Transcriptomics unravels molecular changes associated with cilia and COVID-19 in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper respiratory tract complication where the pathogenesis is largely unknown. Herein, we investigated the transcriptome profile in nasal mucosa biopsies of CRSwNP patients and healthy individuals. We further integrated the transcriptomics data with genes located in chromosomal regions containing genome-wide significant gene variants for COVID-19. Among the most significantly upregulated genes in polyp mucosa were CCL18, CLEC4G, CCL13 and SLC9A3. Pathways involving "Ciliated epithelial cells" were the most differentially expressed molecular pathways when polyp mucosa and non-polyp mucosa from the same patient was compared. Natural killer T-cell (NKT) and viral pathways were the most statistically significant pathways in the mucosa of CRSwNP patients compared with those of healthy control individuals. Upregulated genes in polyp mucosa, located within the genome-wide associated regions of COVID-19, included LZTFL1, CCR9, SLC6A20, IFNAR1, IFNAR2 and IL10RB. Interestingly, the second most over-expressed gene in our study, CLEC4G, has been shown to bind directly to SARS-CoV-2 spike's N-terminal domain and mediate its entry and infection. Our results on altered expression of genes related to cilia and viruses point to the de-regulation of viral defenses in CRSwNP patients, and may give clues to future intervention strategies.

Relative frequencies of symptoms and risk factors among patients with chronic rhinosinusitis with nasal polyps using a case-control study.

OBJECTIVES: The aim of this study was to investigate the relative frequency of important symptoms of chronic rhinosinusitis with nasal polyps (CRSwNP), the link between CRSwNP and the lower airways and the importance of smoking in CRSwNP. METHOD: Three hundred and sixty-eight patients with CRSwNP and 1349 controls were recruited to the study and underwent a structured interview about symptoms from the upper and lower airways, and about smoking habits. Furthermore, all participants were clinically examined using nasal endoscopy. RESULTS: Due to interactions between the outcome variables, a multiple logistic regression model was fitted to the data. Nasal secretions, nasal blockage and impaired sense of smell were symptoms associated with CRSwNP. Furthermore, male gender, increasing age and asthma were also associated with the disease. Current smoking was less frequent among patients with CRSwNP. CONCLUSION: By comparing symptoms and risk factors of patients with CRSwNP with those of a large population-based control group and testing them in a multiple logistic regression model, we have been able to generate data that address key research interests in CRSwNP.

A family-based genome-wide association study of chronic rhinosinusitis with nasal polyps implicates several genes in the disease pathogenesis.

BACKGROUND: The pathogenesis of chronic rhinosinusitis with nasal polyps is largely unknown. Previous studies have given valuable information about genetic variants associated with this disease but much is still unexplained. Our goal was to identify genetic markers and genes associated with susceptibility to chronic rhinosinusitis with nasal polyps using a family-based genome-wide association study. METHODS: 427 patients (293 males and 134 females) with CRSwNP and 393 controls (175 males and 218 females) were recruited from several Swedish hospitals. SNP association values were generated using DFAM (implemented in PLINK) and Efficient Mixed Model Association eXpedited (EMMAX). Analyses of pathway enrichment, gene expression levels and expression quantitative trait loci were then performed in turn. RESULTS: None of the analysed SNPs reached genome wide significant association of 5.0 x 10-8. Pathway analyses using our top 1000 markers with the most significant association p-values resulted in 138 target genes. A comparison between our target genes and gene expression data from the NCBI Gene Expression Omnibus database showed significant overlap for 36 of these genes. Comparisons with data from expression quantitative trait loci showed the most skewed allelic distributions in cases with chronic rhinosinusitis with nasal polyps compared with controls for the genes HLCS, HLA-DRA, BICD2, VSIR and SLC5A1. CONCLUSION: Our study indicates that HLCS, HLA-DRA, BICD2, VSIR and SLC5A1 could be involved in the pathogenesis of chronic rhinosinusitis with nasal polyps. HLA-DRA has been associated with chronic rhinosinusitis with nasal polyps in previous studies and HLCS, BICD2, VSIR and SLC5A1 may be new targets for future research.

