Lund–Mackay Computed Tomography Score Is Associated With Obstructive Pulmonary Function Changes in Chronic Cough Patients

Abstract

Background

A remarkable relationship between upper airway conditions and lung diseases has been reported. At the same time, sinonasal findings in chronic cough patients have not been fully examined.

Objective

The purpose of this study is to show paranasal sinus findings and lung function in chronic cough patients without asthma and chest X-ray abnormalities.

Methods

A total of 1412 patients with persistent cough were enrolled in this study. Of these patients, 376 patients were evaluated for further examination, as the patients with asthma and/or chest X-ray abnormality were excluded from the study. Normal control subjects without any chronic respiratory symptoms were also recruited. Pulmonary function was examined by spirometry. A bronchial obstruction reversibility test was applied. The Lund–Mackay computed tomography (CT) score, peripheral blood eosinophil count, and immunoglobulin E concentration in serum samples were examined. The Sino-Nasal Outcome Test was used to determine the severity of clinical symptoms.

Results

The patients with an abnormal soft tissue shadow in the paranasal sinus had significant obstructive lung function. The percent predicted forced expiratory volume in 1 second (FEV_1.0) and the FEV_1.0/forced vital capacity ratio negatively correlated with Lund–Mackay CT scores both before and after bronchodilator inhalation. There was a statistically significant correlation between pulmonary function and eosinophil count.

Conclusion

The patients with chronic cough frequently had paranasal sinus abnormalities. The Lund–Mackay CT score may be useful for assessing the condition of the lower airway in chronic cough patients. Upper airway examinations should play a part in the management of chronic cough.

Keywords

chronic obstructive pulmonary disease asthma rhinosinusitis sinusitis rhinitis paranasal sinus lung function tobacco cigarette persistent cough

Introduction

The upper and lower respiratory tract have similar physiological and anatomical characteristics, and a close relationship between upper and lower airway diseases has been reported.¹ Chronic rhinosinusitis is a highly prevalent disease and frequently coexists with lung diseases, including asthma and chronic obstructive pulmonary disease (COPD).^2–4 A recent study showed that the treatment of upper airway disease improved the clinical condition of patients with bronchial disease, and an experimental study showed that bronchial hyperreactivity was exacerbated by sinonasal inflammation.^5,6

COPD is a chronic inflammatory lung disease characterized by limited airflow in the lungs. COPD is a term for a group of lung diseases including emphysema and chronic bronchitis, and it is a serious and progressive respiratory condition with a high mortality rate. COPD is caused by long-term exposure to hazardous substances. A major risk factor for COPD is smoking; however, approximately one-fourth of COPD patients are never smokers.⁷ The diagnosis, treatment, and prevention of COPD, especially in never smokers, are critical issues in the management of patients with respiratory diseases.

The Lund–Mackay computed tomography (CT) score is a useful and widely accepted staging system for evaluating the radiological severity of chronic rhinosinusitis.⁸ Possible effects of chronic rhinosinusitis on lung function have been reported.^9–11 However, lung function in patients with paranasal sinus abnormalities has not yet been fully examined. To the best of our knowledge, no previous study has evaluated paranasal sinus abnormalities and lung function in patients with chronic cough. The purpose of this study is to examine the relationship between lung function and paranasal sinus abnormalities in persistent cough patients.

Materials and Methods

Subjects

A total of 1412 patients with persistent cough were enrolled in this study. The patients with recent acute upper respiratory infection were excluded. The patients were carefully interviewed and examined by chest X-ray, paranasal sinus CT scan, and pulmonary function test. The patients with asthma and/or chest X-ray abnormalities were excluded from the study, which left 376 patients to be evaluated. Chronic cough was diagnosed by the American College of Chest Physician guidelines.¹² Age-matched normal control subjects (n = 60) without any chronic respiratory symptoms were also recruited. Informed consent was obtained from the enrolled subjects. The study was approved by the Institutional Review Board (IRB approval number, FS-79 and RINRI-877) and conducted in compliance with the 2013 version of the Declaration of Helsinki.

