A comprehensive gene expression profile of allergic rhinitis-derived nasal fibroblasts and the potential mechanism for its phenotype.

BACKGROUND: Allergic rhinitis (AR) is a common immunoglobulin E-mediated immune response involved various cell types, while the role of nasal fibroblasts (NFs) in the pathogenesis of AR is less understood. PURPOSE: The study aimed to uncover the gene expression profile of AR-derived NFs and the potential mechanism for the changed phenotype of AR-NFs. RESEARCH DESIGN: The primary NFs were isolated from 3 AR patients (AR-NFs) and 3 controls (Ctrl-NFs), and the proliferation, migration and interleukins production abilities of NFs were detected respectively. RNA-sequence was used to identify differentially expressed genes (DEGs) in AR-NFs. Transcription factor (TF) regulatory network and bioinformatic analyses were both conducted to clarify the biological roles of DEGs including the TFs. The DEG with the highest validated |fold change (FC)| value, detected by qPCR, was selected for further confirmation. RESULTS: AR-NFs showed a higher proliferation and migration abilities as well as released higher levels of IL-33 and IL-6, compared to Ctrl-NFs. A total of 729 DEGs were screened out in AR-NFs. TF regulatory network indicated that BARX homeobox 1 (BARX1) and forkhead box L1 were the major node TFs. Bioinformatic analyses showed that a large number of DEGs including several target genes of BARX1 were both enriched cytokine-related GO terms, and immune- or inflammation-related pathways. BARX1 had the highest |FC| value, and silencing BARX1 in AR-NFs resulted in the significant downregulation of proliferation and migration abilities, and the production of interleukins. CONCLUSIONS: Our study for the first time provided the gene expression profile of AR-derived NFs, and BARX1 could be developed as a potent target to alleviate the pathogenesis of AR.

Anxiety-like behavior induced by allergen is associated with decreased irregularity of breathing pattern in rats.

Allergic rhinitis (AR) is a chronic inflammatory disorder associated with a high prevalence of anxiety symptoms and respiratory disorders that adversely affect the quality of life. Studies have shown that allergen exposure induces anxiety-like behaviors. On the other hand, stress impairs the breathing pattern. However, the effect of stress on respiration and the relationship between anxiety-like behavior and stress-induced changes in breathing pattern has not been evaluated in AR. We assessed the impact of ovalbumin (OVA)-induced anxiety-like behaviors on stress-induced breathing pattern changes. Our findings showed that the allergic rhinitis induced by OVA challenge in sensitized rats induces anxiety-like behavior. Also, we found that stress decreases respiratory irregularity and increases respiratory variability, as well as the synchronization between IBI and RV time-series in AR animals. Moreover, in AR animals, we found a significant positive correlation between anxiety-like behavior and respiratory irregularity under non-stress conditions. Besides, a significant negative correlation was observed under stress conditions. The findings showed that anxiety-related behaviors may contribute to respiratory impairments under stress conditions in AR.

The Functional Diversity of Nitric Oxide Synthase Isoforms in Human Nose and Paranasal Sinuses: Contrasting Pathophysiological Aspects in Nasal Allergy and Chronic Rhinosinusitis.

The human paranasal sinuses are the major source of intrinsic nitric oxide (NO) production in the human airway. NO plays several roles in the maintenance of physiological homeostasis and the regulation of airway inflammation through the expression of three NO synthase (NOS) isoforms. Measuring NO levels can contribute to the diagnosis and assessment of allergic rhinitis (AR) and chronic rhinosinusitis (CRS). In symptomatic AR patients, pro-inflammatory cytokines upregulate the expression of inducible NOS (iNOS) in the inferior turbinate. Excessive amounts of NO cause oxidative damage to cellular components, leading to the deposition of cytotoxic substances. CRS phenotype and endotype classifications have provided insights into modern treatment strategies. Analyses of the production of sinus NO and its metabolites revealed pathobiological diversity that can be exploited for useful biomarkers. Measuring nasal NO based on different NOS activities is a potent tool for specific interventions targeting molecular pathways underlying CRS endotype-specific inflammation. We provide a comprehensive review of the functional diversity of NOS isoforms in the human sinonasal system in relation to these two major nasal disorders' pathologies. The regulatory mechanisms of NOS expression associated with the substrate bioavailability indicate the involvement of both type 1 and type 2 immune responses.

