Chronic Rhinosinusitis is Frequent in Chronic Obstructive Pulmonary Disease: a Case Control Study

Background: Prevalence and impact of chronic rhinosinusitis (CRS) in chronic obstructive pulmonary disease (COPD) remain unclear. We hypothesized that CRS is more frequent in patients with COPD compared to controls and we aimed to evaluate the odds of CRS in both groups. Methods: We recruited patients with COPD and a healthy control group in a tertiary referral hospital in Switzerland. Diagnosis of CRS was defined according to published guidelines and supported by computed tomography (CT) findings. Sino-nasal-outcome-test-20 (SNOT-20) and sino-nasal-outcome-test-primary-nasal-symptom-score (SNOT-PNS-score) were self-assessed with a cut-off for abnormality of >12. Results: Data from 83 COPD patients (35 females, age: 67 years ± 10) and 34 controls (18 females, age: 67 years ± 12) were analyzed. In the COPD group 14 out of 83 (20.3%) fulfilled the diagnosis of CRS compared to only 1 out of 34 (3%) in the control group (OR 6.7; 95% CI 0.84-53.10; p = 0.064). Forty-eight COPD patients (59%) and 14 controls (41%) had an abnormal SNOT-20 score (OR 1.96; 95% CI 0.87-4.40; p=0.10), with a median score of 16.0 (ICR 21) in COPD patients compared to a median score of 8.0 (ICR 13) in controls (p=0.001). The SNOT-PNS-score was abnormal in 49 COPD patients (59%) and in 9 controls (26%) (OR 4.00; 95% CI 1.66-9.64; p=0.001). Abnormal findings of the upper airways did not correlate with COPD severity or smoking status. Conclusions: CRS was a frequent diagnosis in patients with COPD. CRS reduces quality of life in this patient group. Abstract Background: Prevalence and impact of chronic rhinosinusitis (CRS) in chronic obstructive pulmonary disease (COPD) remain unclear. We hypothesized that CRS Data from 83 COPD patients (35 females, age: 67 years ± 10) and 34 controls (18 females, age: 67 years ± 12) were analyzed. In the COPD group 14 out of 83 (20.3%) fulfilled the diagnosis of CRS compared to only 1 out of 34 (3%) in the control group (OR 6.7; 95% CI 0.84-53.10; p = 0.064). Forty-eight COPD patients (59%) and 14 controls (41%) had an abnormal SNOT-20 score (OR 1.96; 95% CI 0.87-4.40; p=0.10), with a median score of 16.0 (ICR 21) in COPD patients compared to a median score of 8.0 (ICR 13) in controls (p=0.001). The SNOT-PNS-score was abnormal in 49 COPD patients (59%) and in 9 controls (26%) (OR 4.00; 95% CI 1.66-9.64; p=0.001). Abnormal findings of the upper airways did not correlate with COPD severity or smoking status.


Background
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death globally. The continuation of risk factors and an aging population increase the burden of disease. 1 Affected individuals may suffer from a reduction in quality of life and presence of COPD related comorbidities. 1 The prevalence and impact of upper airway disease as a comorbidity in COPD is unclear. In the general European population and in the population of the United States chronic rhinosinusitis (CRS) has a prevalence of 15%, 2 in asthmatics this number is even higher [3]. Importantly specific treatment may improve health care outcomes. 3,4 Roberts et al and Hurst et al reported a high prevalence of nasal symptoms of 75% and 88% respectively in a group of COPD patients from the East London COPD study, independent of smoking status. 5,6 Others, such as Montnemery et al, found a lower prevalence of nasal symptoms in COPD patients with 40% compared to a prevalence of 33% in the whole study sample with smoking being an important factor. 7 Also Piotrowska et al demonstrated evidence for upper airway disease in COPD, which was more severe in current smokers. 8 Sichtelidis et al reported a non-significantly higher prevalence of rhinitis in patients with (27.5%) compared to patients without (24.5%) COPD associated with smoking status. 9 Hakansson et al did not find a correlation between non-allergic rhinitis and COPD. 10 Furthermore, upper airway diseases impact on COPD outcomes remains controversial. Hurst et al demonstrated an impact on quality of life and bronchial obstruction. 6,11 Kelemence et al reported a reduction in quality of life assessed by the SNOT-20 questionnaire correlating with COPD severity. 12 A previous study reported an association of sinusitis with treatment failure in COPD exacerbations. 13 Others did not find a correlation with upper respiratory tract symptoms and COPD severity. 5,8 In summary even though most studies indicated an association between COPD and upper airway disease such as CRS the evidence remains inconclusive and lacks a comprehensible assessment, such as sinonasal imaging or a control group. 12,14,15 To investigate the prevalence of CRS in COPD and its impact on COPD outcomes we examined symptoms of CRS in COPD patients and a control group using a structured questionnaire, SNOT-20 and computed tomography (CT) of the para-nasal sinuses. We hypothesized that the prevalence of CRS is higher in the COPD compared to the control group.
Furthermore, we aimed to evaluate the possible impact of CRS on COPD outcomes, which we discussed with caution as the study was underpowered for this endpoint.

