Chronic Rhinosinusitis Associated with Erectile Dysfunction: A Population-Based Study

Few studies have investigated the relationship between chronic rhinosinusitis (CRS) and erectile dysfunction (ED). This case-control study aimed to investigate the association between CRS and the risk of ED in a large national sample. Tapping Taiwan’s National Health Insurance Research Database, we identified people 30 years or older with a new primary diagnosis of CRS between 1996 and 2007. The cases were compared with sex- and age-matched controls. We identified 14 039 cases and recruited 140 387 matched controls. Both groups were followed up in the same database until the end of 2007 for instances of ED. Of those with CRS, 294 (2.1%) developed ED during a mean (SD) follow-up of 3.20 (2.33) years, while 1 661 (1.2%) of the matched controls developed ED, mean follow up 2.97 (2.39) years. Cox regression analyses were performed adjusting for sex, age, insurance premium, residence, hypertension, hyperlipidemia, diabetes, obesity, coronary heart disease, chronic kidney disease, chronic obstructive pulmonary disease, asthma, allergic rhinitis, arrhythmia, ischemic stroke, intracerebral hemorrhage, and medications. CRS was revealed to be an independent predictor of ED in the fully adjusted model (HR = 1.51; 95% CI = 1.33–1.73; P < 0.0001).


Materials and Methods
Sample. A retrospective cohort study was conducted using data collected from Taiwan's National Health Insurance Research Database (NHIRD), an insurance claims database managed by Taiwan's National Health Research Institute (NHRI) for research purposes. It contains demographic information, diagnoses, health services provided, and healthcare costs and prescription data for almost all outpatients and inpatients as well as patients receiving dental services in Taiwan. Implemented in 1995, the National Health Insurance (NHI) program provides compulsory universal health insurance, covering the delivery of virtually all health care (98%) to the entire population. In cooperation with the Bureau of the NHI, Taiwan's NHRI extracted a randomly sampled set of representative data for one million people from the 2005 registry of all NHI enrollees to create a subset of the NHIRD for research purposes. The enrollees in this subset, known as the Longitudinal Health Insurance Database (LHID), are not significantly different from all NHI enrollees with regard to age, sex, or health care costs 16 .
CRS was identified in this study by the claims records showing a primary diagnosis of CRS designated with the use of the International Classification of Diseases, Ninth Revision (ICD-9) codes CRS 15,17 (ICD-9 codes: 473, 473.0, 473.1, 473.2, 473.3, 473.8, and 473.9) from 1996 to 2007. Date of diagnosis was set as the index date. Nasal polyps (NP) were identified by a diagnosis of NP ICD-9 codes: 471, 471.0, 471.1, 471.8, and 471.9. CRS without NP (CRSsNP) was defined in subjects who had CRS but no NP. CRS with NP (CRSwNP) was defined in subjects who had CRS with comorbid NP.
The comparison cohort consisted of individuals who had no diagnosis of CRS in the LHID. These individuals were randomly frequency matched with the cases by age and sex at a ratio of 1:10. Their index dates were randomly assigned to months and days within the same year of the index date of the patients in the CRS cohort. We excluded subjects with pre-existing ED (ICD-9 code: 607.84) in both groups.
Both CRS cases and controls were followed up until they were diagnosed with ED, our outcome. ED cases were identified based on a recorded diagnosis of ED ICD-9 code 607.84. All medical claims containing this diagnostic code between 1996 and 2007 were collected from the NHIRD for further analysis. To improve the diagnostic validity of ED, only those patients who had been diagnosed with ED at least twice in an outpatient service or once in an inpatient service by urologists were included in the analysis.
Physicians in Taiwan generally adhere to standardized CRS definitions and management guidelines, such as those provided by the Rhinosinusitis Task Force 18 and Clinical Practice Guidelines: Adult Sinusitis 19 . The diagnosis of ED in Taiwan is based on criteria established by the American Urological Association 20,21 .
The covariates considered in this analysis were sex, age, insurance premium, area of residence (metropolitan, class I cities, class II cities, class I counties, class II counties, and unclassified), hypertension, hyperlipidemia, diabetes, obesity, coronary heart disease, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, arrhythmia, ischemic stroke, intracerebral hemorrhage, and medications [angiotensin-converting enzyme inhibitors (ACEIs), beta-adrenergic blockers, statins, and steroid]. The insurance premium served as an indicator of economic status and subjects were classified into 1 of 3 categories: fixed premium and dependent, NTD20,000 (income per month) or less, and more than NTD20,000 (US$1 = NTD32.8 in 2007).
This study was exempt from full review by the Institutional Review Board of Kaohsiung Medical University Hospital because the NHIRD only contains de-identified secondary data released to the public for research purposes (KMUHIRB-EXEMPT-20150003).
Statistical analysis. The baseline characteristics and comorbidities of the CRS cohort and non-CRS cohort were analyzed descriptively. All data were expressed as mean ± standard deviation (SD) or percentage. Chi-square and t-tests were used to test differences in categorical and continuous variables between the two cohorts. Univariate and multivariable Cox proportional hazards regression were used to assess the hazard ratio (HR) and 95% confidence interval (CI) of ED associated with CRS, compared with the non-CRS cohort. The multivariable analysis model was adjusted for sex, age, insurance premium, residence, hypertension, hyperlipidemia, diabetes, obesity, coronary heart disease, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, arrhythmia, ischemic stroke, intracerebral hemorrhage, and medications of ACEIs, beta-adrenergic blockers, statins, and steroid. This study also investigated the relationship between CRS w/s NP and ED as well as CRS and ED. To find out if CRS is an age-dependent risk factor for ED, we also analyzed the effect of CRS on ED stratified by age group.
The cumulative incidence of ED between the CRS cohort and the non-CRS cohort was analyzed using the Kaplan-Meier method, and the difference was examined by log-rank test. SAS software (version 9.3 for Windows; SAS Institute Inc., Cary, NC) was used for all statistical operations. A P value < 0.05 was considered significant.