Pediatric allergic rhinitis with functional gastrointestinal disease: Associations with the intestinal microbiota and gastrointestinal peptides and therapeutic effects of interventions.

Children are susceptible to allergic rhinitis (caused by external allergens) accompanied by functional gastrointestinal disease, which seriously affects physical and mental health. Antihistamines and nasal spray hormones are commonly used in clinical treatment, but these drugs often have unsatisfactory efficacy and result in high recurrence rates. Therefore, understanding the pathogenesis of allergic rhinitis with functional gastrointestinal disease and seeking safer treatment and prevention methods is essential. Herein, molecular ecology and immunoassays were used to analyze correlations between pediatric allergic rhinitis with functional gastrointestinal disease and both the intestinal microbiota and gastrointestinal peptide levels. Fifty healthy children (healthy group) and 80 children with allergic rhinitis with functional gastrointestinal disease (case group: evenly divided into a control group (conventional drug therapy) and an intervention group (conventional drug therapy + glutamine+probiotics)), were enrolled. Bifidobacterium and Lactobacillus counts and the gastrin and motilin levels were lower in the case group than in the healthy group, whereas Enterobacter, yeast, and Enterococcus counts and the somatostatin, serotonin, and vasoactive intestinal peptide levels were higher. Post treatment, intestinal microbiota indices, gastrointestinal peptide levels, and intestinal barrier function were better in the intervention group than in the control group (p < 0.05). The intervention group had a significantly higher total therapeutic response rate (95.00%) than the control group (77.50%). The intestinal microbiota was closely associated with gastrointestinal peptide levels. Treatment with glutamine and probiotics regulated these levels, re-established balance in the intestinal microbiota, and restored intestinal barrier function.

Comparative nasal airflow with loratadine-pseudoephedrine and fluticasone nasal spray for allergic rhinitis.

BACKGROUND: Although it is known that oral antihistamine-pseudoephedrine combination tablets have a faster onset than intranasal corticosteroid sprays in the treatment of allergic rhinitis after the first dose, the magnitude of change has not been measured in a comparative manner. Furthermore, the sensation of sprayed liquid in the nose may lead patients to mistakenly believe that intranasal steroid sprays work instantly. OBJECTIVE: To evaluate, numerically, nasal airflow changes provided by a single dose of loratadine-pseudoephedrine tablet (LP) and fluticasone propionate nasal spray (FP) in participants experiencing allergic rhinitis symptoms, including nasal congestion. METHODS: This single-center, double-blinded, placebo-controlled, crossover study evaluated objective nasal airflow changes in patients with a documented sensitivity to ragweed pollen. Participants were randomized to receive 1 of 4 treatment sequences, and their peak nasal inspiratory flow (PNIF) was measured in a span of 4 hours after pollen exposure in an environmental exposure unit. RESULTS: Average change in PNIF was 31% with LP in the course of the study, significantly greater than with placebo and FP (12% and 15%, respectively; P < .001). Nevertheless, FP did not produce a significant change compared with its placebo. At hour one post-dose, LP had a clinically significant 31% increase in PNIF, whereas FP only yielded an 8.6% increase (P < .001). Measurable nasal airflow improvements are associated with the opening of nasal passages, allowing congested patients to breathe more freely. CONCLUSION: A single dose of LP quickly and significantly (P < .001) improved nasal airflow after ragweed pollen challenge in an environmental exposure unit. Comparatively, FP did not display this same benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03443843.

Effect of adjunctive sodium hyaluronate versus surfactant nasal irrigation on mucociliary clearance in allergic rhinitis: a single-blind, randomised, controlled study.

OBJECTIVE: To investigate the effects of nasal irrigation with sodium hyaluronate and surfactant solutions on mucociliary clearance time in patients with mild persistent allergic rhinitis. METHODS: A total of 120 patients diagnosed with mild persistent allergic rhinitis were enrolled in this prospective study. The patients were allocated randomly to the surfactant, sodium hyaluronate or isotonic saline (as a control) nasal irrigation group. The mucociliary clearance times and improvements in mucociliary clearance times were compared. RESULTS: Improvements in mean mucociliary clearance time were significantly greater in the surfactant and sodium hyaluronate groups than in the control group (p < 0.01). The mean post-treatment mucociliary clearance time of the surfactant group was significantly lower than that of the control (p < 0.001) and sodium hyaluronate groups (p = 0.03). CONCLUSION: Surfactant and sodium hyaluronate nasal irrigation solutions may both be used as adjunctive treatments for allergic rhinitis. Surfactant nasal irrigation resulted in better mucociliary clearance times.

