Particulate matter exposure is associated with increased inflammatory cytokines and eosinophils in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is thought to result from complex interactions between the host immune system, microbiota, and environmental exposures. Currently, there is limited data regarding the impact of ambient particulate matter ≤2.5 µm in diameter (PM2.5) in the pathogenesis of CRS, despite evidence linking PM2.5 to other respiratory diseases. We hypothesized that PM2.5 may result in differential cytokine patterns that could inform our mechanistic understanding of the effect of environmental factors on CRS. METHODS: We conducted an analysis of data prospectively collected from 308 CRS patients undergoing endoscopic sinus surgery. Cytokines were quantified in intraoperative mucus specimens using a multiplex flow cytometric bead assay. Clinical and demographic data including zip codes were extracted and used to obtain tract-level income and rurality measures. A spatiotemporal machine learning model was used to estimate daily PM2.5 levels for the year prior to each patient's surgery date. Spearman correlations and regression analysis were performed to characterize the relationship between mucus cytokines and PM2.5. RESULTS: Several inflammatory cytokines including IL-2, IL-5/IL-13, IL-12, and 21 were significantly correlated with estimated average 6, 9, and 12-month preoperative PM2.5 levels. These relationships were maintained for most cytokines after adjusting for age, income, body mass index, rurality, polyps, asthma, and allergic rhinitis (AR) (p < .05). There were also higher odds of asthma (OR = 1.5, p = .01) and AR (OR = 1.48, p = .03) with increasing 12-month PM2.5 exposure. Higher tissue eosinophil counts were associated with increasing PM2.5 levels across multiple timeframes (p < .05). CONCLUSIONS: Chronic PM2.5 exposure may be an independent risk factor for development of a mixed, type-2 dominant CRS inflammatory response.

A district-level geospatial analysis of anaemia prevalence among rural men in India, 2019-21.

BACKGROUND: Despite its considerable impact on health and productivity, anemia among men has received limited attention. In a country as diverse as India, characterized by extensive geographic variations, there is a pressing need to investigate the nuanced spatial patterns of anemia prevalence among men. The identification of specific hotspots holds critical implications for policymaking, especially in rural areas, where a substantial portion of India's population resides. METHODS: The study conducted an analysis on a sample of 61,481 rural men from 707 districts of India, utilizing data from the National Family Health Survey-5 (2019-21). Various analytical techniques, including Moran's I, univariate LISA (Local Indicators of Spatial Association), bivariate LISA, and spatial regression models such as SLM (Spatial Lag Model), and SEM (Spatial Error Model) were employed to examine the geographic patterns and spatial correlates of anaemia prevalence in the study population. RESULTS: In rural India, three out of every ten men were found to be anemic. The univariate Moran's I value for anaemia was 0.66, indicating a substantial degree of spatial autocorrelation in anaemia prevalence across the districts in India. Cluster and outlier analysis identified five prominent 'hotspots' of anaemia prevalence across 97 districts, primarily concentrated in the eastern region (encompassing West Bengal, Jharkhand, and Odisha), the Dandakaranya region, the Madhya Pradesh-Maharashtra border, lower Assam, and select districts in Jammu and Kashmir. The results of SLM revealed significant positive association between anaemia prevalence at the district-level and several key factors including a higher proportion of Scheduled Tribes, men in the 49-54 years age group, men with limited or no formal education, individuals of the Muslim faith, economically disadvantaged men, and those who reported alcohol consumption. CONCLUSIONS: Substantial spatial heterogeneity in anaemia prevalence among men in rural India suggests the need for region-specific targeted interventions to reduce the burden of anaemia among men in rural India and enhance the overall health of this population.

Image guided dilation of sinus ostium in revision sinus surgery.