Study design
This cross-sectional, mono-centre study was conducted at the University Hospital Basel, Switzerland.
Participants between 42 and 90 years of age were in COPD GOLD grades I to IV. Thirty-four individuals without COPD who had undergone a CT in the last 4 weeks in the emergency department due to trauma (n=19), suspicion of bleeding (n=13) and suspicion of tumor (n=2), were included as controls to allow the assessment of a significant difference of CRS according to our power analysis.
Respiratory tract infections in the last 6 weeks were reason for exclusion. Vital parameters, medicaland smoking history were recorded. CT and exhaled nitric oxide (NO) were assessed.

Definition of CRS
CRS was defined according to the European position paper on CRS. 2 According to the EPOS guidelines CRS is defined as an inflammation of the nose and the paranasal sinuses characterized by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip). Further possible symptoms included facial pain/pressure and reduction or loss of smell for ≥12 weeks. The symptoms were assessed through the SNOT questionnaire and personal history, specifically those questions were used which assessed primary nasal symptoms. Moreover, these symptoms were supported by demonstrable disease in a sinonasal CT. 2 Definition of COPD COPD was diagnosed in the presence of a post-bronchodilator FEV 1 /FVC of < 0.70 and a lack of bronchodilator response (FEV 1 < 200 ml and < 12%) with a past history of an appropriate noxious stimulus and symptoms such as chronic cough, sputum production or dyspnea. 1 Former history of asthma was reason for exclusion. The classification of airflow limitation severity was graded according to GOLD guidelines into stages 1 (mild) to 4 (very severe). 1 Furthermore participants with COPD were grouped into risk groups A, B, C and D according to results of the COPD assessment test (CAT) and exacerbation rate. 1 Spirometry, NO and skin prick test Spirometry was performed according to published guidelines. 1,16 Bronchial and nasal exhaled NO was measured with an electrochemical analyser (NIOX mino, Aerocrine, Sweden). 17 Evidence of atopy was assessed by skin prick test (SPT) (Trimedal AG, Switzerland). 18 Exacerbation History and Questionnaires Exacerbations in the previous 12 months, defined as an acute worsening of the patient's condition warranting additional treatment, were assessed. 1 The Sino-nasal-outcome-test-20 (SNOT-20) German adapted version questionnaire assessed symptoms of CRS and its impact on quality of life. 19 Subscores, especially the SNOT-primary-nasal-symptom-score (SNOT-PNS-score), were calculated. 19 A score of >12 was considered abnormal (range 0-100). 19

Statistical analysis
For the statistical analysis statistical package of social sciences 22.0 program was applied. The average values were expressed as mean ± standard deviation (SD). Where appropriate, median and interquartile range (IQR) was used. Normally distributed parameters of independent groups were compared with Student's t-test. Not normally distributed parameters were compared using the Mann-Whitney test. Nominal variables were analyzed with the chi-square test and Fisher exact test if appropriate. Odds ratios (OR), their standard errors and 95% Confidence Intervals (CI) were calculated and the correlations between the averages of independent nominal groups were analyzed with the Pearson correlation test. A p-value of less than 0.05 was considered to be significant. The confidence interval was defined as 95%. This study was conducted in accordance with the Declaration of Helsinki (http://www.wma.net/en/30publications/10policies/b3/).

Results
The data of eighty-three participants with COPD and thirty-four participants without COPD was collected ( Figure 1). The demographics are given in Table 1 and Table 2. CRS Fourteen of 83 (20.3%) COPD patients fulfilled the criteria for CRS according to the EPOS guidelines.
There was evidence that this was more frequent than in the control group in which only one out of 34 Computer tomography CT-scans were assessed to be abnormal in seventeen COPD (21%) versus two control patients (6%) (OR 4.12, 95% CI 0.90, 18.93, p=0.0687) with a higher Lund-Mackay score in the COPD group (Table 3 and Figure 2). There was no intergroup difference in sinonasal swelling localization.