Expression of proteins associated with airway fibrosis differs between children with allergic asthma and allergic rhinitis.

Allergic rhinitis (AR) and allergic asthma (AA) exhibit similar inflammatory response in the airways. However, the remodelling is more extensive in the lower airways, suggesting that the inflammation itself is not sufficient for allergic phenotype. We aimed to analyse whether the expression of selected 27 inflammatory and fibrosis-related proteins may be altered in AR and AA in the paediatric population and whether the expression pattern is either similar (due to the inflammation) or disease-specific (due to the remodelling). We analysed 80 paediatric subjects: 39 with AA, 21 with AR and 20 healthy children. The diagnosis of AR and AA was based on clinical manifestation, lung function, positive skin prick tests and increased immunoglobulin E levels. Serum levels of selected inflammatory proteins were measured with custom Magnetic Luminex Assay. Statistical analysis was performed in Statistica v.13. CCL2/MCP1, GM-CSF, gp130 and periostin concentrations were significantly lower, whereas IL-5 levels were higher in AA compared to the control group. CD-40L, CHI3L1/YKL-40, EGF, GM-CSF and periostin levels were significantly decreased in patients with AR than in the control group. Comparison of AA and AR patients revealed significant changes in CHI3L1/YKL-40 (P = 0.021), IL-5 (P = 0.036), periostin (P = 0.013) and VEGFα (P = 0.046). Significantly altered proteins were good predictors to distinguish between AA and AR (P < 0.001, OR 46.00, accuracy 88.57%). Our results suggest that the expression of four fibrotic proteins was significantly altered between AA and AR, suggesting possible differences in airway remodelling between upper and lower airways.

Allergic rhinitis impairs working memory in association with drop of hippocampal - Prefrontal coupling.

Allergic rhinitis (AR) is a chronic inflammatory disease frequently associated with a deficit in learning and memory. Working memory is an important system for decision making and guidance, which depends on interactions between the ventral hippocampus (vHipp) and the prelimbic prefrontal cortex (plPFC). It is still unclear whether AR influences the activity and coupling of these brain areas, which consequently may impair working memory. The current study aimed to examine alterations of the vHipp-plPFC circuit in a rat model of AR. Our results show decreased working memory performance in AR animals, accompanied by a reduction of theta and gamma oscillations in plPFC. Also, AR reduces coherence between vHipp and plPFC in both theta and gamma frequency bands. Cross-frequency coupling analyses confirmed a reduced interaction between hippocampal theta and plPFC gamma oscillations. Granger causality analysis revealed a reduction in the causal effects of vHipp activity on plPFC oscillations and vice versa. A significant correlation was found between working memory performance with disruption of functional connectivity in AR animals. In summary, our data show that in AR, there is a deficit of functional coupling between hippocampal and prefrontal network, and suggest that this mechanism might contribute to working memory impairment in individuals with AR.

Atopic dermatitis: More than just a rash.

Atopic dermatitis' association with allergic rhinitis and asthma is well known, but there is also increased risk of food allergies, ADHD, depression, and anxiety.

Multimorbidity in asthma, association with allergy, inflammatory markers and symptom burden, results from the Swedish GA2 LEN study.