PURPOSE: Assess if a rigid, image-guided balloon could be used effectively and safely in revision sinus surgery. MATERIALS AND METHODS: A prospective, non-randomized, single-arm, multicenter study to assess the safety and device performance of the NuVent™ EM Balloon Sinus Dilation System. Adults with CRS in need of revision sinus surgery were enrolled for balloon sinus dilation of a frontal, sphenoid, or maxillary sinus. The primary device performance endpoint was the ability of the device to (1) navigate to; and (2) dilate tissue in subjects with scarred, granulated, or previously surgically-altered tissue (revision). Safety outcomes included the assessment of any operative adverse events (AEs) directly attributable to the device or for which direct cause could not be determined. A follow-up endoscopy was conducted at 14 days post-treatment for assessment of any AEs. Performance outcomes included the surgeon's ability to reach the target sinus (es) and dilate the ostia. Endoscopic photos were captured for each treated sinus pre- and post-dilation. RESULTS: At 6 US clinical sites, 51 subjects were enrolled; 1 subject withdrew before treatment due to a cardiac complication from anesthesia. 121 sinuses were treated in 50 subjects. The device performed as expected in 100 % of the 121 treated sinuses, with investigators able to navigate to the treatment area and dilate the sinus ostium without difficulty. Ten AEs were seen in 9 subjects, with 0 related to the device. CONCLUSION: The targeted frontal, maxillary or sphenoid sinus ostium were safely dilated in every revision subject treated, with no AEs directly attributed to the device.

Current insight into treatment of chronic rhinosinusitis: Phenotypes, endotypes, and implications for targeted therapeutics.

Chronic rhinosinusitis is characterized by persistent locoregional mucosal inflammation of the paranasal sinuses and upper airway that has substantial associated health care costs. Personalized approaches to care that incorporate use of molecular biomarkers, phenotypes, and inflammatory endotypes is a major focus of research at this time, and the concurrent rise of targeted therapeutics and biologic therapies has the potential to rapidly advance care and improve outcomes. Recent findings suggest that improved understanding of chronic rhinosinusitis phenotypic and endotypic heterogeneity, and incorporation of these characteristics into clinical care pathways, may facilitate more effective selection of surgical and/or therapeutic interventions. Ultimately, these personalized approaches have the potential to target specific inflammatory pathways, increase efficacy, reduce costs, and limit side effects. This review summarizes recent advances in the identification and characterization of chronic rhinosinusitis phenotypes, endotypes, and biomarkers and reviews potential implications for targeted therapeutics.

Menstrual hygiene practices among adolescent women in rural India: a cross-sectional study.

BACKGROUND: Exclusive use of hygienic methods (sanitary napkins, locally prepared napkins, tampons, and menstrual cups) to prevent the visibility of bloodstains during menstruation is still considerably low among adolescent women in rural India. However, no prior research has explored the prevalence and determinants of exclusive hygienic methods among rural Indian adolescent women. To address this gap, this study examines the factors affecting adolescent women's exclusive use of hygienic methods in rural India. Additionally, this study explores state- and district-level geographical disparities in the exclusive use of hygienic methods among adolescent women in rural India. METHODS: Information on 95,551 adolescent women from rural India from the latest round of National Family Health Survey (NFHS-5) was analyzed. Bivariate statistics and multilevel logistic regression analysis were used to assess the Individual- and community-level factors associated with exclusive use of hygienic methods among adolescent women in rural India. Choropleth maps were used to discern the geographical disparities in the exclusive use of hygienic methods. RESULTS: In rural India, only 42% of adolescent women exclusively used hygienic methods, with substantial geographic disparities at the state and district levels. At the state level, the exclusive use of hygienic methods varied from 23% in Uttar Pradesh to 85% in Tamil Nadu. Even greater variation was observed at the district level. There was a clear north-south divide in the exclusive use of hygienic methods among adolescent women in rural India. The results of multilevel logistic regression indicated a considerable amount of variation in the exclusive use of hygienic methods at community level which further reduced when controlled for individual and community-level factors. Rural Indian adolescent women with higher education (AOR:3.20, 95% CI: 2.81-3.64), from general category (AOR: 1.14, 95% CI: 1.07-1.21), with medium mass media exposure (AOR: 1.43, 95% CI: 1.35-1.51), and from richest wealth quintile (AOR: 3.98, 95% CI: 3.69-4.30) were more likely to use hygienic methods exclusively. CONCLUSION: Wide differential across biodemographic and socioeconomic groups, and substantial geographic disparities at state- and district-level in the exclusive use of hygienic methods suggests a need to adopt context-specific interventions for adolescent women in rural India. Distribution of subsidized or free menstrual hygiene methods to disadvantaged adolescent women, and in the low-prevalence districts may increase the level of exclusive use of hygienic methods remarkably.