Pulmonary Function Test

Pulmonary function testing was performed according to the standardized methods of the lung function tests of the American Thoracic Society and European Respiratory Society.¹³ The following parameters were measured or calculated: percent predicted vital capacity (%VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV_1.0), percent predicted FEV_1.0 (%FEV_1.0), and FEV_1.0/FVC ratio.

Paranasal Sinus Assessment by CT Score

The radiographic severity of chronic rhinosinusitis was assessed by the Lund–Mackay CT staging system.⁸

Peripheral Blood Eosinophil Count and Total IgE Level in Serum Samples

Blood samples were taken in the outpatient clinic. The eosinophil count (%) in peripheral blood was determined. The total immunoglobulin E (IgE) in serum samples was also measured.

Bronchodilator Reversibility Test

A bronchial obstruction reversibility test was used to distinguish asthma. The pulmonary function test was performed before and after inhalation of a bronchodilator (salbutamol, 5 mg/mL, 0.3 mL).

Evaluation of Subjective Symptoms

The Sino-Nasal Outcome Test (SNOT-20) is a useful questionnaire designed to determine the severity of clinical symptoms.¹⁴ SNOT-20 (need to blow nose, sneezing, runny nose, cough, postnasal discharge, thick nasal discharge, ear fullness, dizziness, ear pain, facial pain/pressure, difficulty falling asleep, waking up at night, lack of a good night’s sleep, waking up tired, fatigue, reduced productivity, reduced concentration, frustrated/restless/irritable, sad, and embarrassed) was used to evaluate the severity of an individual’s symptoms in this study.

Statistical Analysis

Values are presented as mean ± standard deviation. A nonparametric Mann–Whitney U test was used for comparisons between 2 groups. Correlations were analyzed using Spearman’s rank correlation coefficient. P values less than .05 were considered significant. Statistical analyses were performed with IBM SPSS Statistic (IBM, New York, NY).

Results

Of the total patients, 73.4% (1036/1412) of patients with chronic cough were diagnosed with asthma and/or abnormalities on chest X-ray. Of those patients with a normal chest X-ray finding and no reversible obstructive airway disease, 68.4% (257/376) had abnormal sinus CT scans. In addition, 29.0% (109/376) of those patients had rhinosinusitis based on the European Position Paper on Rhinosinusitis (EPOS) guidelines.¹⁵

The patients were divided into 2 groups based on the presence (positive group, n = 257, Lund–Mackay CT score > 0) or absence (zero group, n = 119, Lund–Mackay CT score = 0) of a soft tissue density shadow in paranasal sinus CT. The clinical characteristics of the subjects in each group are summarized in Table 1.

Table 1.

Characteristics of the Patients and the Normal Controls.

	Positive on CT Score	Zero on CT Score	Control
Number of subjects (n)	257	119	60
Male/Female (n)	128/129	33/86	29/31
Age (years)	49.1 ± 14.9	41.3 ± 13.3	46.5 ± 6.1
CT score	5.2 ± 4.7	0.0 ± 0.0	NA
Smoking status
Ex-smoker	74 (28.8%)	18 (15.1%)	18 (30.0%)
Current smoker	38 (14.8%)	14 (11.8%)	6 (10.0%)
Never smoker	145 (56.4%)	87 (73.1%)	36 (60.0%)
Brinkman index
Ex-smoker	296.7 ± 295.8	405.6 ± 421.5	372.0 ± 328.1
Current smoker	492.5 ± 342.7	384.3 ± 298.2	585.0 ± 346.3

Abbreviations: CT, computed tomography; NA, not applicable.

Data represent means ± standard deviation.

