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Epithelial barrier disruption and failure of epithelial repair by aberrant epithelial-mesenchymal transition (EMT)-induced basal cells observed in nasal mucosa of chronic rhinosinusitis (CRS) are speculated to play important roles in disease pathophysiology. Microparticles (MPs) are a type of extracellular vesicle (EV) released by budding or shedding from the plasma membrane of activated or apoptotic cells. MPs are detected in nasal lavage fluids (NLFs) and are now receiving attention as potential biomarkers to evaluate the degree of activation of immune cells and injury of structural cells in nasal mucosa of subjects with sinus disease. There are three types of epithelial-cell-derived MPs, which are defined by the expression of different epithelial specific markers on their surface: EpCAM, E-cadherin, and integrin β6 (ITGB6). When these markers are on MPs that are also carrying canonical EMT/mesenchymal markers (Snail (SNAI1); Slug (SNAI2); alpha-smooth muscle actin (αSMA, ACTA2)) or pro- and anti-coagulant molecules (tissue factor (TF); tissue plasminogen activator (tPA); plasminogen activator inhibitor-1 (PAI-1)), they provide insight as to the roles of epithelial activation for EMT or regulation of coagulation in the underlying disease. In this review, we discuss the potential of epithelial MPs as research tools to evaluate status of nasal mucosae of CRS patients in the lab, as well as biomarkers for management and treatment of CRS in the clinic.

Abstract 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.

Chronic rhinosinusitis (CRS) is a broad clinical syndrome that is characterized by prolonged mucosal inflammation of the nose and paranasal sinuses, and is typically divided into two subtypes based on the presence or absence of nasal polyps. The etiology and pathogenesis of both forms remain areas of active research. Over the last 15 years, a number of hypotheses have been proposed to explain all or part of the clinical CRS spectrum. These hypotheses reflect the concept that CRS results from a dysfunctional interplay between individual host characteristics and factors exogenous to the host. Six broad theories on CRS etiology and pathogenesis are discussed as follows: (1) the “fungal hypothesis,” (2) the “superantigen hypothesis,” (3) the “biofilm hypothesis,” and (4) the “microbiome hypothesis,” all of which emphasize key environmental factors, and (5) the “eicosanoid hypothesis” and (6) the “immune barrier hypothesis,” which describe specific host factors. These theories are reviewed, and the evidence supporting them is critically appraised.

Chronic rhinosinusitis (CRS) occurs in >10% of the adult population in Europe and the USA and can be differentiated into CRS without nasal polyps and CRS with nasal polyps (CRSwNP). Both phenotypes are characterized by a high disease burden and an overlapping spectrum of symptoms, with facial pain and loss of smell being the most differentiating. Great progress has been made in the understanding of CRS pathophysiology: from the epithelium and epithelial–mesenchymal transition to innate and adaptive immunity pathways and, finally, on the role of eosinophils and Staphylococcus aureus in the persistence of disease. Although clinical manifestations and diagnostic tools (including nasal endoscopy and imaging) have undergone major changes over the past few years, management (including pharmacotherapy, surgery and biologics) has experienced enormous progress based on the growing knowledge of key mediators in severe CRSwNP. The introduction of endotyping has led to a differentiation of ‘tailored’ surgical approaches, focusing on the mucosal concept in those with severe CRSwNP and on the identification of patients eligible for extended surgery and possibly biologics in the future. This Primer on chronic rhinosinusitis summarizes the epidemiology, physiology, diagnosis and management of this disorder and discusses the quality of life of patients with this condition.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production—effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.

Food allergy is a costly, potentially life-threatening condition. Although studies have examined the prevalence of childhood food allergy, little is known about prevalence, severity, or health care utilization related to food allergies among US adults. To provide nationally representative estimates of the distribution, severity, and factors associated with adult food allergies. In this cross-sectional survey study of US adults, surveys were administered via the internet and telephone from October 9, 2015, to September 18, 2016. Participants were first recruited from NORC at the University of Chicago's probability-based AmeriSpeak panel, and additional participants were recruited from the non-probability-based Survey Sampling International (SSI) panel. Demographic and allergic participant characteristics. Self-reported food allergies were the main outcome and were considered convincing if reported symptoms to specific allergens were consistent with IgE-mediated reactions. Diagnosis history to specific allergens and food allergy-related health care use were also primary outcomes. Estimates were based on this nationally representative sample using small-area estimation and iterative proportional fitting methods. To increase precision, AmeriSpeak data were augmented by calibration-weighted, non-probability-based responses from SSI. Surveys were completed by 40 443 adults (mean [SD] age, 46.6 [20.2] years), with a survey completion rate of 51.2% observed among AmeriSpeak panelists (n = 7210) and 5.5% among SSI panelists (n = 33 233). Estimated convincing food allergy prevalence among US adults was 10.8% (95% CI, 10.4%-11.1%), although 19.0% (95% CI, 18.5%-19.5%) of adults self-reported a food allergy. The most common allergies were shellfish (2.9%; 95% CI, 2.7%-3.1%), milk (1.9%; 95% CI, 1.8%-2.1%), peanut (1.8%; 95% CI, 1.7%-1.9%), tree nut (1.2%; 95% CI, 1.1%-1.3%), and fin fish (0.9%; 95% CI, 0.8%-1.0%). Among food-allergic adults, 51.1% (95% CI, 49.3%-52.9%) experienced a severe food allergy reaction, 45.3% (95% CI, 43.6%-47.1%) were allergic to multiple foods, and 48.0% (95% CI, 46.2%-49.7%) developed food allergies as an adult. Regarding health care utilization, 24.0% (95% CI, 22.6%-25.4%) reported a current epinephrine prescription, and 38.3% (95% CI, 36.7%-40.0%) reported at least 1 food allergy-related lifetime emergency department visit. These data suggest that at least 10.8% (>26 million) of US adults are food allergic, whereas nearly 19% of adults believe that they have a food allergy. Consequently, these findings suggest that it is crucial that adults with suspected food allergy receive appropriate confirmatory testing and counseling to ensure food is not unnecessarily avoided and quality of life is not unduly impaired.