Results
Characteristics of the subjects. The two cohorts were comprised of 14 039 people with newly diagnosed CRS and 140 387 (nearly ten for every patient in the CRS group) sex-, age-matched controls, both identified from the NHIRD 1996-2007. As can be seen in Table 1, a summary of cohort characteristics, most cases of CRS occurred in people 36-50 years old. Compared to the controls, more patients with CRS were diagnosed with hypertension, hyperlipidemia, diabetes, obesity, coronary heart disease, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, arrhythmia, ischemic stroke, and intracerebral hemorrhage (P < 0.0001) ( Table 1). The patients in the CRS cohort were also more frequent users of ACEIs, beta-adrenergic blockers, statins, and steroid during the follow-up period than those without (P < 0.0001) (  (Table 3).
Kaplan-Meir analysis of cumulative incidence from ED revealed that patients with CRS had a significantly higher incidence of ED than the non-CRS group (P < 0.0001, based on a modified log-rank test) (Fig. 1). The cumulative incidence of ED in the CRS w/s NP cohort was also higher than that in the non-CRS cohort (P < 0.0001) (Fig. 2).

Discussion
In this large-scale nationwide study using claims data from Taiwan, we observed that although comorbid diseases were more likely to be prevalent in the CRS cohort than in the control cohort, CRS remained an independent risk factor for the development of ED after adjustment for covariates. Patients with CRS were found to be at significantly increased risk of ED (HR = 1.51; 95% CI = 1.33-1.73; P < 0.0001), after adjustment for possible confounding factors.
Treatment of CRS has been found to improve ED. A hospital-based study by Gunhan et al. showed that ED was more common in patients with CRSwNP than in control patients, subjectively measured using the International Index of Erectile Function (IIEF-EF) (P = 0.009) and objectively measured by nocturnal penile tumescence (NPT) (P = 0.0118) 12 . Their results indicated the presence of ED in 34% (IIEF-EF) and 24% (NPT) of their patients with CRSwNP. After comparing the pre-and postoperative results of the CRSwNP patients, the authors further found erectile function to be significantly improved after functional endoscopic sinus surgery 12 . A hospital-based study by Benninger et al., who used the Rhinosinusitis Disability Index, a validated instrument that measures the physical, functional, and emotional impact of CRS on a person's quality of life (QoL), found that patients with CRS had significantly improved sexual function scores after surgery for their CRS (P < 0.001) 11 .
The exact mechanism underlying the development of ED in CRS patients remains unknown. The relationship between CRS and ED could conceivably be influenced by a number of pathophysiologic factors, including QoL, hypoxia, and inflammation. The inflammatory biomarker and cytokines that link CRS and ED may include C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α ), and transforming growth factor beta (TGF-β ). Some consequences of CRS, including low QoL, hypoxia, and cardiovascular disorders, might increase the risk of ED in a select subpopulation of patients with CRS.
Videler et al., administering the Short-Form health survey (SF-36), found that patients with CRS had significantly worse QoL scores than patients with other chronic conditions, including head and neck cancer, hypertension, angina pectoris, and migraine 22 . Interestingly, Ottaviano et al. observed a significant association between olfactory sensitivity and sexual desire in young adults (P = 0.02) 23 . Thus, the CRS symptoms of nasal obstruction, rhinorrhea, smell dysfunction, facial pressure, headache, and postnasal drainage might reduce libido leading to ED.
Ozdemir et al. found that patients with CRSwNP had hypoxia and nasal surgery led to increased blood oxygen saturation 24 . Hypoxia increases afferent sympathetic activation, resulting in increased vasoconstriction and significantly reduced nitric oxide (NO) synthase activity, which is a rate-limiting factor for NO production in the penile corpus cavernosum 25 . Studies have suggested that NO is a bronchodilator and vasodilator involved in mucocililary-regulating activities 26 . Lindberg et al. reported that their patients with CRS had lower concentrations of nasal NO than their healthy control patients 27 . Studies have also shown an inverse correlation between nasal NO and nasal polyp size 28 . Ragab et al. observed that nasal NO levels increased after the