Pulmonary function in the patients with persistent cough and the normal control subjects are shown in Table 2. There was no statistically significant difference in %VC, a parameter showing restrictive lung function changes, between the groups. In contrast, FEV_1.0, %FEV_1.0, and the FEV_1.0/FVC ratio, parameters showing obstructive lung function changes, in both the positive and zero groups were significantly lower than in the normal control subjects (P < .05). Before bronchodilator inhalation, the patients with positive Lund–Mackay CT scores had a significantly decreased %FEV_1.0 (P < .05) and FEV_1.0/FVC ratio (P < .05) as compared to patients without a shadow in the paranasal sinus (zero group). The same findings were observed after bronchodilator inhalation (%FEV_1.0 [P < .05] and FEV_1.0/FVC ratio [P < .05]). %FEV_1.0 and the FEV_1.0/FVC ratio negatively correlated with Lund–Mackay CT scores both before and after bronchodilator inhalation (Figure 1, P < .05). No significant correlation was detected between %VC and Lund–Mackay CT scores.

Table 2.

Pulmonary Function in Enrolled Patients and the Normal Controls Before and After Bronchodilator Inhalation.

	Positive on CT Score	Zero on CT Score	Control
Number of subjects	257	119	60
Before inhalation
%VC (%)	97.0 ± 10.9^#	98.7 ± 11.7^#	114.9 ± 11.8
FVC (L)	3.4 ± 0.9^#	3.3 ± 0.8^#	3.6 ± 0.8
FEV_1.0 (L/s)	2.7 ± 0.8^#	2.7 ± 0.6^#	3.0 ± 0.6
%FEV_1.0 (%)	90.8 ± 12.6^#,**	95.6 ± 12.2^#	108.9 ± 10.8
FEV_1.0/FVC ratio (%)	78.9 ± 7.7^#,**	82.6 ± 7.5	83.5 ± 5.8
After inhalation
FVC (L)	3.5 ± 0.9	3.4 ± 0.8	NA
FEV_1.0 (L/s)	2.8 ± 0.8	2.8 ± 0.6	NA
%FEV_1.0 (%)	92.4 ± 12.6**	97.8 ± 12.1	NA
FEV_1.0/FVC ratio (%)	80.3 ± 7.9**	84.0 ± 7.5	NA

Abbreviations: CT, computed tomography; FEV_1.0, forced expiratory volume in 1 second; %FEV_1.0, percent predicted FEV_1.0; FVC, forced vital capacity; NA, not applicable; %VC, predicted vital capacity.

Data represent means ± standard deviation.

^#P < .05 as compared to normal controls.

**P < .05 as compared to zero on CT score.

Total white blood cell count (WBC), peripheral blood eosinophil level, total serum IgE level, and the Sino-Nasal Outcome Test (SNOT) scores in the patients with chronic cough and the normal controls were shown in Table 3. There was no statistically significant difference between groups in WBC, peripheral blood eosinophil level, and total serum IgE level. The total SNOT score in patients with positive Lund–Mackay CT scores was significantly larger than that in patients with no paranasal soft tissue shadow on CT scans (zero group) (P < .05). However, the differences between groups in each component of the SNOT scores did not reach the statistical significance.

Table 3.

Total WBC, Peripheral Blood Eosinophil Level, Total Serum IgE Level, and the SNOT Score in the Patients With Chronic Cough and the Normal Controls.