What Happens With Untreated Nasal Polyps Over Time? A 13-Year Prospective Study.

OBJECTIVES: Nasal polyps are often seen in ENT practice, but little is known about the pathogenesis and the natural development. Our objective was to follow individuals with untreated nasal polyps prospectively, in terms of polyp size, symptoms, and respiratory function. METHODS: Thirty-three individuals, aged 27 to 87 years, with untreated nasal polyps were identified in a population-based study. Peak nasal inspiratory flow, olfactory function, and size of the nasal polyps were examined. Respiratory symptoms were also registered. Follow-up examinations were performed after 6 and 13 years, with change between visits analyzed. RESULTS: Over time, polyp size as well as occurrence of unilateral or bilateral polyps varied without an obvious pattern, with no consistent trends in respiratory function or symptoms. Twenty-one individuals (64%) were still untreated at the 6-year follow-up, and 12 (36%) remained untreated during the whole 13-year follow-up. Dropouts were due mainly to death. Seven individuals (21%) started treatment during the follow-up and had larger polyps and more subjective respiratory symptoms at baseline compared to the untreated group. CONCLUSION: Nasal polyps found occasionally are often part of a chronic entity but do not necessarily evolve into a more serious condition over time. Treatment should therefore be based on the patients' subjective problems.

Olfactory dysfunction in chronic stroke patients.

BACKGROUND: The aim of the study was to investigate odor identification performance in patients one year after hospital admittance due to stroke. Predictors for olfactory dysfunction were investigated as well as self-reported olfactory function and pleasantness of olfactory items. METHODS: A 1-year prospective study was performed. Stroke location, classification and comorbidities were registered at hospital admission. One year after admission, olfactory function was assessed using standardized olfactory methods (screening for loss of detection sensitivity and an odor identification test). A group of matched controls was derived from a population-based study to compare odor identification performance between groups. Patients were asked for their personal judgment regarding their olfactory function and pleasantness of odorous items. In addition, global cognitive function and symptoms of depression were assessed. RESULTS: A total of 78 patients were enrolled (46 males, 32 females; mean age 68 years) of which 28.2% exhibited reduced olfactory function (hyposmia) and 15.4% exhibited loss of olfactory function (10.3% functional anosmia, 5.1% complete anosmia). Patients showed significantly lower olfactory performance compared to age- and sex-mated matched controls. Predictors of impaired olfactory function were age and NIHSS score. Self-reports indicated no significant differences between patients with normal olfactory function and those with reduced function. Yet, patients having an olfactory dysfunction rated odorous items as significantly less pleasant compared to patients without dysfunction. CONCLUSIONS: Olfactory dysfunction seems to occur frequently after stoke even one year after initial admission. The deficits seem to relate to hyposmia and functional anosmia, and less to a complete loss of smell sensitivity.

Heredity of nasal polyps.

BACKGROUND: Nasal polyps is a common disease but little is known about its` pathogenesis. Our hypothesis was that there are genetic factors involved in the development of this disease. The aim of this study was to examine close relatives of patients with nasal polyps and comparing them with a general population with regard to prevalence of polyps. METHODOLOGY: Patients with nasal polyps who attended the clinic were recruited to the study and were asked whether they had any close adult relatives (siblings, parents or children). We intended to recruit two relatives per patient, one of each gender, for nasal endoscopy. The prevalence of nasal polyps in these relatives was compared with the prevalence of nasal polyps in a general population. RESULTS: During a 4-year period, 368 patients and 410 relatives were recruited to the study. Although we were unable to recruit two close relatives for every patient, we were able to calculate nasal polyp prevalence within families as being 19.2%. Compared with the prevalence of nasal polyps among individuals in a general Swedish population from the same geographical area, the relative risk for polyps among relatives was almost five times higher. CONCLUSION: This study strongly indicates that heredity is a factor of importance for development of nasal polyps.

Inhalation of menthol reduces capsaicin cough sensitivity and influences inspiratory flows in chronic cough.