BACKGROUND: Asthma is common worldwide and a large part of subjects with asthma have concomitant allergic multimorbidity in the form of rhinitis and/or eczema. OBJECTIVE: The aim of this study is to investigate whether the presence of allergic multimorbidity in asthma relates to allergic sensitization, allergic and respiratory symptoms, quality of life, inflammatory markers, lung function, use of medication and background factors. METHODS: A total of 437 asthmatics from the (GA2 LEN) cross-sectional survey in Sweden were grouped depending on the presence of rhinitis and/or eczema. The impact of allergic multimorbidity was assessed in terms of allergic sensitization, allergic and respiratory symptoms, quality of life, type-2 inflammatory markers (exhaled nitric oxide, eosinophil activation markers, periostin), lung function, use of medication and background factors. RESULTS: Subjects with asthma, rhinitis and eczema were more likely to be sensitized to seasonal allergens (67% vs 32%, P < .001), food allergens (54% vs 18%, P < .001) and to have a higher degree of sensitization than subjects with only asthma (23% vs 10%, P < .001). Subjects with allergic multimorbidity more often had allergic reactions to food (28% vs 10%, P = .002), more respiratory symptoms and anxiety/depression (40% vs, 14%, P < .001) than subjects with only asthma, despite having similar levels of type 2 inflammatory markers. Individuals with allergic multimorbidity were more likely to be diagnosed with asthma before the age of 12 (48% vs 27%, P = .016) and to have maternal heredity for allergy (53% vs 33%, P = .011) than subjects with only asthma. CONCLUSION AND CLINICAL RELEVANCE: Asthmatics with allergic multimorbidity are more likely to be sensitized to seasonal aeroallergens, food allergens and they have a higher degree of sensitization compared with those with only asthma. Allergic multimorbidity is associated with respiratory and allergy symptoms, anxiety and/or depression.

Dry Eye and Dry Nose Caused by the Effect of Allergic Rhinitis on Tear and Nasal Secretion Osmolarity.

OBJECTIVE: Allergic rhinitis is a type 1 hypersensitivity reaction of immunoglobulin E in the rhino-ocular mucosa. This study was planned to demonstrate in patients with allergic rhinitis to evaluate changes in tear, nasal secretions, and blood osmolarity compared to healthy individuals. METHOD: Forty allergic rhinitis patients, 25 patients with acute upper respiratory tract infections, and 26 healthy participants were included in the study. Positive patients with allergic symptoms and skin prick test results were included in the allergic rhinitis group. Tear, nasal secretion, and blood osmolarity values were examined for the 3 groups. RESULT: In patients with allergic rhinitis, tear and nasal secretion osmolarity values were significantly higher in patients with acute upper respiratory tract infections and those of the healthy participants (P = .001, P = .038). In blood osmolarity measurements, there was no statistical difference between the groups (P = .489). In patients with allergic rhinitis, Schirmer test results were significantly shorter than patients who had acute upper respiratory tract infection and those of the healthy participants (P = .001, P = .001). Patients with allergic rhinitis and acute upper respiratory tract infections had significantly shorter Schirmer test results than in healthy participants (P = .001, P = .001). CONCLUSION: Tear osmolarity was increased in allergic rhinitis patients, and this was thought to lead to dry eye findings. In the presence of allergic rhinitis, nasal secretions were found more hyperosmolar than tears. Nasal secretion osmolarity was higher in allergic rhinitis patients than in patients with acute upper respiratory tract infections and control group.

Diagnostic value of FeNO and MMEF for predicting cough variant asthma in chronic cough patients with or without allergic rhinitis.

OBJECTIVE: To evaluate the diagnostic value of fractional exhaled nitric oxide (FeNO) and maximum mid-expiratory flow (MMEF) for differentiating cough variant asthma (CVA) from chronic cough in patients with or without allergic rhinitis. METHODS: In total, 328 patients with chronic cough who underwent spirometry and FeNO testing were consecutively included in the retrospective analysis. Patients were divided into the CVA (n = 125) or NCVA (n = 203) groups according to the diagnostic criteria of CVA. Receiver operating characteristic (ROC) curves were established to assess the diagnostic efficiency and optimal cutoff points of FeNO and MMEF for the prediction of CVA. RESULTS: The optimal cutoff values of FeNO and MMEF to discriminate CVA from chronic cough were 24.5 ppb (AUC, 0.765; sensitivity, 69.60%; specificity 72.91%; PPV, 61.27%; NPV, 79.57%) and 66.2% (AUC, 0.771; sensitivity, 67.20%; specificity 78.33%; PPV, 65.63%; NPV, 79.50%). The optimal cutoff values of combining FeNO with MMEF to discriminate CVA from chronic cough were >22 ppb for FeNO and <62.6% for MMEF (AUC, 0.877). In patients with and without allergic rhinitis, the optimal cutoff point of FeNO to discriminate CVA from chronic cough was 24.5 ppb (AUC, 0.820) and 33.5 ppb (AUC, 0.707), respectively. CONCLUSIONS: FeNO and MMEF might have greater value as negative parameters for differentiating CVA from chronic cough. Combining FeNO and MMEF provided a significantly better prediction than either alone. The diagnostic accuracy of FeNO for predicting CVA in chronic cough patients with allergic rhinitis was higher than in chronic cough patients without allergic rhinitis.