	Positive on CT Score	Zero on CT Score	Control
Number of subjects (n)	257	119	60
WBC (×10³/µL)	6.4 ± 1.8	6.0 ± 1.8	5.8 ± 1.2
Eosinophil level (%)	4.2 ± 3.5	2.8 ± 1.9	2.8 ± 1.2
IgE level (IU/mL)	209.6 ± 503.9	163.3 ± 412.0	NA
SNOT score
Total	24.2 ± 14.1	18.4 ± 12.1	NA
Need to blow nose	2.1 ± 1.5	1.1 ± 1.4	NA
Sneezing	1.3 ± 1.2	0.8 ± 1.0	NA
Runny nose	1.6 ± 1.5	0.9 ± 1.3	NA
Cough	3.6 ± 1.3	3.5 ± 1.6	NA
Postnasal discharge	1.5 ± 1.6	0.8 ± 1.4	NA
Thick nasal discharge	1.3 ± 1.5	0.6 ± 1.0	NA
Ear fullness	1.0 ± 1.4	0.5 ± 1.1	NA
Dizziness	0.6 ± 1.1	0.6 ± 1.0	NA
Ear pain	0.3 ± 0.8	0.1 ± 0.3	NA
Facial pain/pressure	0.4 ± 1.1	0.2 ± 0.8	NA
Difficulty falling asleep	1.6 ± 1.8	1.1 ± 1.5	NA
Waking up at night	2.0 ± 1.8	1.7 ± 1.6	NA
Lack of a good night’s sleep	2.1 ± 1.8	1.7 ± 1.7	NA
Waking up tired	2.0 ± 1.5	2.1 ± 1.5	NA
Fatigue	2.6 ± 1.5	2.5 ± 1.5	NA
Reduced productivity	1.8 ± 1.5	1.7 ± 1.6	NA
Reduced concentration	1.8 ± 1.4	1.7 ± 1.6	NA
Frustrated/restless/ irritable	1.6 ± 1.4	1.4 ± 1.4	NA
Sad	1.0 ± 1.3	1.0 ± 1.4	NA
Embarrassed	2.7 ± 1.5	2.3 ± 1.7	NA

Abbreviations: CT, computed tomography; IgE, immunoglobulin E; NA, not applicable; SNOT, Sino-Nasal Outcome Test; WBC, white blood cell count.

Data represent means ± standard deviation.

In patients with chronic cough, there was a statistically significant negative correlation between %FEV_1.0 and eosinophil count both before (P < .05) and after (P < .05) bronchodilator inhalation. The FEV_1.0/FVC ratio also negatively correlated to eosinophil counts both before (P < .05) and after (P < .05) bronchodilator inhalation. There was no statistically significant correlation between pulmonary function and the concentration of serum IgE. SNOT-20 scores did not significantly correlate to pulmonary function.

Smoking has an adverse impact on the respiratory tract. To factor out the harmful effects of smoking, the next part of the study excluded smokers. There were 145 patients with positive Lund–Mackay CT scores, 87 patients with no paranasal soft tissue shadow on CT scans (zero group), and 36 normal control subjects. The pulmonary function of these subjects both before and after bronchodilator inhalation is shown in Table 4. The obstructive pulmonary function change parameters (FEV_1.0, %FEV_1.0, and FEV_1.0/FVC ratio) in patients with positive Lund–Mackay CT scores were significantly lower than those in the zero group and control group before bronchodilator inhalation (P < .05). After bronchodilator inhalation, the patients with positive Lund–Mackay CT scores had obstructive lung function impairment with a significant decrease in %FEV_1.0 and the FEV_1.0/FVC ratio as compared to the zero group (P < .05). %FEV_1.0 and the FEV_1.0/FVC ratio negatively correlated with Lund–Mackay CT scores both before and after bronchodilator inhalation (Figure 2, P < .05). FEV_1.0 tended to negatively correlate with Lund–Mackay CT scores both before (P = .075) and after (P = .053) bronchodilator inhalation. No significant correlation was detected between %VC and Lund–Mackay CT scores.

Table 4.

Pulmonary Function in Never Smoker Patients and the Normal Controls Without Smoke Before and After Bronchodilator Inhalation (CT Cut-off Value: 1).