INTRODUCTION: Chronic cough is a common clinical problem and there is a shortage of effective treatments for it. Within the group of transient receptor potential ion channels a receptor for the cooling substance menthol has been identified. This study aimed to assess whether pre-inhalation of dissolved, nebulised menthol could increase capsaicin cough thresholds and influence spirometric values. METHODS: Fourteen patients with chronic cough and airway sensitivity to environmental irritants and 15 control subjects were tested on three occasions. Each one inhaled a 1 mL of nebulised menthol solution of 0.5% or 1% or placebo (saline with 0.05% menthol) at each visit in a randomized and double-blind order. They were then provoked by capsaicin inhalation. RESULTS: Patients' cough thresholds differed significantly from the controls' on all three provocations (P < 0.0001). After inhalation of 1% menthol, the patients' cough thresholds were significantly higher (P < 0.02) compared to after placebo inhalation and to after 0.5% menthol inhalation (P < 0.05). The patients' peak inspiratory flows were significantly reduced after inhalation of the placebo (saline) (P < 0.05) but not after inhalation of 0.5% or 1% menthol. Forced inspiratory flows 50% were lowered after inhalation of placebo and of 0.5% menthol (P < 0.05) but not after 1% menthol. Among the controls, forced inspiratory flows 50% were lowered after only placebo inhalation (P < 0.05). CONCLUSIONS: In patients with chronic cough, pre-inhalation of menthol reduces cough sensitivity to inhaled capsaicin and influences inspiratory flows. The findings may provide scientific support for the common practice of using menthol as a reliever for variant airway discomfort. The use of menthol in different cigarette brands could be questioned since it could conceal the natural irritation following smoking.

Normative data for the chemical sensitivity scale for sensory hyperreactivity: the Västerbotten environmental health study.

OBJECTIVES: The chemical sensitivity scale for sensory hyperreactivity (CSS-SHR) is used to quantify affective reactions to and behavioral disruptions by odorous/pungent substances in the environment and has documented good metric properties. However, normative data have not been available. The main objective of the present study was therefore to establish normative data for reference by means of a large-scale population-based study. MATERIALS AND METHODS: From a random sample of 8,520 reachable inhabitants in the county of Västerbotten in Sweden, aged 18-79 years, stratified for age and gender, 3,406 individuals agreed to participate. RESULTS: The results show fairly high internal consistency (Cronbach's α = 0.78-0.83) of the CSS-SHR and that it generates scores with approximately normal distributions (skewness: 0.045-0.454; kurtosis: -0.314 to 0.230), irrespective of age group and gender. Mean scores, standard deviations, confidence intervals, and proportions of individuals who met the diagnostic cutoff score for the CSS-SHR were obtained for reference of normality. CONCLUSIONS: CSS-SHR can be recommended for quantification of affective reactions to and behavioral disruptions by odorous/pungent environmental substances, and with the advantage of comparing scores with normality.

Prevalence of chronic cough in relation to upper and lower airway symptoms; the Skövde population-based study.

The aim of this study was to determine the prevalence of chronic cough in relation to upper airway symptoms, in a cross-sectional, population-based epidemiological study. Another aim was to relate coughing to other explanatory variables and risk factors. A random sample of 1900 inhabitants from the age of 20, stratified for age and gender, was recruited. Subjects were invited for clinical examinations that included questions about general odor intolerance, respiratory symptoms, and smoking habits, and a smell identification test. In total, 1387 volunteers (73% of the sample) were investigated. The overall prevalence of self-reported chronic cough was 6.3% [95% confidence interval (CI): 5.0-7.6%]. Female gender, age, height, BMI, and smoking were significantly related to cough. Furthermore, nasal blockage, nasal secretion, sneezing, asthma, odor and cold air sensitivity, and aspirin intolerance also related to cough with statistical significance, indicating a close connection between chronic cough and upper airway symptoms. In keeping with other studies, this study demonstrates that chronic cough is a widespread problem in society, and is about twice as common in women than in men.

