Overuse of diagnostic tools and medications in acute rhinosinusitis in Spain: a population-based study (the PROSINUS study).

Objectives Acute rhinosinusitis (ARS) has a high incidence. Diagnosis is clinical, and evolution is mostly self-limited. The aim of this study was to describe the sociodemographic characteristics and use of diagnostic tools and medications in patients with ARS. Design This is a prospective observational study in real-life clinical practice. Setting Patients with clinical diagnosis of ARS (n=2610) were included from ear, nose and throat clinics in Spain. A second visit at resolution was done. Participants Patients were classified according to the duration of symptoms: viral ARS (≤10 days), postviral ARS (>10 days, ≤12 weeks) and chronic rhinosinusitis (>12 weeks). Main outcome measures Sociodemographic characteristics, symptoms, disease severity, quality of life (Sino-Nasal Outcome Test-16), used diagnostic tools and medications, and the management performed by primary care physicians (PCPs) and by otorhinolaryngologists (ORLs) were assessed. Results Of the patients 36% were classified as having viral ARS, 63% postviral ARS and 1% as chronic rhinosinusitis. Working in a poorly air-conditioned environment was a risk factor (OR: 2.26, 95% CI 1.27 to 4.04) in developing postviral ARS. A higher number of diagnostic tools (rhinoscopy/endoscopy: 80% vs 70%; plain X-ray: 70% vs 55%; CT scan: 22% vs 12%; P<0.0001) were performed in postviral than viral cases. PCPs performed more X-rays than ORLs (P<0.0001). Patients, more those with postviral than viral ARS, received a high number of medications (oral antibiotics: 76% vs 62%; intranasal corticosteroids: 54% vs 38%; antihistamines: 46% vs 31%; mucolytic: 48% vs 60%; P<0.0001). PCPs prescribed more antibiotics, antihistamines and mucolytics than ORLs (P<0.0068). More patients with postviral than viral ARS reported symptoms of potential complications (1.5% vs 0.4%; P=0.0603). Independently of prescribed medications, quality of life was more affected in patients with postviral (38.7±14.2 vs 36.0±15.3; P=0.0031) than those with viral ARS. ARS resolution was obtained after 6.04 (viral) and 16.55 (postviral) days, with intranasal corticosteroids being associated with longer (OR: 1.07, 95% 1.02 to 1.12) and phytotherapy with shorter (OR: 0.95, 95% CI 0.91 to 1.00) duration. Conclusions There is a significant overuse of diagnostic tools and prescribed medications, predominantly oral antibiotics, by PCPs and ORLs, for viral and postviral ARS

Effect of lipopolysaccharide on glucocorticoid receptor function in control nasal mucosa fibroblasts and in fibroblasts from patients with chronic rhinosinusitis with nasal polyps and asthma

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the upper airways frequently associated with asthma. Bacterial infection is a feature of CRSwNP that can aggravate the disease and the response to glucocorticoid treatment.We examined whether the bacterial product lipopolysaccharide (LPS) reduces glucocorticoid receptor (GR) function in control nasal mucosa (NM) fibroblasts and in nasal polyp (NP) fibroblasts from patients with CRSwNP and asthma.NP (n = 12) and NM fibroblasts (n = 10) were in vitro pre-incubated with LPS (24 hours) prior to the addition of dexamethasone. Cytokine/chemokine secretion was measured by ELISA and Cytometric Bead Array. GR?, GR?, mitogen-activated protein-kinase phosphatase-1 (MKP-1) and glucocorticoid-induced leucine zipper (GILZ) expression was measured by RT-PCR and immunoblotting, GR? nuclear translocation by immunocytochemistry, and GR? localization by immunoblotting. The role of MKP-1 and GILZ on dexamethasone-mediated cytokine inhibition was analyzed by small interfering RNA silencing.Pre-incubation of nasal fibroblasts with LPS enhanced the secretion of IL-6, CXCL8, RANTES, and GM-CSF induced by FBS. FBS-induced CXCL8 secretion was higher in NP than in NM fibroblasts. LPS effects on IL-6 and CXCL8 were mediated via activation of p38?/? MAPK and IKK/NF-?B pathways. Additionally, LPS pre-incubation: 1) reduced dexamethasone's capacity to inhibit FBS-induced IL-6, CXCL8 and RANTES, 2) reduced dexamethasone-induced GR? nuclear translocation (only in NM fibroblasts), 3) did not alter GR?/GR? expression, 4) decreased GILZ expression, and 5) did not affect dexamethasone's capacity to induce MKP-1 and GILZ expression. MKP-1 knockdown reduced dexamethasone's capacity to suppress FBS-induced CXCL8 release.The bacterial product LPS negatively affects GR function in control NM and NP fibroblasts by interfering with the capacity of the activated receptor to inhibit the production of pro-inflammatory mediators. This study contributes to the understanding of how bacterial infection of the upper airways may limit the efficacy of glucocorticoid treatment

