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Marte Rystad Øie,1,2 Anne-Sofie Helvik,1,3 Malcolm Sue-Chu,4,5 Sverre Karmhus Steinsvåg,6,7 Wenche Moe Thorstensen1,2 1Department of Otolaryngology, Head and Neck Surgery, St. Olavs hospital, 7006 Trondheim University Hospital, Trondheim, Norway; 2Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 3Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway; 4Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; 5Department of Thoracic Medicine, St. Olavs hospital, Trondheim University Hospital, Trondheim, Norway; 6Department of Otolaryngology, Head and Neck Surgery, Sørlandet Hospital, Kristiansand, 4604, Norway; 7Haukeland University Hospital, Bergen, NorwayCorrespondence: Marte Rystad Øie, Department of Otolaryngology, Head and Neck Surgery, St. Olavs hospital, Trondheim University Hospital, 3250 Torgarden, Trondheim, NO-7006, Norway, Tel +47 926 42 329, Email marte.oie@gmail.com; marte.r.oie@ntnu.noPurpose: Sinonasal symptoms are prevalent in COPD, and knowledge of the relationship between these symptoms and clinical markers of COPD is limited. This study explores the associations between the burden of sinonasal symptoms and clinical markers and thresholds recommended for guiding treatment decisions in the GOLD guidelines.Patients and Methods: Sinonasal symptoms were quantified with the rhinological subscale of the Sino-Nasal-Outcome-Test (SNOT-22) in 93 COPD patients characterized by the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2012 diagnostic criteria for rhinosinusitis without nasal polyps (RSsNP). Associations between a high burden, defined as a SNOT22_rhinological score of ≥ 11, and the following markers were assessed by adjusted multivariable linear regressions; severity of dyspnea [modified Medical Research Council (mMRC)] and cough [Visual Analogue Scale (VAS)], physical activity [6-minute walking distance (6MWD)], mortality risk (BODE index), and HRQoL [disease-specific COPD Assessment Test (CAT) and St. Georges Respiratory Questionnaire (SGRQ), and physical component summary, Short Form-36 version 2.0 (PCS SF-36v2)]. Odds ratios for the association of a high burden and threshold levels for regular treatment were estimated by adjusted binomial logistic regression models.Results: A high burden was associated with greater severity of dyspnea and cough, lower 6MWD, higher BODE index and poorer HRQoL. The odds ratio of having CAT and SGRQ scores that are above the thresholds recommended for treatment was 5– 7-fold greater in the high burden group.Conclusion: A high burden of sinonasal symptoms is positively associated with the clinical markers of symptom severity and mortality risk and is inversely associated with physical activity and HRQoL in COPD. These findings add further support that the UAD concept also applies to COPD. Enquiry about sinonasal symptoms in COPD patients should be incorporated into the clinical routine.Keywords: united airways disease, chronic nasal symptoms, rhinosinusitis, HRQoL

Rhinosinusitis without nasal polyps (RSsNP) is prevalent in COPD. Previous studies on its association with health-related quality of life (HRQoL) have limitations, and RSsNP is currently not recognized as a comorbidity. This study investigates HRQoL in COPD including a focus on RSsNP. Generic HRQoL was assessed with the Short Form-36 (SF-36v2) questionnaire and compared between 90 COPD and 93 control subjects and in subgroups with and without RSsNP. The association between RSsNP and COPD versus not and generic HRQoL was assessed by multivariable linear regression with adjustments for age, education, and body mass index (BMI). Disease-specific HRQoL was assessed by Sinonasal outcome test-22 (SNOT-22), St. Georges Respiratory Questionnaire (SGRQ), and COPD Assessment Test (CAT) and compared between COPD with and without RSsNP, and their association to RSsNP was assessed by multivariable linear regression with adjustments for age, BMI, and FEV 1 % predicted. RSsNP was associated with poorer disease-specific HRQoL, with higher SNOT-22 total score (14.67 points; 95% CI, 7.06-22.28; P < .001) and psychological subscale score (3.24 points; 95% CI, 0.37-6.11; P = .03), SGRQ symptom score (13.08 points; 95% CI, 2.73-23.4; P = .014), and CAT score (4.41 points; 95% CI, 1.15-7.66; P = .009). Generic HRQoL was poorer in COPD patients than in the control subjects. In addition to COPD, concomitant RSsNP was associated with poorer physical functioning, general health, vitality, and physical component summary. RSsNP in COPD is associated with poorer disease-specific HRQoL that is clinically relevant and, as it is amenable for treatment, should be recognized as a comorbidity of COPD., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The validity of the united airway disease concept for rhinosinusitis (RS) and chronic obstructive pulmonary disease (COPD) has been questioned because of methodological limitations in previous studies. In this study we investigated the prevalence of RS without nasal polyps (RSsNP) and the severity of sinonasal symptoms in COPD and a corresponding control group. We also evaluated the diagnostic accuracy of these symptoms for RSsNP in COPD. 90 COPD patients and 93 controls were included in an observational cross-sectional study where globally accepted diagnostic criteria of RS and COPD (EPOS 2012 and GOLD) were incorporated; symptomatic and endoscopic criteria for the diagnosis of RS, and spirometry with reversibility for diagnosis of COPD. RS symptoms were identified by responses to the sinonasal outcome test (SNOT-22), nasal endoscopy identified signs of sinonasal disease and discriminated between RS with and without nasal polyps, and visual analogue scales (VAS) rated the severity of sinonasal symptoms. We found RSsNP in 51% of our COPD patients which is threefold greater than in the control group (p<0.001). Nasal discharge (72%) and nasal obstruction (62%) were the two most frequently reported symptoms in COPD. The diagnostic accuracy for RSsNP is better for the composite VAS for rhinological symptoms than for facial symptoms. We conclude that RSsNP is present in 51% of our COPD patients, which is significantly more prevalent compared to a corresponding control group. These results suggest that COPD is associated with RS., Competing Interests: Conflict of interest: M.R. Øie has nothing to disclose. Conflict of interest: S.B. Dahlslett has nothing to disclose. Conflict of interest: M. Sue-Chu has nothing to disclose. Conflict of interest: A-S. Helvik has nothing to disclose. Conflict of interest: S.K. Steinsvåg has nothing to disclose. Conflict of interest: W.M. Thorstensen has nothing to disclose., (Copyright ©ERS 2020.)