Relationship of airway sensory hyperreactivity to asthma and psychiatric morbidity.

BACKGROUND: Patients with airway symptoms induced by chemicals and odors are common in allergy clinics, but the problems cannot be explained by allergic or asthmatic reactions. Previous studies have shown that these patients often have increased sensitivity to inhaled capsaicin, which is known to reflect sensory reactivity; a diagnosis of airway sensory hyperreactivity (SHR) has been suggested for this condition. OBJECTIVES: To examine the relationship between asthma and SHR and to investigate whether patients with SHR show signs of increased psychiatric morbidity. METHODS: This study included 724 patients who were attending an allergy center because of suspected allergy or asthma. All the patients completed a quantitative questionnaire on self-reported affective reactions and behavioral disruptions caused by odorous/pungent substances. A standardized capsaicin inhalation test was performed and a questionnaire to assess psychiatric morbidity was administered in patients with pronounced chemical sensitivity to identify those with SHR. RESULTS: The prevalence of SHR was approximately 6% in asthmatic patients in the allergy center population, which is in accordance with the prevalence in a general population. There was no significant indication that SHR was related to either depression or anxiety. CONCLUSION: There is no strong relationship between SHR and either asthma or psychiatric morbidity.

Chemosensory interaction: acquired olfactory impairment is associated with decreased taste function.

Olfaction, taste and trigeminal function are three distinct modalities. However, in daily life they are often activated concomitantly. In health and disease, it has been shown that in two of these senses, the trigeminal and olfactory senses, modification of one sense leads to changes in the other sense and vice versa. The objective of the study was to investigate whether and (if so) how, the third modality, taste, is influenced by olfactory impairment. We tested 210 subjects with normal (n = 107) or impaired (n = 103) olfactory function for their taste identification capacities. Validated tests were used for olfactory and gustatory testing (Sniffin' Sticks, Taste Strips). In an additional experiment, healthy volunteers underwent reversible olfactory cleft obstruction to investigate short-time changes of gustatory function after olfactory alteration. Mean gustatory identification (taste strip score) for the subjects with impaired olfaction was 19.4 +/- 0.6 points and 22.9 +/- 0.5 points for those with normal olfactory function (t = 4.6, p < 0.001). The frequencies of both, smell and taste impairments interacted significantly (Chi(2), F = 16.4, p < 0.001), and olfactory and gustatory function correlated (r (210) = 0.30, p < 0.001). Neither age nor olfactory impairment cause effects interfered with this olfactory-gustatory interaction. In contrast, after short-lasting induced olfactory decrease, gustatory function remained unchanged. The present study suggests that longstanding impaired olfactory function is associated with decreased gustatory function. These findings seem to extend previously described mutual chemosensory interactions also to smell and taste. It further raises the question whether chemical senses in general decrease mutually after acquired damage.

The idiopathic environmental intolerance symptom inventory: development, evaluation, and application.

OBJECTIVE: To develop, evaluate, and apply a questionnaire-based instrument for investigation of specific symptoms in idiopathic environmental intolerance (IEI), called the Idiopathic Environmental Intolerance Symptom Inventory (IEISI). METHODS: Participants with IEI to chemicals responded to 82 candidate symptoms and to three subscales of the Quick Environmental Exposure and Sensitivity Inventory (QEESI) at a test (n = 207) and retest (n = 193) occasion. RESULTS: The 27 most commonly reported symptoms were selected and grouped into five symptom categories. Internal consistency, test-retest reliability, and concurrent validity were found to be satisfying. Cluster analysis identified two subgroups of IEI to chemicals. CONCLUSIONS: The results provide support for the IEISI being a reliable, valid, and fast tool for the study of specific symptom prevalence in IEI and encourage further study of subgroups.

Attention bias and sensitization in chemical sensitivity.

