 28 All study participants provided informed consent for inclusion in this study. To narrow the study population to patients with CRS and avoid any patients with systemic disease with sinonasal manifestations, exclusion criteria were created, including comorbid diagnoses of vasculitis, cystic fibrosis, sarcoidosis, and immunodeficiency. Also, to avoid confounding results due to treatment, any patient who had undergone sinonasal surgery in the past 6 months was excluded. Study Design and Data Collection This is a cross-sectional cohort study. A total of 350 study participants were recruited. All data were collected at the time of enrollment into the study. The age, sex, race, history of sinus surgery, intranasal steroid use, and smoking history of all participants were recorded from each participant. At enrollment, participants were asked by the evaluating rhinologist to report a history of aeroallergen hypersensitivity based on formal allergy testing and aspirin sensitivity based on a clinical history or formal testing. The presence of nasal polyps was determined based on nasal endoscopy by the evaluating rhinologist. Patients were considered asthmatic from prior diagnosis made based on clinical consensus guidelines. 29 All asthmatic patients were being treated with at least an albuterol rescue inhaler, to be used on an as-needed basis. Asthmatic patients were also asked to report whether they were using an inhaled corticosteroid at the time of enrollment. All participants completed a 22-item Sinonasal Outcome Test (SNOT-22) 30 survey to measure CRS symptom severity and the EuroQol 5-dimensional (EQ-5D) general 31 health survey and visual analog scale (EQ-5D VAS), which reflects general health-related QOL. Asthma control was assessed with the Asthma Control Test (ACT). 32,33 Statistical Analysis All analysis was performed with the statistical software package R ( Patients with CRS without asthma were assigned an ACT score of 25, which is the maximum score possible and indicates completely controlled, asymptomatic asthma. All associations with asthma (as an independent variable) and SNOT-22 and EQ-5D VAS scores (as dependent variables) were investigated with linear regression analysis. Multivariable models were then used to evaluate these associations controlling for participant age, sex, aeroallergen hypersensitivity, polyps, and intranasal steroid use. Next, we controlled for asthma control by including ACT scores in the multivariable model. Multivariable models used to study these associations controlled for participant age, sex, aeroallergen hypersensitivity, asthma, polyps, and intranasal steroid use. Results Characteristics of Study Participants A total of 350 patients (51.3% male, 48.7% female) were enrolled in the study with a mean (standard deviation [SD]) age of 51.9 (15.7) years (95% confidence interval [CI], ), and their characteristics are summarized in Table 1. Of those enrolled, 28.3% had a history of asthma, 24.9% were active or former smokers, and 45.7% had a history of aeroallergen hypersensitivity. With respect to CRS characteristics, 43.1% of study participants had nasal polyps and 34.0% had undergone prior endoscopic sinus surgery. The mean (SD) SNOT-22 score was 32.7 (22.0; 95% CI, 1-80), and the mean (SD) EQ-5D VAS score was 74.4 (18.6; 95% CI, ). Among patients with asthma, the mean (SD) ACT score was 20.1 (4.8; 95% CI, 8-25), and 48.5% were on a long-term inhaled corticosteroid. Asthma Status Is Associated with Sinonasal QOL In this study, we first determined that asthma was associated with worse sinonasal QOL, as reflected by higher SNOT- 22, on univariate analysis (b = 13.7; 95% CI, ; P \.001). We then tested whether asthma was associated with

3 388 Otolaryngology Head and Neck Surgery 158(2) Table 1. Characteristics of Study Participants (N = 350). Characteristic Value Demographics Age, mean (SD), y 51.9 (15.7) Sex, % Male 51.3 Female 48.7 Race, % White 59.7 Black or African American 1.4 American Indian/Alaskan Native 0.6 Asian 2.9 Declined to respond 35.4 Smoking, % 24.9 Clinical characteristics Aeroallergen hypersensitivity, % 45.7 Asthma, % 28.3 ACT score, a mean (SD) 20.1 (4.8) CRS characteristics Nasal polyps, % 43.1 Previous sinus surgery, % 34.0 Intranasal steroid use, % 46.3 SNOT-22 score, mean (SD) 32.7 (22.0) EQ-5D VAS, mean (SD) 74.4 (18.6) Abbreviations: ACT, Asthma Control Test; CRS, chronic rhinosinusitis; EQ- 5D, EuroQol 5-dimensional general health survey; SD, standard deviation; SNOT-22, 22-item Sinonasal Outcome Test; VAS, visual analog scale. a In asthmatic participants. the SNOT-22 score in multivariable linear regression analysis controlling for age, sex, smoking, polyps, aeroallergen hypersensitivity, and intranasal steroid use. Using this multivariable model, asthma was still associated with a higher SNOT-22 score (b = 11.8; 95% CI, ; P \.001). However, there was no longer a statistically significant association between asthma and SNOT-22 score (b = 6.0; 95% CI, 2.1 to 14.1; P =.147) after the addition of ACT score as a covariate to our multivariable model. In contrast, while simply having comorbid asthma was not associated with SNOT-22, in this multivariable model, ACT score was significantly associated with SNOT-22 score (b = 22.1; 95% CI, 23.2 to 21.1; P \.001). Stratifying study participants by the presence of nasal polyps or smoking status did not qualitatively change the associations we found between comorbid asthma, ACT score, and SNOT-22 score. In other words, in participants with or without nasal polyps, who were smokers or nonsmokers, ACT score was significantly associated with SNOT-22 while just having comorbid asthma was not using our multivariable model. Asthma Status Is Associated with Worse General Health-Related QOL We next determined that asthma was associated with worse general health-related QOL, reflected by lower EQ-5D VAS scores, on univariate analysis (b = 25.3; 95% CI, 29.6 to 21.0; P =.016). After controlling for age, sex, smoking, polyps, aeroallergen hypersensitivity, and intranasal steroid use, asthma remained associated with lower EQ-5D VAS scores (b = 26.2; 95% CI, to 21.3; P =.014). However, there was no longer a statistically significant association between asthma and EQ-5D VAS (b = 0.0; 95% CI, 27.2 to 7.3; P =.994) after adding ACT score as a covariate to our multivariable model. In contrast, while