Background: The aim of the present study was to explore the relationship between excessive daytime sleepiness (EDS), Peak Nasal Inspiratory Flow (PNIF), and patient reported symptoms from the nose., Methology: Six hundred and fifty one consecutive patients referred to a hospital on suspicion of sleep related breathing disorder (SRBD) were included in the study. Daytime sleepiness was assessed by Epworth Sleepiness Scale (EpSS). Nasal airflow was measured with Peak Nasal Inspiratory Flow (PNIF). Symptoms of sino-nasal dysfunction and diseases were graded on Visual Analogue Scales (VAS)., Results: EpSS score was not correlated with nasal flow as measured by PNIF or nasal obstruction - VAS scores. There were significant associations between daytime sleepiness and patient-reported VAS-scores on nasal discharge, headache, coughing, general health and to some extent sneezing when age, gender, BMI and reported co-morbidity levels were adjusted for., Conclusion: A clinical implication of this is that patients with EDS may be evaluated and treated for sino-nasal disease, while medical and surgical measures to open the nose per se may not be effective therapeutic options. A scientific implication is that the relationship between SRBD and sino-nasal disease should be further investigated.

Introduction: The pathophysiology of chronic rhinosinusitis (CRS) is unclear. It has been discussed for decades whether gastro-oesophageal reflux (GOR) may be a contributing factor for some patients. The aim of the present study was to evaluate the level of GOR in an unselected group of patients with CRS using multichannel impedance-pH monitoring., Methods: Consecutive patients with CRS diagnosed using the EPOS2012 criteria, completed questionnaires on GOR symptoms and were offered 24-h multichannel intraluminal impedance (MII)-pH monitoring. The results were compared with a group of healthy controls., Results: Forty-six patients completed MII-pH-monitoring and were compared with 45 control subjects, with comparable age and gender distributions. The median number of reflux episodes in the patients was 56.5 compared with 33 in controls, while, the numbers of proximal reflux episodes was 27.5 versus 3, respectively. Thirty nine patients had abnormal pH-impedance recordings compared with five controls., Conclusion: The CRS patients had significantly higher incidences of gastro-oesophageal reflux compared with asymptomatic controls. The results of this study suggest that GOR may be a causative or contributing factor of CRS.

Background: The effect of pulmonary pathology on peak nasal inspiratory flow (PNIF) remains largely unknown. We investigated an association between a diagnosis of asthma and of lung function on PNIF when adjusted for possible confounders. Further, we investigated the perception of nasal obstruction in asthmatics compared to healthy controls when adjusted for PNIF., Methodology: Eighty-seven asthmatics and 92 non-asthmatic controls underwent PNIF (categorized into groups of high, medium and low), acoustic rhinometry (AR) and spirometry, and we assessed symptoms of nasal obstruction on visual analogue scales (VAS) in three categories., Results: PNIF was significantly associated with asthma and forced expiratory volume in the first second (FEV1) (% predicted). Other factors associated with PNIF were the degree of nasal obstruction measured both subjectively on a VAS and objectively with AR, age and disease status. Asthma patients were 19 times more likely to be in a higher VAS category compared to non-asth- matic controls independent of PNIF group., Conclusion: Special care has to be taken when interpreting PNIF values in patients with asthma or reduced FEV1 (% predicted). The sensation of nasal obstruction in asthmatics is different from controls despite being in the same PNIF group.