medical and surgical treatment of CRS 26 . NO plays a crucial role in the molecular mechanism of penile smooth muscle relaxation 9 , Crude HR a 95% CI b P-value Adjusted HR 95% CI b P-value  and decreased levels of NO can contribute to ED. In addition, Verratti et al. revealed that men who are sexually potent at sea level had pathological rigidometric records at a high altitude in a hypoxic environment 25 . Therefore, a selected subpopulation of CRS patients with hypoxia may develop ED. Recent epidemiological studies have identified an increased risk of subsequent stroke and acute myocardial infarction in patients with CRS [13][14][15] . In previous studies on CRS patients, the HRs of stroke, ischemic stroke, and acute myocardial infarction were 1.34 (95% CI = 1.04-1.74) 13 , 1.34 (95% CI = 1.18-1.53), and 1.48 (95% CI = 1.32-1.67) 15 , respectively, after adjustment for potential confounding factors. CRS is defined as a group of disorders associated with inflammation of the nasal mucosa and sinuses lasting at least 12 weeks 29 . Inflammation is thought to play a central role in the pathogenesis of atherosclerotic initiation, plaque rupture, thrombosis, and    stroke 30 . In the first stages of atherosclerosis, the penis is typically first affected, manifesting as ED, making ED a possible warning sign that a heart attack or stroke is imminent, often within 3 to 5 years 31 . Thompson et al. proposed that ED is a sentinel symptom in patients with occult cardiovascular disease 10 , suggesting that CRS could be a risk factor for ED. Elevation of the systemic inflammatory marker, CRP, has been reported to correlate significantly with increasing severity of penile vascular disease in men with ED as measured by penile Doppler 32 . In a study by Giugliano et al., circulating CRP levels were significantly higher in obese men with ED than in obese men without ED (P < 0.05) 33 . In other studies, patients with sinusitis have had higher CRP levels compared with control patients 34,35 . Hirshoren et al. observed a significant association between CRP levels and the severity of sinusitis 36 , suggesting that CRP might play a direct role in the pathogenesis of atherosclerosis. These findings have led to the hypothesis that CRS might induce local inflammation in the upper airway and induce systemic inflammatory effects that contribute to ED. CRP might thus play a role in both CRS and ED.

Development of ED
TNF-α might also play a key role in inducing ED or contribute to the pathophysiology of ED. Oyer et al. reported that the mucus of patients with CRSwNP had higher levels of the proinflammatory cytokine TNF-α than their control patients 37 . Carneiro et al. found increased serum TNF-α levels in patients with moderate to severe ED 38 .
The fibrogenic cytokine TGF-β plays key roles in CRS and ED. Van Crombruggen et al. observed upregulated TGF-β expression in patients with CRSsNP 39 . In a study by Ryu et al., plasma TGF-β expression was significantly higher in ED patients than in control patients 40 . Previous studies have also revealed that TGF-β is involved in cavernous fibrosis, promoting the development of vasculogenic ED in men 41 .
Our results indicate a stronger association between CRS and ED men aged ≥ 35 years than in other age groups, particularly in men aged 36-50 years (Table 3). However, the mechanism underlying these age-associated effects remains unclear.

Strengths and limitations.
The key strengths of this study are its nationally representative sample, physician-based diagnosis to identify CRS cases, longitudinal analysis, and range of covariates considered, including sociodemographic factors and general health status. However, this study has some limitations, particularly those caused by the use of routine claims data, which do not include information on other potential confounders such as severity of CRS status, stressful life events, smoking, air pollution, body mass index, and family history. This study was conducted in Taiwan. Whether our findings can be extrapolated to other countries is not known.

Conclusion
In summary, this study found an association between having CRS and a significantly higher risk of developing ED than the general population, regardless of age, presence of comorbidity, and medications. Because of the high (and potentially increasing) prevalence of CRS, clinicians should be aware of the risk of ED in CRS patients. Further research is required to determine the underlying mechanism linking these two adverse health outcomes.