Signal transduction pathways (MAPKS, NF-kB, and C/EBP) regulating COX-2 expression in nasal fibroblasts from asthma patients with aspirin intolerance

Background Recent studies have revealed that cyclooxygenase-2 (COX-2) expression is down-regulated in aspirin-induced asthma (AIA). Various signal pathways (MAPKs, NF-κB and C/EBP) are involved in COX-2 regulation. Objective To investigate the regulation of COX-2 expression through MAP-kinase pathway activation and nuclear factor translocation in aspirin-induced asthma (AIA). Methods Fibroblasts were isolated from specimens of nasal mucosa (NM, N = 5) and nasal polyps (NP, N = 5). After IL-1β (1 ng/ml) incubation, COX-2 and phosphorylated forms of ERK, JNK and p38 MAPK were measured by Western blot. MAPK's role in IL-1β-induced COX-2 expression was assessed by treating cells with ERK (PD98059), JNK (SP600125) and p38 MAPK (SB203580) inhibitors (0.1-10 µM) prior to IL-1β exposure. NF-κB and C/EBP nuclear translocation was measured by Western blot and TransAM® after IL-1β (10 ng/ml) exposure. Results No differences were observed in the MAPK phosphorylation time-course between NM and NP-AIA fibroblasts. The p38 MAPK inhibitor at 10 µM significantly reduced IL-1β-induced COX-2 expression in NM fibroblasts (85%). In NP-AIA fibroblasts the COX-2 inhibition (65%) at 1 and 10 µM was not statistically significant compared to non-treated cells. ERK and JNK inhibitors had no significant effect in either the NM or NP-AIA cultures. The effect of IL-1β on NF-κB and C/EBP subunits' nuclear translocation was similar between NM and NP-AIA fibroblasts. Conclusions These results suggest that p38 MAPK is the only MAPK involved in IL-1β-induced COX-2 expression. NM and NP-AIA fibroblasts have similar MAPK phosphorylation dynamics and nuclear factor translocation (NF-κB and C/EBP). COX-2 downregulation observed in AIA patients appears not to be caused by differences in MAPK dynamics or transcription factor translocation

Low prostaglandin E2 and cyclooxygenase expression in nasal mucosa fibroblasts of aspirin-intolerant asthmatics.

Background and objective: Anomalies in the regulation of cyclooxygenase (COX)-1 and-2 have been described in nasal polyps of aspirin-induced asthma (AIA). Whether these anomalies are specific to nasal polyps or affect all the nasal mucosa (NM) of upper airways is still unclear. The objective of this study was to compare the COX pathway in NM of AIA patients with the NM of control subjects. Methods: Fibroblasts were isolated from NM of 5 AIA patients (AIA-NM) and 5 control subjects (control-NM). Cells were treated with 10 ng/ml IL-1b for up to 72 hours. Prostaglandin E2 (PGE2) production was measured by ELISA, expression of COX-1 protein by Western blot, and COX-2 protein by ELISA, Western blot and immunofluorescence techniques. Results: IL-1b increased PGE2 production and COX-1 protein expression in control-NM fibroblasts, but no changes were found in AIA-NM. IL-1b provoked a significant timedependent increase in COX-2 protein expression in control-NM fibroblasts but had a very mild effect on COX-2 protein expression in AIA-NM. Conclusions: Our data suggest that abnormalities in the COX pathway are not a phenomenon exclusive to nasal polyp mucosa as they are also present in all the nasal mucosa of AIA patients. These anomalies may be involved in the pathogenesis of airway inflammation and NSAID intolerance in asthma patients with chronic rhinosinusitis and nasal polyposis