Background: The Unified Airways hypothesis suggests an involvement of the upper airways in asthma. Critical parameters of the nasal airway can be quantified objectively with acoustic rhinometry (AR) and peak nasal inspiratory flow (PNIF)., Objective: We aimed to investigate nasal airway patency in asthmatics compared to non-asthmatic controls. Nasal volume, cross sectional area and flow were measured using acoustic rhinometry (AR) and peak nasal inspiratory flow (PNIF) in 87 asthmatics and 93 non-asthmatic controls before and after decongestion with xylometazoline. Nasal congestion index (NCI) was calculated, and allergy status was assessed by skin prick test or specific IgE., Results: We found significantly smaller minimum cross sectional area and nasal cavity volume in asthmatics than controls, and the cross sectional area is at its minimum at 2-3 cm from the nasal orifice in both groups. AR and PNIF measurements are not different in allergic and non allergic subjects in either group. The effect of xylometazoline is not significantly different between the 2 groups with regard to AR, but there is a significant improvement in PNIF for the asthmatics when assessed by the NCI., Conclusion: The present study demonstrates a significantly smaller nasal airway when assessed by minimum cross sectional area and nasal cavity volume in asthmatics than controls, and these findings apply to asthmatics and controls irrespective of allergy status., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: The Unified Airways Hypothesis suggests an involvement of the upper airways in asthma. We aimed to evaluate the association between subjective sino-nasal complaints, nasal air flow, and sino-nasal quality of life (QOL) in patients with asthma compared with nonasthmatic subjects., Study Design: Case-control study., Setting: A tertiary referral center., Subjects and Methods: Symptoms, quality of life, and nasal airflow were assessed in 91 asthmatics and 95 nonasthmatic controls with Visual Analog Scale (VAS, 0-100), Sino-Nasal Outcome Test (SNOT-20), and Peak Nasal Inspiratory Flow (PNIF), respectively. Asthma and allergy status were assessed by Asthma Control Questionnaire (ACQ) and skin prick test or specific IgE., Results: Asthmatic patients (men/women, 37/54; mean age, 43.7 years; range, 19-64 years) reported significantly more nasal obstruction (mean VAS, 37 mm; SD = 26, 95% CI, 32-43 vs 9 mm, SD = 11, 95% CI, 7-11, P < .001) and lower sino-nasal quality of life (mean SNOT-20, 1.3; SD = 0.8, 95% CI, 1.1-1.5 vs 0.4, SD = 0.5, 95% CI, 0.3-0.5, P < .001) than controls (men/women, 42/53; mean age, 43.8 years; range, 20-65 years). PNIF was significantly lower in asthmatic patients than controls (mean PNIF, 84 l/min; SD = 24, 95% CI, 79-89 vs 100 l/min SD = 24, 95% CI, 95-105, P < .001)., Conclusion: Both allergic and nonallergic asthma were associated with increased sino-nasal symptoms, reduced sino-nasal QOL, and reduced inspiratory nasal air flow compared to controls. This provides further evidence of the clinical importance of the upper airway in the diagnostic and therapeutic management of asthma patients beyond the scope of allergy.

Though some data indicate an association between gastroesophageal reflux disease (GERD) and upper airway inflammatory disease, a connection between GERD and chronic rhinosinusitis (CRS) is a matter of controversy in today's medicine. The aim of this study was to examine whether patients with GERD have a different nose- and sinus-related quality of life compared to a control group. A total of 77 patients with GERD diagnosed by gastroscopy were evaluated according to their nose- and sinus-related quality of life. It was scored using the Sino-Nasal Outcome Test-20 (SNOT-20). Total SNOT-20 score was compared with a control group consisting of 480 teachers. The average total SNOT-20 score in patients with GERD was 22.1, and in the control group 9.4 (p < 0.005). In the patient group, the median was 17.0 and standard deviation 18.4 corresponding to 5.0 and 11.5 in the controls. The 95% confidence interval in the patient group was (18.0, 26.3), and (8.3, 10.4) in the control group. Patients with GERD have a reduced nose- and sinus-related quality of life compared to a control group based on the fact that they have a significantly higher total SNOT-20 score than the controls. Accordingly, this study indicates that there is a causal relationship between GERD and CRS.

Habitual smoking represents a chronic insult to the airway. However, the effects of smoking on upper airway health remains poorly described. Our objective was to examine the relationship between cigarette smoking and self-assessed upper airway health and evaluate dose-response relationships between exposure and complaints in a sample of 2,523 patients. Eligible subjects were adults referred to ENT specialist for evaluation of chronic nasal or sleep-related complaints. Thirteen specific symptoms and conditions, mainly related to the upper airway, were graded based on visual analog scales (VAS). Smokers, representing 33% of the sample, were more likely to report severe upper airway complaints compared to non-smokers (odds ratio 1.31-2.08) and exhibited significantly higher visual analog scale scores than non-smokers for 9 out of 13 outcome variables (p < 0.001-0.007). Further, significant associations were found between cigarette consumption and severity of complaints (p < 0.001-0.01), heavy smokers generally being more likely to exhibit high VAS scores than light smokers. In several cases smoking status and self-reported asthma/allergy had similar impact on subjective outcomes. Cigarette smoking was clearly associated with impaired upper airway health and seemed to be an important determinant in subjects seeking medical attention due to chronic nasal or sleep-related complaints. Both threshold and dose-response like relationships were evident between cigarette consumption and the outcome measures.