Exhaled Nitric Oxide (NO)
Nasal NO had a trend to be higher in controls compared to the COPD group (p=0.3) ( Table 3).
Health care outcomes Diagnosis of CRS did not correlate with COPD GOLD grades, COPD risk groups, and exacerbation rate (Table 4). No significant correlation between COPD GOLD grade, an abnormal SNOT-20 score (p=0.20), an abnormal SNOT-PNS score (p=0.55) or an abnormal Lund-Mackay CT score (p=0.44) was found. The exacerbation rate of COPD was not significantly related to the SNOT-20 (p=0.42), SNOT-PNS (p=0.99) or Lund-Mackay score (p=0.68).

Discussion
We found evidence of high frequency of CRS in patients with COPD with a reduction of quality of life.
Strengths of this study are that we aimed to establish a diagnosis of CRS according to the current EPOS guidelines. Furthermore, for the first time we used objective CT data to support this finding and included a control group.
Limitations of the study shall also be discussed. Sparse data bias may play a role as especially due to the lower number of controls only a couple of cases were recorded, e.g. only one patient without COPD fulfilled the criteria for CRS. Also, a selection bias may have affected the COPD as well as the control group. Many COPD patients with severe disease did not consent to participate and exacerbation rate was therefore low. Furthermore, a selection bias may have affected the control group as due to ethical reasons, only controls that had already undergone a CT were approached.
Although the control group may not have been representative of the general population, the high rate of co-morbidities allowed us to differentiate between disease specific versus general quality of life impairment. Due to the same reason we were not able to match for smoking status thus we cannot exclude that the difference of the prevalence between the two groups was caused by smoking alone.
We selected our control group on the basis of a previously performed CT-scan we had to accept that frequency of never smokers was high with 68%.
Coming to the main results, firstly the odds of CRS in COPD was higher compared to participants without COPD. Symptoms ranged from 59% considering abnormal SNOT-PNS in the COPD compared to 26% in the control group to 84% in the COPD vs. 66% in the controls looking at one symptom alone. These results were comparable to the findings of Hurst et al who reported nasal symptoms in 88% of COPD patients and Roberts et al who demonstrated a prevalence of 75% [5,6]. The lower prevalence of 40% seen by Montnemery et al compared to our results may have been due to selfreported diagnosis of COPD and nasal symptoms and the inclusion of a younger population group (20-59 years of age) [7]. The frequency of abnormal CT findings in 21% was lower compared to the results of Kelemence et al. (64%), probably due to the fact that a higher cut-off for an abnormal CT scan was used in our study (0 in Sichtelidis et al. vs. > 4.26 in our study) [12]. Also Celakovsky et al. found a higher rate of abnormal CTs with 38% even though they excluded patients with sino-nasal surgery, which was frequent in our cohort [15]. Also in this case they used a different cut-off compared to our study as they rated CTs to be abnormal if there was an opacity of one or more sinuses.
Secondly disease specific quality of life was reduced. Even though the rate of abnormal SNOT-20 as well as abnormal SNOT-QoL reflecting general quality of life were similar between COPD and control patients, the scores of RQLQ reflecting disease specific quality of life in patients with CRS were significantly different. In the SNOT-20, 50% of the questions are unspecific for the nose and as the amount of total co-morbidities and psychological disorders did not differ between groups this may be the reason for the lack of difference in general quality of life.
Interestingly controls had a very high rate of positive SPTs with 52% and most frequent symptoms were sneezing and runny nose, possibly reflecting allergic disease. Also, a trend towards a lower nasal NO in COPD was seen, which may reflect an eosinophilic rather than a neutrophilic inflammatory process, and high evidence for neutrophilic inflammation in COPD exists while eosinophilic inflammation may be present in allergic diseases [22]. Atopy in COPD and the general population is discussed controversially in the literature. Tschopp

Conclusion
We found evidence that COPD patients suffer frequently from CRS; CRS reduced quality of life in COPD. We did not detect a significant impact on health outcomes.

Ethics approval and consent to participate
The local ethics committee 'Beider Basel', currently ‚Ethikkommission Nordwest-und Zentralschweiz (EKNZ)' approved the study (EK-163/11). Written informed consent was obtained from every participant in this study, for every procedure performed and for the medical data used.

Consent for publication
Not applicable Availability of data and material The de-identified datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors have no conflict of interest in relation to this paper.     Representative example of a CT scan from a COPD patient with CRS.

Supplementary Files
This is a list of supplementary files associated with this preprint. Click to download.