	Positive on CT Score	Zero on CT Score	Control
Number of subjects (n)	145	87	36
Male/Female (n)	40/105	10/77	11/25
Age (years)	48.8 ± 15.9	40.1 ± 12.8	45.8 ± 5.9
CT score	4.6 ± 4.4**	0.0 ± 0.0	NA
Before inhalation
%VC (%)	97.2 ± 10.8^#	98.1 ± 11.7^#	113.2 ± 11.8
FVC (L)	3.1 ± 0.9	3.1 ± 0.7	3.4 ± 0.7
FEV_1.0 (L/s)	2.5 ± 0.8**^,#	2.6 ± 0.6	2.8 ± 0.6
%FEV_1.0 (%)	92.6 ± 12.0**^,#	97.0 ± 12.1^#	108.9 ± 12.1
FEV_1.0/FVC ratio (%)	79.7 ± 7.1**^,#	83.9 ± 6.0	84.6 ± 5.6
After inhalation
FVC (L)	3.2 ± 0.9	3.2 ± 0.6	NA
FEV_1.0 (L/s)	2.6 ± 0.8	2.7 ± 0.6	NA
%FEV_1.0 (%)	93.9 ± 12.5**	99.5 ± 12.0	NA
FEV_1.0/FVC ratio (%)	81.2 ± 7.5**	85.5 ± 5.9	NA

Data represent means ± standard deviation.

^#P < .05 as compared to normal controls.

**P < .05 as compared to zero on CT score.

Incidental detection of sinus mucosal abnormalities on CT has been reported, and several normative values for the Lund–Mackay CT score have been proposed.^16,17 Because the Lund–Mackay CT score ≤3 may be within normal limits, next, we divided the chronic cough patients without smoking into 2 groups (Lund–Mackay CT score ≥4 or Lund–Mackay CT score ≤3).^18,19 The clinical features and pulmonary functions were shown in Table 5. The obstructive pulmonary function change parameters (%FEV_1.0 and FEV_1.0/FVC ratio) in patients with Lund–Mackay CT scores ≥4 were significantly lower than those in patients with Lund–Mackay CT scores ≤3 both before and after bronchodilator inhalation (P < .05).

Table 5.

Pulmonary Function in Never Smoker Patients and the Normal Controls Without Smoke Before and After Bronchodilator Inhalation (CT Cut-off Value: 4).

	CT Score ≥ 4	CT Score ≤ 3	Control
Number of subjects (n)	59	173	36
Male/Female (n)	19/40	31/142	11/25
Age (years)	48.2 ± 16.3	44.6 ± 15.0	45.8 ± 5.9
CT score	8.8 ± 4.1**	0.9 ± 1.0	NA
Before inhalation
%VC (%)	96.7 ± 11.9	97.9 ± 10.6	113.2 ± 11.8
FVC (L)	3.2 ± 0.9	3.1 ± 0.8^#	3.4 ± 0.7
FEV_1.0 (L/s)	2.6 ± 0.8^#	2.6 ± 0.7^#	2.8 ± 0.6
%FEV_1.0 (%)	91.0 ± 11.9**^,#	95.4 ± 12.2^#	108.9 ± 12.1
FEV_1.0/FVC ratio (%)	79.7 ± 6.3**^,#	81.9 ± 7.2^#	84.6 ± 5.6
After inhalation
FVC (L)	3.2 ± 1.0	3.1 ± 0.8	NA
FEV_1.0 (L/s)	2.6 ± 0.8	2.6 ± 0.7	NA
%FEV_1.0 (%)	92.7 ± 12.8**	97.3 ± 12.3	NA
FEV_1.0/FVC ratio (%)	81.5 ± 6.8**	83.4 ± 7.4	NA

Abbreviations: CT, computed tomography; FVC, forced vital capacity; FEV_1.0, forced expiratory volume in 1 second; %FEV_1.0, percent predicted FEV_1.0; NA, not applicable; %VC, predicted vital capacity.

Data represent means ± standard deviation.

^#P < .05 as compared to normal controls.