Background: Diseases in the upper and lower airways often occur concomitantly, and evidence indicates a close relationship between them. Optimal treatment of airway disease requires knowledge about this relationship; the article presents an updated overview of the field., Material and Methods: This paper is based on extensive clinical experience with airway disease, own research and literature studies., Results: It is well documented that patients suffering from asthma have rhinitis more often than those without. Likewise, those suffering from nose and sinus disease, e.g. allergic rhinitis, sinusitis and nasal polyposis, have an increased incidence of asthma. Treatment of disorders in one airway compartment often has a positive impact on the airways in general., Interpretation: Disorders in the upper and lower airways should be considered as the same disease to a larger extent than they are today. Patients with disease in one airway compartment should be considered for pathology elsewhere in the airways. Therapeutically, the airways should be regarded as one entity.

Objectives: The relationship between congestion of the nasal mucosa and subjective nasal obstruction remains poorly defined. Applying the novel Nasal Congestion Index (NCI), we compared subjective nasal obstruction with objective measures for reversible congestion of the nasal mucosa., Study Design: A total of 2,523 consecutive patients were included in this cross-sectional study. Eligible subjects were adults referred to the ENT department, Sørlandet Hospital, Kristiansand, Norway, for evaluation of chronic nasal or sleep-related complaints., Methods: Subjects underwent acoustic rhinometry (AR) and peak nasal inspiratory flow (PNIF) at baseline and after decongestion of the nasal mucosa. Based on these registrations, an NCI was calculated for minimal cross-sectional area (MCA), nasal cavity volume (NCV), and PNIF, and employed for quantification of reversible mucosal congestion. Subjective nasal obstruction was measured by nasal obstruction visual analogue scales (NO-VAS). Statistical analyses were based on ANOVA and multiple linear and logistic regression, adjusting for age, gender, body mass index, asthma, allergy, smoking history, and type of planned intervention., Results: Crude estimates indicated that the NCIs were significantly higher in subjects with severe complaints of nasal obstruction compared with subjects with lesser symptoms (P < .001). These associations were confirmed by linear and logistic regression analyses. NCI for MCA, NCV, and PNIF showed highly significant associations with subjective nasal obstruction (P < .001)., Conclusions: We have clearly demonstrated an association between subjective nasal obstruction and reversible congestion of the nasal mucosa by employing the NCI. The measure has proven to be useful for evaluating patients with complaints of nasal obstruction.

Nasal blockage is a common complaint in Family Practice. Decongestive nosedrops are frequently employed therapeutic measures. Due to a considerable risk of abuse and side effects, alternatives are wanted. The purpose of this study was to elucidate to what extent ENDS might represent an alternative to decongestive nose sprays (DNS). The effects of DNS (xylometazolin) and ENDS (BreatheRight) on subjective and objective nasal blockage were compared in 89 patients. Main outcome measures were recordings of nasal symptom scores on visual analogue scales (VAS), minimal cross-sectional areas (MCA) and nasal cavity volumes (NCV) as measured by acoustic rhinometry (AR), and peak nasal inspiratory flow (PNIF). ENDS significantly increased the MCA and the NCV in the anterior 0.0-3.0 cm of the nose compared to DNS, but had no effect on MCA from 3.0 to 5.4 cm behind the nostrils. In contrast to DNS, ENDS had no effect on the posterior NCV. ENDS and DNS gave comparable increase in nasal inspiratory flow as measured by PNIF, and in the subject's own experience of nasal obstruction. ENDS may represent an alternative to DNS as a measure against nasal blockage.

Background: Bronchial hyperresponsiveness (BHR) is common in bakery workers. The relation between bronchial responsiveness measured with a tidal breathing method and smoking, airway symptoms, IgE-sensitization, nasal indices of inflammation and flour dust exposure have been studied with bronchial responsiveness expressed as a continuous outcome., Material and Methods: Bakery workers (n = 197) were subjected to interviews, questionnaires, allergy tests, workplace dust measurements and bronchial metacholine provocation. Eosinophil cationic protein (ECP) and alpha(2)-macroglobulin were measured in nasal lavage. Bronchial responsiveness was expressed as slope(conc), a measurement based on regressing the per cent reduction in FEV(1) at each provocation step., Results: BHR expressed as slope(conc) was associated with smoking (P = 0.009), asthma symptoms at work (P = 0.001), and occupational IgE sensitization (P = 0.048). After adjusting for baseline lung function the association between BHR and IgE sensitization was no longer present. We demonstrated an association between nasal ECP and BHR (slope(conc) < 3: P = 0.012), but not to alpha(2)-macroglobulin in nasal lavage. No association was seen between BHR and current exposure level of flour dust, number of working years in a bakery or a history of dough-making., Conclusion: BHR is related to baseline lung function, work-related asthma symptoms, smoking and nasal eosinophil activity, but not to occupational IgE sensitization and current flour dust exposure when measured with metacholine provocation. The slope(conc) expression seems to be a useful continuous outcome in bronchial responsiveness testing.