Clinical features and risk factors in patients with asthma complicated with obstructive sleep apnea-hypopnea syndrome: a hospital-based study.

PURPOSE: The current study was conducted to explore the clinical features and risk factors of patients with asthma complicated by obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: Patients with asthma who underwent polysomnography in our hospital from August 2017 to December 2019 were enrolled in the study. Data on demographics, pulmonary function testing, polysomnography, blood gases, mean pulmonary artery pressure, and vascular endothelial growth factor (VEGF) were compared between the two groups. RESULTS: Of 238 patients with asthma, 93 who also had OSAHS formed the observation group and were subclassified into mild (n = 33), moderate (n = 41), and severe (n = 19) categories, while 145 patients with asthma alone were assigned to the control group. No significant differences were found in sex, age, course of disease, or pulmonary function between the two groups (P > 0.05), while the observation group showed more frequent allergic rhinitis and had greater BMI, neck circumference, mean pulmonary artery pressure (mPAP), and VEGF than those in the control group (P < 0.001). The peak expiratory flow (PEF), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC in the mild group and the moderate group were higher than those in the severe group (P < 0.001). The durations of AHI and SaO2 < 90% in the mild group and the moderate group were shorter than that in the severe group, and the lowest level of SaO2 in the mild group and the moderate group was higher than that in the severe group (P <  0.05). The mPAP and VEGF of the mild and moderate groups were lower than those of severe group (P < 0.001), with mild group lower than moderate group (P < 0.001). CONCLUSION: Significant differences in allergic rhinitis, BMI, neck circumference, AHI, SaO2, mPAP, and VEGF were observed in patients with asthma complicated by OSAHS. These parameters are risk factors associated with asthma complicated by OSAHS.

Efficacy and safety of Tian moxibustion in treating allergic rhinitis: A protocol for a systematic review and meta-analysis.

BACKGROUND: Allergic rhinitis, abbreviated AR, modern medicine considers AR to be a chronic inflammatory reactive disease of the nasal mucosa mediated by exposure to allergens such as pollen and mites immunoglobulin E. AR not only affects patients' daily life, sleep, work, and study, but also brings huge economic burden to patients and society. At present, desensitization therapy, antiallergic drugs, antihistamines, hormones, and other drugs are used to improve symptoms or immune regulation, but the clinical short-term and long-term efficacy is general, the symptoms are easy to be repeated after drug withdrawal, and the long-term toxicity and side effects of drugs are obviously insufficient. Tian moxibustion therapy has a good effect on AR. Therefore, this paper will carry out a systematic evaluation and meta-analysis of the efficacy and safety of moxibustion in the treatment of allergic rhinitis. METHODS: Eight electronic databases will be searched, including PubMed, Embase, Web of Science, Cochrane Library, the China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP), Wanfang Database (WF), and Chinese Biomedical Literature Database (CBM). We will search above electronic databases from the beginning to November 2020, without any language restriction, but involving only the human subjects. Clinical efficacy, including total effective rate or cure rate, and recurrence rate will be accepted as the primary outcomes. The Rhinoconjunctivitis quality of life questionaire (RQLQ) score, symptom score (nasal congestion, snot, continuous sneezing) will be used as secondary outcomes. The Cochrane Handbook of Systematic Review (5.3.0) randomized controlled trials (RCT) risk assessment tool will be used to evaluate the risk of bias by 2 independent researchers. RESULTS: After the completion of this study, the results will be reported, so it is not possible to give accurate results at present. CONCLUSIONS: The results of this study will provide reliable evidence for the efficacy and safety of Tian moxibustion in the treatment of allergic rhinitis. ETHICS AND DISSEMINATION: This paper does not need to be approved by the Ethics Committee, because this paper is a systematic review and quality evaluation of relevant literature. The results of this study will be disseminated in the form of a paper to help better guide the clinical practice of Tian moxibustion in the treatment of allergic rhinitis. INPLASY REGISTRATION NUMBER: INPLASY2020110058.

Intranasal GSK2245035, a Toll-like receptor 7 agonist, does not attenuate the allergen-induced asthmatic response in a randomized, double-blind, placebo-controlled experimental medicine study.