Paediatric Barcelona Olfactory Test-6 (pBOT-6): Validation of a Combined Odour Identification and Threshold Screening Test in Healthy Spanish Children and Adolescents

Background: Few odour tests have been created for children. Objectives: The aim of the present study was to develop and validate a simple and quick olfactory test, suitable for the evaluation of odour identification and threshold in a Spanish paediatric population, the paediatric Barcelona Olfactory Test-6 (pBOT-6).The pBOT-6 consisted in a set of 6 odorants for a forced-choice identification test (IT), and a 6 dilutions phenyl ethyl alcohol geometric series for the threshold test (TT). The pBOT-6 was compared with the U-sniff test (a validated international paediatric smell test) in 131 Spanish healthy volunteers aged 6-17 years. A Bland-Altman plot was used to determine the agreement between two tests. Reliability was analyzed in fifteenvolunteers using the intraclass correlation coefficient (ICC). Normative data was obtained and 8 children diagnosed with subjective smell loss were tested for validation.Bland-Altman analysis demonstrated a minimal bias of -1.71% with upper and lower limit of agreement of -31.1% and 27.6%, respectively. The ICC was 0.83 (95% CI 0.6-0.96) for the IT and 0.73 (95% CI 0.36-0.9) for the TT, showing excellent and good consistency between measurements over time. Mean pBOT-6 scores were significantly higher in healthy volunteers compared with patients with smell loss. Discrimination between normosmia and smell loss was achieved with a sensitivity of 96.9% and a specificity of 100%.The pBOT-6 offers an effectiveand fast method useful in clinical routine to distinguish, with high sensitivity and specificity, between paediatric patients with normosmia and those with smell dysfunction

Superior effect of MP-AzeFlu than azelastine or fluticasone propionate alone on reducing inflammatory markers

Background: MP-AzeFlu, intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP), is superior to AZE or FP alone for treatment of allergic rhinitis (AR). However, the precise anti-inflammatory mechanism of action of MP-AzeFlu has not been characterized. Objective: To investigate the anti-inflammatory effects of MP-AzeFlu compared with AZE or FP alone in an established in vitro model of eosinophilic inflammation. Methods: Nasal mucosal epithelial cells and peripheral blood eosinophils were obtained from human volunteers. Epithelial cells were stimulated with 10% fetal bovine serum (FBS) in the presence of MP-AzeFlu, AZE, or FP (1:102 to 1:105 dilution). Concentrations of interleukin (IL)-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured by ELISA. Eosinophils were incubated in 10% human epithelial cell-conditioned medium (HECM) and survival assessed by trypan blue dye exclusion. Results are expressed as mean ± SEM percentage secretion/survival compared with FBS/HECM (respectively). Results: FP and MP-AzeFlu (all dilutions) and AZE (1:102) significantly reduced IL-6 secretion and eosinophil survival compared with positive controls. At 1:102 dilution, IL-6 secretion was significantly lower with MP-AzeFlu (38.3 ± 4.2%, compared with FBS = 100%) than with AZE (76.1 ± 4.9%) or FP (53.0 ± 4.9%). At 1:102 dilution, eosinophil survival was significantly lower with MP-AzeFlu at day 3 (17.5 ± 3.0%) and day 4 (2.4 ± 1.4%, compared with HECM = 100%) than with AZE (day 3: 75.2 ± 7.2%; day 4: 44.0 ± 9.7%) or FP (day 3: 38.5 ± 3.5%; day 4: 14.6 ± 4.0%). Conclusion: Greater reductions in cytokine secretion and eosinophil survival observed with MP-AzeFlu in vitro may underlie MP-AzeFlu's superior clinical efficacy vs. AZE or FP alone observed in AR patients

Reconstituted human upper airway epithelium as 3-d in vitro model for nasal polyposis.