Objective: A link between the upper and lower airways has been convincingly demonstrated both in health and disease. To what extent the nose may be involved in children's asthma, has so far not been thoroughly investigated. In this study, we compared symptoms and signs from the upper airways in children with asthma and in children without to find out more about this., Methods: The study group included 27 asthmatic children, the control group 29 age and sex-matched healthy volunteers. The children were investigated by a senior ENT-specialist. Their parents completed questionnaires about symptoms and signs of upper airway disorders. Skin prick tests, total IgE, acoustic rhinometry, and an X-ray of the epipharynx were performed. The data from the groups were compared., Results: Nasal blockage, mouth breathing, day time sleepiness, apnoeas, itching, sneezing, and hearing impairment were more prevalent in asthmatics compared with controls (p<0.05). For nasal blockage the mean VAS-scores were 52.4 and 30.6 for asthmatics and controls, respectively. For daytime sleepiness the corresponding figures were 34.6 and 23.1. The adenoid-nasopharynx-index was larger, indicating reduced palatal airway in the former compared with the latter (p<0.05)., Conclusions: As the site of upper airway obstruction in asthmatic children appears to be the epipharynx, the adenoids may play a key-role.

Aims: Rhinitis symptoms frequently occur in bakery-workers. Yet, little is known about the pathophysiology of this condition. The objective of the present study was to examine nasal indices of inflammation in relation to occupational dust exposure, occupational rhinitis according to defined criteria, rhinitis symptoms associated to the workplace, and occupational sensitization in bakery-workers., Methods: Bakery-workers (n = 197) were subjected to interviews, questionnaires, workplace dust measurements, allergy tests, and nasal lavages with and without histamine. alpha(2)-Macroglobulin and eosinophil cationic protein (ECP) were measured in saline lavages as indices of plasma exudation and eosinophilic activity, respectively. Histamine lavages were employed to explore the nasal exudative responsiveness., Results: alpha(2)-Macroglobulin and ECP increased significantly by increased workplace dust exposure (P< or =0.035). Furthermore, the exudative responsiveness to histamine increased significantly by such exposure (P< or =0.016). Similar patterns were seen in workers with occupational rhinitis and in subjects with rhinitis symptoms associated to the workplace, but not in workers with occupational sensitization., Conclusions: We conclude that occupational dust exposure in bakery-workers is associated with nasal eosinophilic exudative inflammation. In contrast, occupational sensitization is not a discriminating factor with regard to indices of eosinophilic, exudative inflammation in the present material.

Conclusions: The use of different diagnostic criteria has considerable consequences for the prevalence estimates of occupational rhinitis. There is a strong relationship between occupational rhinitis and lower airway symptoms. Storage mites appear to be important occupational allergens in Norwegian bakeries., Objectives: To study the consequences of various diagnostic criteria on the prevalence of occupational rhinitis, assess the prevalence of IgE sensitization and explore the relationships between upper and lower airway symptoms and between symptoms and IgE sensitization., Material and Methods: A total of 197 employees in 6 bakeries were interviewed and completed a questionnaire. A skin prick test was performed, total and specific IgE were determined and a histamine release test was performed for relevant allergens. The criteria for the diagnosis of occupational rhinitis were based on the 1994 International Consensus Report on Rhinitis., Results: The prevalence of occupational rhinitis varied between 23% and 50%, depending on the criteria used. The occurrence of nasal symptoms was found to precede the development of lower airway symptoms. Occupational rhinitis, both IgE- and non-IgE-mediated, was associated with asthma symptoms. The most frequent causes of sensitization (20%) were different species of storage mites. Storage mite sensitization was related to occupational rhinitis and work exposure.