Aberrant immune responses to environmental allergens including insect allergens from house dust mites and cockroaches contribute to allergic inflammatory diseases such as asthma in susceptible individuals. Airway epithelial cells (AECs) play a critical role in this process by sensing the proteolytic activity of allergens via protease-activated receptors (PAR2) to initiate inflammatory and immune responses in the airway. Elevation of cytosolic Ca 2+ is an important signaling event in this process, yet the fundamental mechanism by which allergens induce Ca 2+ elevations in AECs remains poorly understood. Here we find that extracts from dust mite and cockroach induce sustained Ca 2+ elevations in AECs through the activation of Ca 2+ release-activated Ca 2+ (CRAC) channels encoded by Orai1 and STIM1. CRAC channel activation occurs, at least in part, through allergen mediated stimulation of PAR2 receptors. The ensuing Ca 2+ entry then activates NFAT/calcineurin signaling to induce transcriptional production of the proinflammatory cytokines IL-6 and IL-8. These findings highlight a key role for CRAC channels as regulators of allergen induced inflammatory responses in the airway.

Chronic rhinosinusitis (CRS) is a prevalent condition. Clinical diagnosis requires subjective evidence (i.e. symptoms) and objective evidence of inflammation (e.g. sinus computed tomography [CT]). Few studies have assessed differences in common CT scoring approaches for CRS, the Lund-Mackay (LM) system and its modified version (mLM); none in a general population sample. The aims of this study were to answer the following: (1) Is mLM superior to LM? (2) Should nasal cavity opacification be included in scoring? (3) How should location-specific scores be utilized? (4) If location-specific scores are summed, what should be the cutoff? (5) Are associations of opacification with symptoms observed when using different measurement approaches? We scored sinus CTs using LM and mLM from 526 subjects selected from a larger CRS study. Exploratory factor analysis (EFA) assessed similarity of mLM and LM. Latent class analysis (LCA) identified subgroups of sinus opacification patterns. Factors associated with group membership and relations with nasal and sinus symptoms (NSS) guided clinical relevance. EFA suggested no differences between LM and mLM, or after addition of nasal cavity opacification. LCA identified three opacification groups: no/mild, localized, and diffuse. Males were 2.7x more likely to have diffuse opacification than females, as were those with asthma or hay fever. A LM cutoff of 3 had similar performance to the currently used 4. Diffuse opacification was associated with nasal blockage and smell loss. Differing patterns of opacification may be clinically relevant, improving measurement of objective evidence in studies of CRS and sinus diseases.

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. 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). 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. 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. 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.

This work extends the understanding of how toxic exposures to amphetamine (AMPH) adversely affect the immune system and lead to tissue damage. Importantly, it determines which effects of AMPH are and are not due to pronounced hyperthermia. Whole blood messenger RNA (mRNA) and whole blood and serum microRNA (miRNA) transcripts were identified in adult male Sprague-Dawley rats after exposure to toxic AMPH under normothermic conditions, AMPH when it produces pronounced hyperthermia, or environmentally-induced hyperthermia (EIH). mRNA transcripts with large increases in fold-change in treated relative to control rats and very low expression in the control group were a rich source of organ-specific transcripts in blood. When severe hyperthermia was produced by either EIH or AMPH, significant increases in circulating organ-specific transcripts for liver (Alb, Fbg, F2), pancreas (Spink1), bronchi/lungs (F3, Cyp4b1), bone marrow (Np4, RatNP-3b), and kidney (Cesl1, Slc22a8) were observed. Liver damage was suggested also by increased miR-122 levels in the serum. Increases in muscle/heart-enriched transcripts were produced by AMPH even in the absence of hyperthermia. Expression increases in immune-related transcripts, particularly Cd14 and Vcan, indicate that AMPH can activate the innate immune system in the absence of hyperthermia. Most transcripts specific for T-cells decreased 50-70% after AMPH exposure or EIH, with the noted exception of Ccr5 and Chst12. This is probably due to T-cells leaving the circulation and down-regulation of these genes. Transcript changes specific for B-cells or B-lymphoblasts in the AMPH and EIH groups ranged widely from decreasing ≈ 40% (Cd19, Cd180) to increasing 30 to 100% (Tk1, Ahsa1) to increasing ≥500% (Stip1, Ackr3). The marked increases in Ccr2, Ccr5, Pld1, and Ackr3 produced by either AMPH or EIH observed in vivo provide further insight into the initial immune system alterations that result from methamphetamine and AMPH abuse and could modify risk for HIV and other viral infections.