**P < .05 as compared to CT score ≤ 3.

Discussion

It is well known that inflammatory upper airway diseases (allergic rhinitis and chronic rhinosinusitis) and asthma often coexist.²⁰ In addition, chronic rhinosinusitis is frequently detected in other lower airway diseases including cystic fibrosis, primary ciliary dyskinesia, COPD, and sinobronchial syndrome.²¹ Sinobronchial syndrome is one of the chronic bronchial disorders characterized as a coexisting chronic rhinosinusitis and chronic neutrophilic inflammation of the lung, and the lower airway diseases of sinobronchial syndrome include chronic bronchitis, diffuse bronchiectasis, and diffuse panbronchiolitis.^22,23 Although the united airway concept has been widely accepted, the upper airway diseases tend to be overlooked by respiratory physicians.²⁴

Chronic cough is a common disorder and usually caused by smoking. Smoking is the most important risk factor for developing COPD. However, a large number of people suffer from COPD even though they have never smoked.^25–27 The upper airway is not usually examined in persistent cough patients. Recent studies reported that the chronic rhinosinusitis patients diagnosed by EPOS criteria had latent obstructive lung function changes, and that upper airway conditions had critical effects on lower airway inflammation and hypersensitivity both in vivo and in vitro.^5,6,11,15 We showed in this study that a soft tissue shadow in the paranasal sinus was frequently detected in persistent cough patients with neither asthma nor abnormal chest X-ray findings. In addition, although the correlations were weak, the radiological severity of chronic rhinosinusitis measured by the Lund–Mackay CT score significantly correlated to the level of lower airway obstruction. Similar findings were also observed in never-smoker patients. Our findings suggest that the examination of the upper airway is important in patients with chronic cough and no remarkable findings from chest X-rays.

Circulating and/or local leukocytes (neutrophils, eosinophils, lymphocytes, monocytes, and basophils) play a critical role in the inflammation. The etiology of inflammation is classified into infectious and noninfectious. The relationship between rhinitis and asthma in the united airway concept is mainly explained by eosinophilic (noninfectious) inflammation. On the other hand, many lung diseases complicating chronic rhinosinusitis (eg, cystic fibrosis, primary ciliary dyskinesia, COPD, and sinobronchial syndrome) have neutrophil-dominant inflammation. We showed in this study that the eosinophil count in peripheral blood correlated with the spirometric parameters showing airway obstruction (%FEV_1.0 and FEV_1.0/FVC ratio). Eosinophilic inflammation both in sinonasal mucosa and lung may be a possible explanation for the coexistence of chronic rhinosinusitis and obstructive change in the peripheral airways of the lung.

Several explanations for the close association of the upper and lower airway diseases have been reported. One of these hypotheses is the effect of postnasal drip with inflammatory mediators and/or pathogens. Other mechanisms including systemic reactions, nasobronchial reflex, pharyngobronchial reflex, the effect of nasal obstruction, smoking, and inhalation of environmental pollutants have also been suggested.¹⁰ There was a considerable difference between genders for the symptoms of chronic rhinosinusitis including postnasal drip.^28,29 There were more female than male in some groups in this study. The gender imbalance might have a bias on the results.

A previous study showed that the concentration of interleukin (IL)-1β and IL-5 in nasal discharge significantly correlated with the FEV_1.0/FVC ratio in patients with chronic rhinosinusitis.⁹ IL-1β is an essential cytokine in various inflammatory conditions. IL-5 is an important factor for eosinophil differentiation, proliferation, priming, activation, and survival. IL-5 is required for the development of allergic airway eosinophilia. Recently, a novel disease concept for intractable chronic rhinosinusitis (eosinophilic chronic rhinosinusitis) has been established, and the JESREC study group proposed diagnostic criteria for eosinophilic chronic rhinosinusitis.³⁰ Eosinophilic chronic rhinosinusitis patients frequently have coexisting lower airway diseases, particularly asthma.^30,31 In this study, even though the patients clinically diagnosed as having asthma and the patients with abnormal chest X-ray findings were excluded, the significant relationship between peripheral blood eosinophil count and lung function was detected. These findings suggest that subclinical eosinophilic inflammation may have some effect on the airway obstruction in chronic cough patients. The medical therapies including anti-inflammatory/anti-eosinophilic agents might be useful for the management for patients with chronic cough.