Nasal obstruction can be monitored objectively by measurement of nasal airflow, as evaluated by nasal peak flow, or as airways resistance/conductance as evaluated by rhinomanometry. Peak flow can be measured during inspiration or expiration. Of these measurements, nasal inspiratory peak flow is the best validated technique for home monitoring in clinical trials. The equipment is portable, relatively inexpensive, and simple to use. One disadvantage, however, is that nasal inspiratory peak flow is influenced by lower airway as well as upper airway function. Rhinomanometry is a more sensitive technique that is specific for nasal measurements. The equipment, however, requires an operator, is more expensive, and is not portable. Thus, it is applicable only for clinic visit measures in clinical trials. Measurements require patient cooperation and coordination, and not all can achieve repeatable results. Thus, this objective measure is best suited to laboratory challenge studies involving smaller numbers of selected volunteers. A nonphysiological measure of nasal patency is acoustic rhinometry. This sonic echo technique measures internal nasal luminal volume and the minimum cross-sectional area. The derivation of these measures from the reflected sound waves requires complex mathematical transformation and makes several theoretical assumptions. Despite this, however, such measures correlate well with the nasal physiological measures, and the nasal volume measures have been shown to relate well to results obtained by imaging techniques such as computed tomography scanning or magnetic resonance imaging. Like rhinomanometry, acoustic rhinometry is not suitable for home monitoring and can be applied only to clinic visit measures or for laboratory nasal challenge monitoring. It has advantages in being easy to use, in requiring little patient cooperation, and in providing repeatable results. In addition to nasal obstruction, allergic rhinitis is recognized to be associated with impaired mucociliary clearance and altered nasal responsiveness. Measures exist for the monitoring of these aspects of nasal dysfunction. Although measures of mucociliary clearance are simple to perform, they have a poor record of reproducibility. Their incorporation into clinical trials is thus questionable, although positive outcomes from therapeutic intervention have been reported. Measures of nasal responsiveness are at present largely confined to research studies investigating disease mechanisms in allergic and nonallergic rhinitis. The techniques are insufficiently standardized to be applied to multicenter clinical trials but could be used in limited-center studies to gain insight into the regulatory effects of different therapeutic modalities.

Objective: Benzalkonium chloride (BC) is a preservative commonly used in nasal decongestant sprays. It has been suggested that BC may be harmful to the nasal mucosa. The present study, involving healthy volunteers, examines effects of BC on nasal mucosal end-organ functions., Methods: Isotonic saline and BC (0.1 mg/mL) were administered acutely to the nasal mucosa using a nasal pool device. Nasal symptoms were determined. Nasal lavage fluid levels of alpha2-macroglobulin and fucose were measured as indices of plasma exudation and glandular secretion, respectively. In addition, BC (0.1 mg/mL) was given as single actuations of 100 microL per nasal cavity three times daily for 10 days. The ability of histamine (0.4 mg/mL) to evoke nasal symptoms and plasma exudation responses was determined before and after the repeated BC administration series., Results: BC produced immediate nasal smart or pain (P < .05), but tolerance to this response developed by repeated administrations. BC increased nasal mucosal output of fucose (P < .05), whereas nasal lavage fluid levels of alpha2-macroglobulin were unaffected. Histamine produced significant symptoms and mucosal exudation of alpha2-macroglobulin (P values < .01), equally before and after the 10 days of BC exposure., Conclusions: BC in dosages commonly used as preservative in nasal decongestant sprays produced short-term glandular secretion and nasal smart or pain. However, 10 days' frequent exposure to BC was not associated with untoward symptomatic effects, nor was a sensitive mucosal variable such as histamine-induced exudative responsiveness affected by this repeated exposure 1 BC.

Benzalkonium chloride (BC) is a bactericidal compound used as a topical antiseptic and as a preservative in various products for local treatment, e.g., eye and nose drops. BC is toxic to human cells, including those of the respiratory mucosa. Few studies have, however, focused on what cellular functions BC interferes with. The effects of BC were studied on washed human blood platelets in vitro . Cellular energy production as well as secretion were studied. Incubation of platelets with BC resulted in rapid swelling and toxic morphological changes. After incubation with BC oxidation of [1-14C] palmitate was inhibited, and both lactate dehydrogenase and endogenous serotonin were spontaneously released. Thrombin-induced secretion of serotonin was strongly reduced after BC exposure. Histological changes with increased size, spherical form, decreased numbers of pseudopodia, loss of an intact continuous tubulus system and reduced number of granules were found by scanning and transmission electron microscopy. It is concluded that the toxic effects of BC are because of interference with membrane function and energy production.

The incidence of allergic rhinitis is increasing, as is our knowledge of its pathogenesis, epidemiologic factors and optimal therapeutic principles. This paper discusses various allergy promoting factors and gives a brief update on current immunological concepts of allergy. Recent achievements in the pathogenesis of allergic rhinitis are discussed, as well as pharmacological and non-pharmacological treatment.

Fifty rats were treated with topical nasal steroids with and without the preservative benzalkonium chloride in their right nostril twice daily for 21 days, while the left nostrils were exposed to 0.9% NaCl. By cutting the noses serially in frontal sections, the structure of the mucosal lining of all parts of the nose could be investigated. Areas with squamous cell metaplasia were observed in all nostrils exposed to topical steroids containing benzalkonium chloride. Such alterations were not observed in any nasal cavities exposed to the topical nasal steroid without the preservative or to 0.9% NaCl. In conclusion, benzalkonium chloride appears to be potentially toxic to the mucosa in vivo.

Human respiratory mucosa and human granulocytes were exposed to topical nasal steroids in vitro. The preparations containing benzalkonium chloride and benzalkonium chloride alone destroyed the mucosa within 10 days. The same preparations also inhibited human neutrophil actin polymerization, degranulation and oxidative burst in vitro in a time and concentration dependent manner. Preparations without benzalkonium chloride, as well as the steroid compounds themselves, did not have these effects. It is concluded that benzalkonium chloride has toxic effects on human respiratory mucosa and human neutrophils in vitro.