OBJECTIVE: We investigated whether persons with self-reported chemical sensitivity (CS) have an attention bias and enhanced sensitization to chemical exposure. METHODS: Chemosomatosensory, olfactory, and auditory event-related potentials (ERPs) were recorded from 21 CS subjects and 17 controls in attend and ignore conditions. Reaction times (RTs) and magnitude estimations of perceived intensity were collected in the attend condition. ERPs were averaged over attention conditions and during the first/second part of the testing. RESULTS: ERP patterns indicated that CS subjects did not habituate to the same extent as the controls and had difficulties ignoring the chemical exposure. CS subjects had faster overall RT, and the perceived intensities for the chemosomatosensory stimuli did not decrease with time in the CS group, which was the case for the controls. CONCLUSIONS: These results indicating attention bias and enhanced sensitization in CS suggest alterations in central, cognitive responses to chemical exposure.

"Taste Strips" - a rapid, lateralized, gustatory bedside identification test based on impregnated filter papers.

OBJECTIVE: To elaborate normative values for a clinical psychophysical taste test ("Taste Strips"). BACKGROUND: The "Taste Strips" are a psychophysical chemical taste test. So far, no definitive normative data had been published and only a fairly small sample size has been investigated. In light of this shortcoming for this easy, reliable and quick taste testing device, we attempted to provide normative values suitable for the clinical use. SETTING: Normative value acquisition study, multicenter study. METHODS: The investigation involved 537 participants reporting a normal sense of smell and taste (318 female, 219 male, mean age 44 years, age range 18-87 years). The taste test was based on spoon-shaped filter paper strips ("Taste Strips") impregnated with the four (sweet, sour, salty, and bitter) taste qualities in four different concentrations. The strips were placed on the left or right side of the anterior third of the extended tongue, resulting in a total of 32 trials. With their tongue still extended, patients had to identify the taste from a list of four descriptors, i. e., sweet, sour, salty, and bitter (multiple forced-choice). To obtain an impression of overall gustatory function, the number of correctly identified tastes was summed up for a "taste score". RESULTS: Taste function decreased significantly with age. Women exhibited significantly higher taste scores than men which was true for all age groups. The taste score at the 10(th) percentile was selected as a cut-off value to distinguish normogeusia from hypogeusia. Results from a small series of patients with ageusia confirmed the clinical usefulness of the proposed normative values. CONCLUSION: The present data provide normative values for the "Taste Strips" based on over 500 subjects tested.

Dyspnea from exercise in cold air is not always asthma.

In the absence of other explanations, exercise-induced dyspnea is often labeled as a manifestation of asthma. The aim of this study was to use exercise provocation in cold air among patients with exercise-induced dyspnea, but without any bronchoconstriction, in order to study induced symptoms and different physiological parameters and to measure the possible influence of exercise in cold air on capsaicin cough sensitivity. Eleven patients with exercise-induced dyspnea but no asthma, along with 11 healthy controls, performed a capsaicin inhalation provocation on two occasions. One of these provocations was preceded by an exercise provocation in a cold chamber. Number of coughs, airway symptoms, spirometry, respiratory rate, pulse rate, end-tidal CO(2), and PSaO(2) were registered. During exercise, the patients coughed more than the controls and also had more airway symptoms. After exercise provocation, spirometry values remained unchanged, but capsaicin cough sensitivity was increased and end-tidal CO(2) decreased among the patients, both in comparison to the controls and in comparison to the patients themselves prior to exercise. Exercise-induced dyspnea may be associated with hypocapnia from hyperventilation and increased capsaicin cough sensitivity. The diagnosis of exercise-induced asthma should be questioned when the patient has no signs of bronchoconstriction.

Capsaicin provocation using two different inhalation devices.