Conclusion

In this study, Lund–Mackay CT score correlated directly with evidence of obstructive pulmonary disease, and FEV_1.0/FVC ratio negatively correlated to eosinophil counts in patients with chronic cough. The significant correlation was not found between the SNOT scores and lung function in this study. Previous studies reported that a significant correlation was determined between Lund–Mackay CT score and SNOT scores in COPD or chronic rhinosinusitis patients.^32,33 To the best of our knowledge, there is no study reporting the SNOT scores in chronic cough patients. The SNOT score might not be useful for examining patients with chronic cough.

Several diseases including nonasthmatic eosinophilic bronchitis and cough hypersensitivity syndrome can cause chronic cough.^34–36 The patients with nonasthmatic eosinophilic bronchitis have airway hyperresponsiveness without airflow obstruction. Chronic cough has a complex pathophysiology. In nonasthmatic chronic cough patients, not only neutrophilic inflammation but also eosinophilic inflammation should be considered. The clinical evaluation of chronic cough should include a chest X-ray, pulmonary function tests, and consideration of an otolaryngology referral or careful examination of the upper airway including CT.

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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by JSPS KAKENHI (Grants-in-Aid for Scientific Research; Grant Number, JP17K11329).

References

Brozek

Bousquet

Baena-Cagnani

et al . Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010; 126:466–476.

Bachert

Claeys

Tomassen

et al . Rhinosinusitis and asthma: a link for asthma severity. Curr Allergy Asthma Rep. 2010; 10:194–201.

Dixon

AE.

Rhinosinusitis and asthma: the missing link.

Curr Opin Pulm Med. 2009; 15:19–24.

Kariya

Okano

Nishizaki

Relationship between chronic rhinosinusitis and lower airway diseases: an extensive review.

World J Otorhinolaryngol. 2015; 5:44–52.

Liang

Jiang

Wang

et al . Upper airway inflammation exacerbates bronchial hyperreactivity in mouse models of rhinosinusitis and allergic asthma. Int Forum Allergy Rhinol. 2013; 3:532–542.

Hellings

Hens

Rhinosinusitis and the lower airways.

Immunol Allergy Clin North Am. 2009; 29:733–740.

Lamprecht

McBurnie

Vollmer

et al . COPD in never smokers: results from the population-based burden of obstructive lung disease study. Chest. 2011; 139:752–763.

Lund

Mackay

IS.

Staging in rhinosinusitus.

Rhinology. 1993; 31:183–184.

Kariya

Okano

Oto

et al . Pulmonary function in patients with chronic rhinosinusitis and allergic rhinitis. J Laryngol Otol. 2014; 128:255–262.

10.

Kariya

Okano

Higaki

et al . Chronic rhinosinusitis patients have decreased lung function. Int Forum Allergy Rhinol. 2014; 4:828–833.

11.

Kariya

Okano

Higaki

et al . Pulmonary function in never-smoker patients with chronic rhinosinusitis. Int Forum Allergy Rhinol. 2015; 5:990–995.

12.

Gibson

Wang

McGarvey

et al . Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149:27–44.

13.

Miller

Hankinson

Brusasco

et al . Standardisation of spirometry. Eur Respir J. 2005; 26:319–338.

14.

Lindemann

Tsakiropoulou

Konstantinidis

Lindemann

Normal aging does not deteriorate nose-related quality of life: assessment with “NOSE” and “SNOT-20” questionnaires.

Auris Nasus Larynx. 2010; 37:303–307.

15.