The supply of fresh bronchial tissue from human donors for in vitro culture is limited. Routine fiberoptic bronchoscopy offers a safe and easy procedure for obtaining minor biopsies and we wanted to see if the material provided could be used for organ culture by using a simple liquid overlay technique. Bronchial biopsies were cut into fragments 400-500 microns and kept immersed in a standard serum-supplemented medium for 40 days. An agar base prevented adhesion of the tissue. By light and electron microscopy it was shown that the tissue fragments had a differentiated epithelium at their surface throughout the culture period. An outgrowth of epithelial cells on the scaffold of the exposed stroma, covering the surface of the whole fragment, occurred within the first 5 days of culture. This epithelium was partly ciliated, 2-4 cell layers thick with squamous and cuboidal cells and expressed epithelial markers (cytokeratin and Ber-Ep4). The amount of cilia increased during the first 15 days of culture. The epithelium rested on a neosynthesized basement membrane as visualized by electron microscopy and immunohistochemistry with antibodies directed against collagen IV, laminin, and fibronectin. The central stroma consisted of loose connective tissue with fibroblasts. This simple tissue culture model combines maintenance and neoformation of bronchial epithelium on top of a living natural substrate, thus enabling direct biological studies on clinical biopsy material under perfectly viable conditions.

Chronic rhinitis can be defined as an inflammation of the nasal mucosa lasting for more than three months. The condition may be due to allergy or infection, or to a number of non-allergic and non-infectious causes, such as trauma, hormonal imbalance, toxic influence or locally applied drugs. The etiology, diagnostic procedures and treatment of non-allergic chronic rhinitis are discussed.

Human respiratory mucosa was exposed to oxymetazoline nasal spray in varying concentrations and for varying periods of time in vitro. The drug destroyed the tissue in a concentration- and time-dependent manner. In the experiments with various concentrations of the spray, some tissue fragments retained their viability throughout the experiment. This number increased parallel to a decrease in concentrations of the test substance. All the tissue fragments exposed to undiluted nose spray underwent severe destructive alterations during the exposure period. These alterations appeared first and were most extensive in those exposed for the longest periods of time. It has previously been demonstrated that the toxic effect of oxymetazoline nasal spray in vitro is probably due to the preservative benzalkonium chloride. The apparent lack of consistency between the toxic effects of benzalkonium chloride in vitro and in vivo is discussed, with special reference to protective systems absent in vitro but present in vivo.

The aim of this study was to investigate the morphological effects of decongestive drops and sprays on human respiratory mucosa in vitro. Precultured fragments of adenoid tissue in a specially designed tissue culture system were exposed to decongestive preparations for 10 minutes once a day for 10 days. Tissue exposed to preparations preserved with benzalkonium chloride and tissue exposed to benzalkonium chloride alone underwent severe morphological alterations. Unpreserved decongestive substances did not have this effect. Benzalkonium chloride is a well-documented toxic substance in several respects. Supported by previous studies, it may seem unfortunate to use it as an additive in decongestive preparations.

Human neutrophil functions have been examined after exposure of leukocytes to components of decongestive nosedrops in vitro. Both the vasoactive components oxymethazoline chloride and xylomethazoline chloride, as well as the preservative benzalkonium chloride, showed a concentration- and time-dependent deleterious effect on neutrophil actin polymerization, phagocytosis and oxidative burst. The most toxic of the drug components was benzalkonium chloride, which in the commercial nosedrops tested was present in concentrations about 20 times higher than that compatible with intact neutrophil functions. These findings suggest possible inhibition of mucosal neutrophil activity following exposure to nosedrops in vivo, and support earlier reports that have questioned the use of preservatives in decongestive nosedrops.

Fragments of human adenoid tissue were transferred to a nonadhesive, stationary organ culture system. The culture period was 40 days. In culture, beating cilia could be observed at the surface of the fragments. Light microscopy, scanning electron microscopy, and transmission electron microscopy showed that the tissue fragments were covered by a multilayered, pseudostratified, ciliated epithelium. Beneath the epithelium was a basement membrane. At the start of the culture period, the central parts of the fragments were dominated by lymphocytes. These lymphocytes gradually disappeared and were replaced by a collagen-containing stroma with scattered fibroblasts. The tissue fragments can be used as an organ culture model for normal respiratory mucosa.

Scanning electron microscopy was employed to investigate cocultures between normal rat brain fragments and spheroids consisting of rat glioma cells. Lamellipodia were seen to arise from tumor cells at the border between the two structures and touch the surface of the fragment. Cytoplasmic extensions from malignant cells appeared to penetrate into the brain fragment. Leading lamellae were extended from the tumor cells as they migrated along the normal surface and gradually covered the fragment. Tumor cells formed broad foot-plates against the normal surface. No alterations of the brain fragment were observed ahead of the tumor cells. Thus there were specific changes of the surface microarchitecture of the malignant cells, but not of the normal brain tissue.