Analysis of suppressive effects of pesticide triazophos on leucocyte immune responses in a teleost, Channa Punctatus.

Triazophos is a commonly used organophosphate insecticide, which inhibits the acetylcholinesterase enzyme and causes paralysis and death of insects. Impact of the pesticides on immunity has scarcely been investigated, especially in fishes. The present study was designed to analyze the immunotoxic role of in vitro triazophos exposure to the leucocytes in freshwater teleost, Channa punctatus. Triazophos, at in vitro concentrations of 0.1, 0.5, and 1 µg ml-1, was used to study leucocyte phagocytosis, superoxide production, nitrite release, and lymphocyte proliferation. Dose-dependent suppression of various immune responses was observed. Nitrite release and superoxide production by leucocytes were reduced in cultures incubated with triazophos. Mitogen-induced lymphocyte proliferation was significantly reduced at 0.5 and 1 µg ml-1 but not at 0.1 µg ml-1 concentration of pesticide. The biphasic suppressive effect was also discovered while evaluating phagocytic response. These investigations describe the effects of pesticide on immune responses in C. punctatus, which are helpful in understanding the immunotoxicity in fish. Substantially more researches are required to help design the measures to combat ecotoxicity in freshwater bodies.

Inflammatory heterogeneity in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a mechanistically distinct subtype of chronic rhinosinusitis with nasal polyps (CRSwNP). Although frequently associated with type 2 inflammation, literature characterizing the milieu of inflammatory cytokines and lipid mediators in AERD has been conflicting. OBJECTIVE: We sought to identify differences in the upper airway inflammatory signature between CRSwNP and AERD and determine whether endotypic subtypes of AERD may exist. METHODS: Levels of 7 cytokines representative of type 1, type 2, and type 3 inflammation, and 21 lipid mediators were measured in nasal mucus from 109 patients with CRSwNP, 30 patients with AERD, and 64 non-CRS controls. Differences in inflammatory mediators were identified between groups, and patterns of inflammation among patients with AERD were determined by hierarchical cluster analysis. RESULTS: AERD could be distinguished from CRSwNP by profound elevations in IL-5, IL-6, IL-13, and IFN-γ; however, significant heterogeneity existed between patients. Hierarchical cluster analysis identified 3 inflammatory subendotypes of AERD characterized by (1) low inflammatory burden, (2) high type 2 cytokines, and (3) comparatively low type 2 cytokines and high levels of type 1 and type 3 cytokines. Several lipid mediators were associated with asthma and sinonasal disease severity; however, lipid mediators showed less variability than cytokines. CONCLUSIONS: AERD is associated with elevations in type 2 cytokines (IL-5 and IL-13) and the type 1 cytokine, IFN-γ. Among patients with AERD, the inflammatory signature is heterogeneous, supporting subendotypes of the disease. Variability in AERD immune signatures should be further clarified because this may predict clinical response to biologic medications that target type 2 inflammation.

Cultural determinants of food attitudes in anosmic patients.