Fokkens

Lund

Mullol

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

16.

Nazri

Bux

Tengku-Kamalden

et al . Incidental detection of sinus mucosal abnormalities on CT and MRI imaging of the head. Quant Imaging Med Surg. 2013; 3:82–88.

17.

Ashraf

Bhattacharyya

Determination of the “incidental” Lund score for the staging of chronic rhinosinusitis.

Otolaryngol Head Neck Surg. 2001; 125:483–486.

18.

Lim

Ramirez

Garneau

et al . Three-dimensional image analysis for staging chronic rhinosinusitis. Int Forum Allergy Rhinol. 2017; 7:1052–1057.

19.

Hill

Bhattacharyya

Hall

et al . Incidental paranasal sinus imaging abnormalities and the normal Lund score in children. Otolaryngol Head Neck Surg. 2004; 130:171–175.

20.

Samitas

Carter

Kariyawasam

Xanthou

Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: the one airway concept revisited.

Allergy. 2018; 73:993–1002.

21.

Reid

Carlson

AA.

Clinical use of aclidinium in patients with COPD.

Int J Chron Obstruct Pulmon Dis. 2014; 9:369–379.

22.

Ishiura

Fujimura

Yamamoto

et al . Role of COX-2 in cough reflex sensitivity to inhaled capsaicin in patients with sinobronchial syndrome. Cough. 2010; 6:7.

23.

Homma

Yamanaka

Tanimoto

et al . Diffuse panbronchiolitis. A disease of the transitional zone of the lung. Chest. 1983; 83:63–69.

24.

Hox

Maes

Huvenne

et al . A chest physician’s guide to mechanisms of sinonasal disease. Thorax. 2015; 70:353–358.

25.

Accordini

Janson

Svanes

Jarvis

The role of smoking in allergy and asthma: lessons from the ECRHS.

Curr Allergy Asthma Rep. 2012; 12:185–191.

26.

Polosa

Thomson

NC.

Smoking and asthma: dangerous liaisons.

Eur Respir J. 2013; 41:716–726.

27.

Tønnesen

Smoking cessation and COPD.

Eur Respir Rev. 2013; 22:37–43.

28.

Lal

Golisch

Elwell

et al . Gender-specific analysis of outcomes from endoscopic sinus surgery for chronic rhinosinusitis. Int Forum Allergy Rhinol. 2016; 6:896–905.

29.

Lal

Rounds

Divekar

Gender-specific differences in chronic rhinosinusitis patients electing endoscopic sinus surgery.

Int Forum Allergy Rhinol. 2016; 6:278–286.

30.

Tokunaga

Sakashita

Haruna

et al . Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study. Allergy. 2015; 70:995–1003.

31.

Uraguchi

Kariya

Makihara

et al . Pulmonary function in patients with eosinophilic chronic rhinosinusitis. Auris Nasus Larynx. 2018; 45:476–481.

32.

Kelemence

Abadoglu

Gumus

et al . The frequency of chronic rhinosinusitis/nasal polyp in COPD and its effect on the severity of COPD. COPD. 2011; 8:8–12.

33.

Brooks

Trope

Blasetti

et al . Preoperative Lund-Mackay computed tomography score is associated with preoperative symptom severity and predicts quality-of-life outcome trajectories after sinus surgery. Int Forum Allergy Rhinol. 2018; 8:668–675.

34.

Lai

Chen

Peng

Zhan

Non-asthmatic eosinophilic bronchitis and its relationship with asthma.

Pulm Pharmacol Ther. 2017; 47:66–71.

35.

Song

Morice

AH.

Cough hypersensitivity syndrome: a few more steps forward.

Allergy Asthma Immunol Res. 2017; 9:394–402.

36.

Morice

Millqvist

Belvisi

et al . Expert opinion on the cough hypersensitivity syndrome in respiratory medicine. Eur Respir J. 2014; 44:1132–1148.