A stationary tissue culture system for reaggregation cultures of rat brain cells is described. Aggregates were formed by placing cells at high concentration in liquid overlay cultures on a nonadherent nutrient agar surface. No physical stress in the form of rotation or shaking was applied to the aggregating cell population. Transmission electron microscopy and immunohistochemistry showed that the cells developed from homogeneously dispersed, immature cells in Day 4 aggregates, to mature astrocytes, oligodendrocytes, and neurons in Day 20 aggregates. Twenty days older aggregates had a tightly packed neuropil which was most prominent in a cell-sparse outer layer of the aggregates. When the aggregates were allowed to adhere to a substrate, both glial fibrillary acidic protein (GFAP) positive and negative cells were observed migrating out from the aggregates. Cells giving a positive reaction for neuron specific enolase (NSE) were also present. This reaggregation procedure, with transfer of selected brain cell aggregates into agar-coated multiwells is an alternative three-dimensional culture system which can be potentially useful in the study of morphogenesis and cell interactions in the nervous system.

Primary malignant neoplasms of the nervous system differ from other types of malignancy in several ways. Clinical progression is due to local invasive growth, while metastases outside the skull are rare. The tumors show no sharp delimitation from the surrounding normal tissue. At the edge, an ill-defined area of invasive tumor cells, reacting glial cells and inflammatory cells is present. At the same time the primary brain tumors are biologically heterogeneous. In this review, a short survey of markers for malignancy in primary brain tumors is given, and some properties of importance for invasive behavior, are listed. These include different cellular enzymes, phagocytotic property, locomotive and proliferative characteristics. Studies of primary brain tumors in situ show invasive growth into the surrounding brain tissue, often followed by hemorrhage and necrosis. In addition spread of tumor cells takes place along preexisting intracranial structures. Recently, several systems for the study of brain tumor invasiveness in culture have been elaborated. Both experimental and human gliomas have been tested. The target tissues include organ culture of embryonic chick heart muscle, chorioallantoic membrane, fetal rat brain tissue and reconstructed vessel walls. It has been shown that glioma cells are able to split junctions between normal cells. They destroy and phagocytose the normal cells and penetrate the normal tissue. The use of brain tissue and reaggregated brain cell cultures as target for glioma cells in culture opens the possibility for an elucidation of invasiveness as one of the most important properties of malignancy in the nervous system.

An ultrastructural study of cocultures between fragments of normal rat brain tissue and aggregates of BT 5C rat glioma cells is herein described. Glioma cells invaded and replaced the peripheral parts of the brain fragments. Degeneration of brain tissue was seen all over the normal structures. Specialized junctional structures between normal and malignant cells were observed. The phagocytic activity of invading glioma cells was not increased as compared to non-invading cells. Insofar as interaction between normal brain tissue and glioma cells can be studied in detail in these cocultures, they may also be useful as a test system for the study of potential chemotherapeutic agents against gliomas.

Fetal rat brain fragments grown in nonadherent stationary organ culture for 50 days have been investigated ultrastructurally. Synaptogenesis and myelin formation occurred at the same time as the corresponding time-dependent events in the developing brain in vivo. Intermediate junctions were observed between cellular processes lining a central cavity in the fragments and later associated with astrocytes at the surface. Gap junctions and tight junctions were also present. In some fragments cilia were observed in the central cavity. Subependymal basement membrane labyrinths were observed in all fragments after 10 days in culture. The ultrastructural characteristics and the tissue-like structure in general were preserved for at least 50 days in this tissue culture system. The brain fragments may therefore be a valuable supplement to existing culture methods for nervous tissue.

A system for coculture between normal rat brain fragments and multicellular spheroids of rat glioma cells is described. The tumor cells were derived from fetal BD IX rats treated transplacentally with the carcinogen N-ethyl-N-nitrosourea (CAS: 759-73-9). Brain fragments were obtained from fetal BD IX rats and precultured for 20 days before confrontation with multicellular tumor spheroids. The cocultures were grown in nonadherent stationary organ culture for 30 days. Due to morphologic similarities between normal brain cells and tumor cells, the tumor cells were labeled with tritiated thymidine, which made them easily recognizable in autoradiographs. The two structures adhered to each other, and glioma cells progressively invaded and replaced the normal brain tissue. Invasion and replacement are characteristic features of brain tumors in vivo. Therefore, this organotypic and syngeneic model may be useful for investigation of these phenomena outside the body.

A simple organ culture system for brain tissue is described. Fragments of fetal rat brain hemisphere tissue are explanted to multiwell dishes base-coated with semisolid agar. In this system nonadherent organ culture can be performed for at least 50 days. Cell migration, biochemical and morphological differentiation and the formation of a layered architecture seem to mimic some of the phenomena occurring in the developing rat brain in vivo. The fragments may therefore be a useful organ culture model for nervous tissue.