BACKGROUND: Sensory hyperreactivity (SHR) has been suggested as one explanation for chemically induced airway symptoms; it can be diagnosed with a capsaicin inhalation test. Previous capsaicin inhalation studies of SHR have used a Pari Boy device. This model of inhalator device has become outdated, hence it is necessary to abandon it in favour of a new device. The aim of this study was to transfer the capsaicin inhalation test using the Pari Boy device to a corresponding model using the Maxin MA3 device. METHODS: Twenty-one patients with SHR and 44 healthy controls visited the clinic twice and underwent a randomised protocol. The participants were provoked with saline and capsaicin using one of two devices, Pari Boy and Maxin MA3. Eight patients also underwent two additional capsaicin provocations with Maxin MA3. A new series of capsaicin concentrations was chosen for Maxin MA3. The results from each device were analysed, the agreement between the two devices and the repeatability of the Maxin MA3 were evaluated. RESULTS: Among all participants, the mean number of coughs with the Pari Boy was 5.5 (95% CI: 2.7; 8.2) after inhalation of 0.4 micromol/L capsaicin and 20.0 (95% CI: 14.1; 25.9) after 2.0 micromol/L. With the Maxin MA3, the mean number of coughs was 3.6 (95% CI: 1.3; 4.0) after 0.06 micromol/L capsaicin, and 17.8 (95% CI: 12.0; 23.6) after 0.3 micromol/L. The Maxin MA3 showed good repeatability and the agreement between the devices with the capsaicin concentrations chosen for each device was considered to be good.

Event-related potentials in patients with olfactory loss.

CONCLUSION: The olfactory event-related potential (OERP) method provides a means of objectively assessing olfactory function. However, further validation is needed before OERPs can be routinely applied in clinical assessment of olfactory dysfunction. OBJECTIVE: To assess OERPs in patients with olfactory impairment and in healthy controls to investigate possible dose-response effects of odor concentration on OERP parameters in these groups, thereby exploring possibilities and limitations regarding the clinical utility of the OERP method. SUBJECTS AND METHODS: Twenty-three patients with a history of impaired olfactory function and 24 controls participated in the study. Olfactory function was assessed with psychophysical tests, i.e. assessment of the odor threshold, and odor identification. OERPs were obtained in response to the olfactory stimulant butanol at two different concentrations, presented via an olfactometer. RESULTS: The OERP amplitudes increased and the latencies shortened with increasing stimulus concentration. Furthermore, a difference between the groups was found, with higher OERP amplitudes and shorter latencies in healthy subjects compared with patients.

Inhaled ethanol potentiates the cough response to capsaicin in patients with airway sensory hyperreactivity.

A suggested explanation for airway symptoms induced by chemicals and scents is sensory hyperreactivity (SHR) of airway mucosal nerves. Patients with SHR have increased cough sensitivity to inhaled capsaicin, mediated by transient receptor potential (TRP) ion channels. In animal experiments, some TRP receptors are potentiated by ethanol, which is why in this study, the aim was to evaluate whether a pre-inhalation of ethanol could influence the capsaicin cough response in patients with SHR. Fifteen patients with SHR and 15 healthy controls were provoked on three occasions with two concentrations of inhaled capsaicin. Before each capsaicin provocation, a pre-inhalation of saline or one of two concentrations of ethanol was given in a double-blind, randomized fashion. The participants reacted in a dose-dependent way with cough on the capsaicin inhalations. Among the patients, but not in the control group, pre-inhalation of ethanol increased the cough response dose-dependently. The results suggest that the pathophysiology of SHR is related to airway mucosal TRP receptors in the sensory nerves. In scented products, the combination of ethanol as a solvent and perfume may augment an airway reaction in sensitive individuals.

Prevalence and risk factors for chemical sensitivity and sensory hyperreactivity in teenagers.

The prevalence of chemical sensitivity (CS) and sensory hyperreactivity (SHR) was assessed in a teenage population. Among a random sample of 401 teenagers, 326 (81.3%) answered questionnaires assessing sensitivity to chemicals and noise, anxiety and depression. A subgroup of 85 teenagers conducted a capsaicin inhalation test. The estimated prevalence was 15.6% for general self-reported CS, 3.7% for CS with affective and behavioral consequences, about 1% for SHR. Sensitivity variables were positively intercorrelated. Risk factors for general CS were noise sensitivity (OR: 2.1), probable anxiety (OR: 2.5) and female sex (OR: 2.0). CS problems seem to be present also in teenagers, although less so than in adults. Furthermore, CS seems to be related to other environmental sensitivities.