BACKGROUND: Allergic asthma is a heterogenous disorder predominantly driven by a type 2 inflammatory response to aeroallergens. Therapeutic modulation to rebalance these type 2 responses may offer clinical benefit for allergic respiratory inflammatory diseases, with the potential for disease modification. GSK2245035, a selective toll-like receptor-7 agonist, preferentially stimulates the induction of type 1 interferon alpha, reducing type 2 responses. OBJECTIVE: This study investigated whether intranasal GSK2245035 reduced allergen-induced bronchial reactivity in mild allergic asthma. METHODS: This double-blind, placebo-controlled, parallel-group Phase IIa trial randomized (1:1) participants with mild allergic asthma to intranasal GSK2245035 20 ng or placebo once weekly for 8 weeks; follow-up was conducted 1, 4, and 12 weeks after treatment. Allergen-induced late asthmatic response 1 week after treatment was measured as minimum and weighted mean forced expiratory volume in 1 second (FEV1) 4-10 hours following bronchial allergen challenge (primary endpoint). Pharmacodynamic and allergic biomarkers, and adverse events, were assessed. A Bayesian analysis framework was used; a posterior probability >0.7 denoted primary endpoint success. RESULTS: Thirty-six participants were randomized (GSK2245035, n = 22; placebo, n = 14). The percentage attenuation in late asthmatic response was -4.6% (posterior probability: 0.385) and -10.5% (posterior probability: 0.303) for minimum and weighted mean FEV1, respectively. Type 2 responses were confirmed by changes in lung function, eosinophils (blood and sputum), interleukin-5 (sputum) and fractional exhaled nitric oxide biomarkers pre- and post-bronchial allergen challenge. However, no treatment effect was observed. Adverse events were reported by 10/14 (71%) and 21/22 (95%) participants in the placebo and GSK2245035 groups, respectively; headache was the most common. CONCLUSIONS AND CLINICAL RELEVANCE: Although target engagement was observed, weekly intranasal GSK2245035 20 ng for 8 weeks did not substantially attenuate the late asthmatic response in participants with mild allergic asthma. Overall, treatment was well tolerated.

Constipation might be associated with risk of allergic rhinitis: A nationwide population-based cohort study.

BACKGROUND: Allergic rhinitis (AR) is a burdensome respiratory disorder whose etiology and pathophysiology remain controversial and most likely multifactorial. Accumulated evidence indicates that gut dysbiosis contributes to AR via the gut-airway axis. Constipation could result in alteration of the intestinal microflora. The clinical impact of constipation on AR has not been studied. We aimed to evaluate the risk of AR in constipated patients using a nationwide longitudinal population-based cohort. METHODS: We identified 57786 patients with constipation and 57786 matched controls between 1999 and 2013 from the Longitudinal Health Insurance Database, which is a subset of Taiwanese National Health Insurance Research Database. Propensity score analysis was used for matching age, sex, comorbidities, and medications at a ratio of 1:1. Multiple Cox regression and subgroup analyses were used to estimate the adjusted hazard ratio of AR. RESULTS: The incidence of AR was 32.2 per 1,000 person-years in constipated patients, which was twice that of non-constipated patients. After adjustment for patients' age, gender, comorbidities, and medications, patients with constipation had a 2.3-fold risk of AR compared to those without constipation (adjusted hazard ratio [aHR]: 2.30; 95% CI, 2.23-2.37). In subgroup analyses, patients aged 20-39 years had a 2.24-fold higher risk of AR in the constipation cohort (aHR; 95% CI, 2.12-2.36). Patients aged <20, 40-64, and ≥65 years had a 2.09, 2.05, and 2.07-fold risk of AR in the constipation cohort, respectively (aHR; 95% CI, 1.98-2.20, 1.94-2.18, and 1.92-2.23). Also, patients with constipation had a higher likelihood of AR, regardless of sex, and with or without comorbidities including hyperlipidemia, hypertension, chronic kidney disease, chronic liver disease, diabetes, chronic obstructive pulmonary disease, rheumatoid arthritis, dyspepsia, irritable bowel syndrome, and anxiety. CONCLUSION: Constipation might be associated with an increased risk of incidental AR. It seems that physicians should keep a higher index of suspicion for AR in people with constipation. The patency issue of gut could not be ignored in patients with AR.