The decrease in food enjoyment is a major factor why patients suffer from depression when having anosmia, or total loss of smell. While we have some knowledge about how food preferences and attitudes change with dysosmia, these findings are limited because other factors such as culture are not factored in. It is likely that the culture in which an anosmic patient identifies with will influence how their smell loss impacts their relationship with food. This study examined the current attitudes within the United States and Germany towards foods, focusing on the comparison between anosmic patients (N = 53) and those with a healthy sense of smell (N = 121). A survey was used to collect free responses for liking on a variety of foods (N = 15) that were also rated for their overall liking. Additionally, individuals rated and ranked their liking for sensory attributes in relation to their enjoyment of food. Free responses were classified into categories and subcategories, the frequency of those responses were then compared across groups. The patient population of each culture gave lower importance to aroma and flavor; however, the U.S.A. patient population showed a larger decrease from their healthy counterparts. Furthermore, anosmic patients from the U.S.A. showed less overall liking towards the food stimuli compared to their healthy counterparts, while no such effect observed among the German population. Reasons to enjoy a food were largely explained by the culture, and patients within a culture took on different compensation strategies which we use to explain their effectiveness.

Chronic rhinosinusitis in elderly patients is associated with an exaggerated neutrophilic proinflammatory response to pathogenic bacteria.

BACKGROUND: Potential effects of aging on chronic rhinosinusitis (CRS) pathophysiology have not been well defined but might have important ramifications given a rapidly aging US and world population. OBJECTIVE: The goal of the current study was to determine whether advanced age is associated with specific inflammatory CRS endotypes or immune signatures. METHODS: Levels of 17 mucus cytokines and inflammatory mediators were measured in 147 patients with CRS. Hierarchical cluster analysis was used to identify and characterize inflammatory CRS endotypes, as well as to determine whether age was associated with specific immune signatures. RESULTS: A CRS endotype with a proinflammatory neutrophilic immune signature was enriched in older patients. In the overall cohort patients 60 years and older had increased mucus levels of IL-1ß, IL-6, IL-8, and TNF-α when compared with their younger counterparts. Increases in levels of proinflammatory cytokines were associated with both tissue neutrophilia and symptomatic bacterial infection/colonization in aged patients. CONCLUSIONS: Aged patients with CRS have a unique inflammatory signature that corresponds to a neutrophilic proinflammatory response. Neutrophil-driven inflammation in aged patients with CRS might be less likely to respond to corticosteroids and might be closely linked to chronic microbial infection or colonization.

Cytokines in Chronic Rhinosinusitis. Role in Eosinophilia and Aspirin-exacerbated Respiratory Disease.

RATIONALE: The mechanisms that underlie the pathogenesis of chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD) are not clear. OBJECTIVES: To first evaluate the inflammatory profiles of CRSsNP and CRSwNP tissues and then to investigate whether clinical differences observed between CRSwNP and AERD are in part secondary to differences in inflammatory mediator expression within nasal polyp (NP) tissues. METHODS: Expression levels of numerous inflammatory mediators were determined by quantitative real-time polymerase chain reaction, ELISA, and multiplex immunoassay. MEASUREMENTS AND MAIN RESULTS: CRSwNP NP had increased levels of type 2 mediators, including IL-5 (P < 0.001), IL-13 (P < 0.001), eotaxin-2 (P < 0.001), and monocyte chemoattractant protein (MCP)-4 (P < 0.01), compared with sinonasal tissue from subjects with CRSsNP and control subjects. Expression of IFN-γ messenger RNA or protein was low and not different among the chronic rhinosinusitis subtypes examined. Compared with CRSwNP, AERD NP had elevated protein levels of eosinophil cationic protein (ECP) (P < 0.001), granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.01), and MCP-1 (P = 0.01), as well as decreased gene expression of tissue plasminogen activator (tPA) (P = 0.02). Despite the higher eosinophilia in AERD, there was no associated increase in type 2 mediator protein levels observed. CONCLUSIONS: CRSwNP was characterized by a predominant type 2 inflammatory environment, whereas CRSsNP did not reflect a classic type 1 milieu, as has been suggested previously. AERD can be distinguished from CRSwNP by elevated ECP levels, but this enhanced eosinophilia is not associated with elevations in traditional type 2 inflammatory mediators associated with eosinophil proliferation and recruitment. However, other factors, including GM-CSF, MCP-1, and tPA, may be important contributors to AERD pathogenesis.