simply having comorbid asthma was not associated with EQ-5D VAS, in this multivariable model, ACT score was significantly associated with EQ-5D VAS scores (b = 2.1; 95% CI, ; P \.001). As was the case with sinonasal QOL, stratifying study participants by the presence of nasal polyps or smoking status did not qualitatively change the associations between comorbid asthma, ACT score, and EQ-5D VAS. For participants with or without nasal polyps, who were smokers or nonsmokers, ACT score was significantly associated with EQ-5D VAS while just having comorbid asthma was not using our multivariable model. Discussion Asthma and comorbid CRS are heavily linked epidemiologically, and up to 40% of asthmatics have comorbid CRS. 8 Previous studies have evaluated the impact of CRS on comorbid asthma and have shown that in asthmatic patients, comorbid CRS is associated with increased frequency of emergency room visits, hospitalizations, and systemic corticosteroid use secondary to asthma. 24,34 Asthmatics with comorbid CRS have also been shown to have worse pulmonary function and decreased asthma-specific and general QOL outcomes than patients with asthma alone. 35 In comparison, comorbid asthma in CRS has been shown to be associated with worse radiographic evidence of sinus disease than nonasthmatic patients with CRS, 22 and greater asthma severity is associated with worse radiographic disease in patients with CRS with asthma. 23 Unfortunately, radiographic evaluation of CRS has not been shown to correlate well with PROMs. 36 While it is intuitive that patients with asthma and CRS have an overall worse QOL and more severe sinonasal symptomatology, it remains unclear how this association is modulated by the clinical status of the asthma. Filling this gap in knowledge is important to both the clinician and patient as it provides information regarding the relationship between CRS and asthma. In this study, we found that while comorbid asthma was associated with more severe sinonasal symptomatology and worse general healthrelated QOL in CRS, this association was entirely dependent on the level of asthma control. Previous work has demonstrated a clear clinical link in the disease courses of CRS and asthma when these conditions are concomitantly present. The severity of CRS is associated with the degree of asthma control in asthmatic patients with CRS. 2 In addition, treatment of CRS has been shown to improve asthma outcome measures in asthmatic patients with CRS. Medical and surgical treatment of CRS in children with asthma has been shown to decrease

4 Campbell et al 389 bronchial hyperresponsiveness. 21 In adult asthmatic patients with CRS, endoscopic sinus surgery has led to improved sinonasal symptomatology and improved asthma control, decreased frequency of asthma attacks, and decreased asthma-related medication use. 37,38 Patients with CRS with asthma tend to have evidence of more severe CRS than patients with CRS without asthma. 2,39 However, no study has sought to determine whether this association between comorbid asthma and more severe CRS may be due to some intrinsic property of the asthma or if this association is modulated by the clinical status of the comorbid asthma. In this study, we found that asthma was associated with decreased sinonasal QOL and general health-related QOL measures similar to what has been reported in previous studies. However, on further analysis, we found that asthma was no longer associated with worse CRS symptoms or general health-related outcomes measures after controlling for asthma control. These findings indicate that the impact of asthma on QOL is driven by the asthmatic CRS patient s level of asthma control. We believe that these results will be clinically informative for both the patient and the clinician, demonstrating that comorbid asthma alone is not indicative of decreased QOL in CRS, but rather that worsening CRS symptoms and general QOL may be related to poor asthma control in asthmatic patients with CRS. While these results do not imply that improved asthma control or the escalation of asthma treatment will lead to resolution of sinonasal symptomatology in patients with CRS, these results do spark questions regarding the pathophysiologic mechanisms that may lead to concomitant inflammation of the upper and lower airways. The findings of this study should be interpreted in the context of its limitations. While both the SNOT-22 and ACT instruments are well validated, we collected data at a single time point, which prevents us from establishing a longitudinal or definitive causal relationship. To fully understand the impact of asthma control in the association between comorbid asthma and sinonasal QOL outcomes, a longitudinal study of this patient population will be necessary. We also did not assess for any objective measures of asthma for this study, including lung function testing, which would objectively support our findings. Finally, it is possible that there is a direct association of comorbid asthma on QOL metrics, but we simply did not detect it with the 350 participants enrolled. However, even if that is the case, that effect size for the direct impact of comorbid asthma on QOL would be expected to be much smaller than the dominant indirect effect of comorbid asthma, through asthma control, on QOL that we have described here. Conclusion Comorbid asthma is associated with worse CRS-specific and general health-related QOL. However, this association is entirely driven by the level of asthma control such that comorbid asthma is not associated with worse QOL in patients with CRS when asthma control is taken into account. These findings indicate that the diagnosis of asthma is not necessarily predictive of worse CRS symptom severity in patients with good asthma control. Acknowledgements The authors gratefully acknowledge the contribution of the patients who participated in this study. Author Contributions Adam P. Campbell, acquisition, analysis, and interpretation of data; drafting and revising the manuscript; Katie M. Phillips, acquisition, analysis, and interpretation of data; revising the manuscript; Lloyd P. Hoehle, acquisition, analysis, and interpretation of data; revising the manuscript; Robert A. Gaudin, acquisition, analysis, and interpretation of data; revising the manuscript; David S. 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