BACKGROUND: Primary human airway epithelial cells cultured in an air-liquid interface (ALI) develop a well-differentiated epithelium. However, neither characterization of mucociliar differentiation overtime nor the inflammatory function of reconstituted nasal polyp (NP) epithelia have been described. OBJECTIVES: 1st) To develop and characterize the mucociliar differentiation overtime of human epithelial cells of chronic rhinosinusitis with nasal polyps (CRSwNP) in ALI culture system; 2nd) To corroborate that 3D in vitro model of NP reconstituted epithelium maintains, compared to control nasal mucosa (NM), an inflammatory function. METHODS: Epithelial cells were obtained from 9 NP and 7 control NM, and differentiated in ALI culture for 28 days. Mucociliary differentiation was characterized at different times (0, 7, 14, 21, and 28 days) using ultrastructure analysis by electron microscopy; ΔNp63 (basal stem/progenitor cell), β-tubulin IV (cilia), and MUC5AC (goblet cell) expression by immunocytochemistry; and mucous (MUC5AC, MUC5B) and serous (Lactoferrin) secretion by ELISA. Inflammatory function of ALI cultures (at days 0, 14, and 28) through cytokine (IL-8, IL-1β, IL-6, IL-10, TNF-α, and IL-12p70) and chemokine (RANTES, MIG, MCP-1, IP-10, eotaxin-1, and GM-CSF) production was analysed by CBA (Cytometric Bead Array). RESULTS: In both NP and control NM ALI cultures, pseudostratified epithelium with ciliated, mucus-secreting, and basal cells were observed by electron microscopy at days 14 and 28. Displaying epithelial cell re-differentation, β-tubulin IV and MUC5AC positive cells increased, while ΔNp63 positive cells decreased overtime. No significant differences were found overtime in MUC5AC, MUC5B, and lactoferrin secretions between both ALI cultures. IL-8 and GM-CSF were significantly increased in NP compared to control NM regenerated epithelia. CONCLUSION: Reconstituted epithelia from human NP epithelial cells cultured in ALI system provides a 3D in vitro model that could be useful both for studying the role of epithelium in CRSwNP while developing new therapeutic strategies, including cell therapy, for CRSwN

Real-life assessment of chronic rhinosinusitis patients using mobile technology: the mySinusitisCoach project by EUFOREA

Background: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease associated with a substantial personal and socioeconomic burden. Monitoring of patient‐reported outcomes by mobile technology offers the possibility to better understand real‐life burden of CRS. Methods: This study reports on the cross‐sectional evaluation of data of 626 users of mySinusitisCoach (mSC), a mobile application for CRS patients. Patient characteristics of mSC users were analysed as well as the level of disease control based on VAS global rhinosinusitis symptom score and adapted EPOS criteria. Results: The mSC cohort represents a heterogeneous group of CRS patients with a diverse pattern of major symptoms. Approximately half of patients reported nasal polyps. 47.3% of all CRS patients were uncontrolled based on evaluation of VAS global rhinosinusitis symptom score compared to 40.9% based on adapted EPOS criteria. The impact of CRS on sleep quality and daily life activities was significantly higher in uncontrolled versus well‐controlled patients. Half of patients had a history of FESS (functional endoscopic sinus surgery) and reported lower symptom severity compared to patients without a history of FESS, except for patients with a history of more than 3 procedures. Patients with a history of FESS reported higher VAS levels for impaired smell. Conclusion: Real‐life data confirm the high disease burden in uncontrolled CRS patients, clearly impacting quality of life. Sinus surgery improves patient‐reported outcomes, but not in patients with a history of more than 3 procedures. Mobile technology opens a new era of real‐life monitoring, supporting the evolution of care towards precision medicine

The EUFOREA pocket guide for chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is known to affect around 5 % of the total population, with major impact on the quality of life of those severely affected (1). Despite a substantial burden on individuals, society and health economies, CRS often remains underdiagnosed, under-estimated and under-treated (2). International guidelines like the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) (3) and the International Consensus statement on Allergy and Rhinology: Rhinosinusitis 2021 (ICAR) (4) offer physicians insight into the recommended treatment options for CRS, with an overview of effective strategies and guidance of diagnosis and care throughout the disease journey of CRS