Differential effect of omalizumab on pulmonary function in patients with allergic asthma with and without chronic rhinosinusitis.

BACKGROUND: Omalizumab, an anti-immunoglobulin E monoclonal antibody, is approved by the U.S. Food and Drug Administration for the management of patients with allergic asthma and with refractory disease, and has also proven beneficial in the management of selected patients with chronic rhinosinusitis (CRS). The common airway model indicates that patients with both allergic asthma and CRS may be more challenging to manage clinically. This is the first study to evaluate the response of omalizumab in patients with asthma and CRS versus those with asthma alone. OBJECTIVE: To compare pulmonary function test (PFT) responses in omalizumab-treated patients with asthma with CRS with omalizumab-treated patients with asthma without CRS. METHODS: This was a retrospective case-control study at a tertiary university clinic. Between 2007 and 2014, a total of 259 patients with allergic asthma had been prescribed omalizumab for asthma. Outcome measures were absolute, and the percentage changes in PFT results were compared with the baseline. RESULTS: Overall, 81 patients had serial PFT results available for evaluation, among whom 59 (73%) had CRS. Average treatment duration was 27.2, 27.7, and 25.8 months for the entire sample, for patients with asthma and CRS, and for patients with asthma and without CRS, respectively. Overall, PFT metrics improved across all parameters (forced expiratory volume in 1 second, forced vital capacity, forced expiratory volume in 1 second to forced vital capacity ratio, and forced expiratory flow 25-75%). Significant improvement (p < 0.05, paired t-test) was observed for three of four metrics in patients with comorbid CRS but in none of these parameters in patients without CRS. CONCLUSION: Patients with allergic asthma who were treated with omalizumab manifested some improvement in PFT scores. CRS may add to the overall symptom burden experienced by patients with asthma, especially in those with increasing severity, but comorbid CRS did not adversely impact the therapeutic potential of omalizumab. In fact, the benefit of omalizumab was more likely to be observed in patients with asthma and with CRS than in patients with asthma and without CRS.

Increased expression of the epithelial anion transporter pendrin/SLC26A4 in nasal polyps of patients with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a multifactorial disease of unknown cause characterized by sinonasal inflammation, increased mucus production, and defective mucociliary clearance. Expression of Pendrin, an epithelial anion transporter, is increased in asthma and chronic obstructive pulmonary disease. Pendrin increases mucus production and regulates mucociliary clearance. OBJECTIVES: We sought to investigate the expression of pendrin and the mucus-related protein Muc5AC in sinonasal tissues of control subjects and patients with CRS and to evaluate the regulation of pendrin expression in nasal epithelial cells (NECs) in vitro. METHODS: The expression and distribution of pendrin in sinonasal tissues was analyzed by using real-time PCR, immunoblot analysis, and immunohistochemistry. Differentiated NECs were used to study the regulation of pendrin expression. RESULTS: Increased pendrin expression was observed in nasal polyp (NP) tissue of patients with CRS. Immunohistochemistry analysis revealed that pendrin was largely restricted to the epithelial layer. Pendrin expression significantly correlated with inflammatory cell markers, suggesting that the factors made by these cells might induce pendrin expression. Furthermore, both pendrin and periostin levels (a biomarker in asthma) correlated with IL-13 levels, suggesting that pendrin can be induced by this cytokine in sinonasal tissues. Expression of the mucus component protein Muc5AC correlated weakly with pendrin expression, indicating that pendrin might modulate mucus production in NPs. In cultured NECs pendrin expression was induced by TH2 cytokines and induced synergistically when TH2 cytokines were combined with IL-17A. Interestingly, human rhinovirus had a potentiating effect on IL-13-induced pendrin expression. Dexamethasone suppressed pendrin expression, suggesting that the therapeutic benefit of dexamethasone in asthmatic patients and those with CRS might involve regulation of pendrin expression. CONCLUSIONS: TH2-mediated pendrin expression is increased in NPs of patients with CRS and might lead to increased inflammation, mucus production, and decreased mucociliary clearance.

Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease.

BACKGROUND: Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asthma, chronic rhinosinusitis (CRS), and eosinophilic esophagitis. OBJECTIVE: The objective of this study was to investigate the role of oncostatin M (OSM) in epithelial barrier dysfunction in human mucosal disease. METHODS: OSM expression was measured in tissue extracts, nasal secretions, and bronchoalveolar lavage fluid. The effects of OSM stimulation on barrier function of normal human bronchial epithelial cells and nasal epithelial cells cultured at the air-liquid interface were assessed by using transepithelial electrical resistance and fluorescein isothiocyanate-dextran flux. Dual-color immunofluorescence was used to evaluate the integrity of tight junction structures in cultured epithelial cells. RESULTS: Analysis of samples from patients with CRS showed that OSM mRNA and protein levels were highly increased in nasal polyps compared with those seen in control uncinate tissue (P < .05). OSM levels were also increased in bronchoalveolar lavage fluid of allergic asthmatic patients after segmental allergen challenge and in esophageal biopsy specimens from patients with eosinophilic esophagitis. OSM stimulation of air-liquid interface cultures resulted in reduced barrier function, as measured by decreased transepithelial electrical resistance and increased fluorescein isothiocyanate-dextran flux (P < .05). Alterations in barrier function by OSM were reversible, and the viability of epithelial cells was unaffected. OSM levels in lysates of nasal polyps and uncinate tissue positively correlated with levels of α2-macroglobulin, a marker of epithelial leak, in localized nasal secretions (r = 0.4855, P < .05). CONCLUSIONS: These results suggest that OSM might play a role in epithelial barrier dysfunction in patients with CRS and other mucosal diseases.

Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression.

RATIONALE: Nasal polyps (NPs) are characterized by intense edema or formation of pseudocysts filled with plasma proteins, mainly albumin. However, the mechanisms underlying NP retention of plasma proteins in their submucosa remain unclear. OBJECTIVES: We hypothesized that formation of a fibrin mesh retains plasma proteins in NPs. We assessed the fibrin deposition and expression of the components of the fibrinolytic system in patients with chronic rhinosinusitis (CRS). METHODS: We assessed fibrin deposition in nasal tissue from patients with CRS and control subjects by means of immunofluorescence. Fibrinolytic components, d-dimer, and plasminogen activators were measured using ELISA, real-time PCR, and immunohistochemistry. We also performed gene expression and protein quantification analysis in cultured airway epithelial cells. MEASUREMENTS AND MAIN RESULTS: Immunofluorescence data showed profound fibrin deposition in NP compared with uncinate tissue (UT) from patients with CRS and control subjects. Levels of the cross-linked fibrin cleavage product protein, d-dimer, were significantly decreased in NP compared with UT from patients with CRS and control subjects, suggesting reduced fibrinolysis (P < 0.05). Expression levels of tissue plasminogen activator (t-PA) mRNA and protein were significantly decreased in NP compared with UT from patients with CRS and control subjects (P < 0.01). Immunohistochemistry demonstrated clear reduction of t-PA in NP, primarily in the epithelium and glands. Th2 cytokine-stimulated cultured airway epithelial cells showed down-regulation of t-PA, suggesting a potential Th2 mechanism in NP. CONCLUSIONS: A Th2-mediated reduction of t-PA might lead to excessive fibrin deposition in the submucosa of NP, which might contribute to the tissue remodeling and pathogenesis of CRS with nasal polyps.