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1.
Article in English | MEDLINE | ID: mdl-38797240

ABSTRACT

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation in the US, yet the actual roles of eosinophils in CRSwNP are largely unclear. OBJECTIVE: To reveal the roles and heterogeneity of eosinophils in nasal polyp (NP) tissue by single cell RNA-Sequencing (scRNA-Seq) analysis of NP tissue. METHODS: Sinonasal tissues (NP and control sinus tissue) and patient matched peripheral blood (PB) samples were obtained from 5 control patients and 5 patients with CRSwNP. Eosinophils were enriched prior to processing for scRNA-Seq. The gene expression profiles in eosinophils were determined by the microwell-based scRNA-Seq technology (BD Rhapsody platform). We predicted the overall function of NP eosinophils by gene ontology (GO) enrichment and pathway analyses and confirmed expression of selected genes by flow cytometry. RESULTS: After filtering out contaminating cells, we detected 5,542 eosinophils from control PB, 3,883 eosinophils from CRSwNP PB, 101 eosinophils from control sinus tissues (not included in further analyses) and 9,727 eosinophils from NPs by scRNA-Seq. We found that 204 genes were down-regulated, and 354 genes were up-regulated in NP eosinophils, compared to all PB eosinophils (>1.5-fold, Padj<0.05). Up-regulated genes in NP eosinophils were associated with activation, cytokine-mediated signaling, growth factor activity, NF-κB signaling and anti-apoptotic molecules. NP eosinophils displayed 4 clusters revealing potential heterogeneity of eosinophils in NP tissue. CONCLUSIONS: Elevated eosinophils in NP tissue appear to exist in several subtypes that may play important pathogenic roles in CRSwNP, in part via controlling inflammation and hyperproliferation of other cells.

2.
J Allergy Clin Immunol ; 153(5): 1292-1305, 2024 May.
Article in English | MEDLINE | ID: mdl-38157944

ABSTRACT

BACKGROUND: Type 2 (T2) inflammation plays a pathogenic role in chronic rhinosinusitis (CRS). The effects of endoscopic sinus surgery (ESS) on T2 inflammation are unknown. OBJECTIVE: The aim of this study was to compare T2 inflammatory biomarkers from middle meatal (MM) mucus for distinguishing patients with CRS from CRS-free patients, identifying major phenotypes (CRS without nasal polyps [CRSsNP] and CRS with nasal polyps [CRSwNP]), assessing endotypic change, and establishing cross-sectional and longitudinal outcomes in patients undergoing ESS. METHODS: MM mucus samples were collected from patients with CRSsNP and patients with CRSwNP before and 6 to 12 months after ESS and compared with samples from CRS-free control patients. T2 biomarkers were evaluated both continuously and using threshold-based definitions of T2 endotype to identify relationships with patient-reported (based on the 22-Item Sinonasal Outcomes Test and Chronic Rhinosinusitis Patient-Reported Outcomes Measure) and clinician-reported (radiographic and endoscopic) severity. Linear mixed models were developed to analyze clinical variables associated with T2 biomarker levels. RESULTS: A total of 154 patients with CRS (89 with CRSsNP and 65 with CRSwNP) were enrolled, with a mean interval of 9 months between ESS and follow-up. An analysis of pre-ESS MM mucus samples revealed elevated levels of T2 mediators in patients with CRSwNP versus in patients with CRSsNP and CRS-free controls. Temporally stable correlations between levels of IL-13 and IL-5, levels of periostin and complement 5a, and levels of eosinophil cationic protein (ECP) and eotaxin-3 were observed. On this basis and on the basis of pathologic significance, levels of IL-13, periostin and ECP were further analyzed. After ESS, levels of IL-13 and periostin decreased significantly, whereas ECP levels remained unchanged. Across pre- and post-ESS evaluation, the T2 endotype was associated with radiographic severity but did not predict outcomes. CRSwNP status and African American race were associated with higher levels of IL-13 and periostin, whereas ECP level was higher in patients undergoing extensive surgery. CONCLUSION: ESS decreased levels of IL-13 and periostin in the middle meatus. T2 inflammation after ESS was correlated with patient- and clinician-reported severity across phenotypes. Pre-ESS T2 inflammation did not predict post-ESS outcomes.


Subject(s)
Biomarkers , Cell Adhesion Molecules , Endoscopy , Interleukin-13 , Nasal Polyps , Rhinitis , Sinusitis , Humans , Sinusitis/surgery , Rhinitis/surgery , Rhinitis/immunology , Chronic Disease , Female , Male , Middle Aged , Adult , Nasal Polyps/surgery , Nasal Polyps/immunology , Paranasal Sinuses/surgery , Aged , Cross-Sectional Studies , Mucus/metabolism , Rhinosinusitis , Periostin
3.
J Allergy Clin Immunol ; 151(5): 1379-1390.e11, 2023 05.
Article in English | MEDLINE | ID: mdl-36623776

ABSTRACT

BACKGROUND: Oncostatin M (OSM) may promote type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) by inducing thymic stromal lymphopoietin (TSLP). OBJECTIVE: We sought to study the impact of OSM on TSLP synthesis and release from nasal epithelial cells (NECs). METHODS: OSM receptors, IL-4 receptors (IL-4R), and TSLP were evaluated in mucosal tissue and primary NECs from patients with CRSwNP by quantitative PCR and immunofluorescence. Air-liquid interface-cultured NECs were stimulated with cytokines, including OSM, and quantitative PCR, ELISA, Western blot, and flow cytometry were used to assess the expression of OSM receptors, IL-4R, and TSLP. RESULTS: Increased levels of OSM receptor ß chain (OSMRß), IL-4Rα, and TSLP were observed in nasal polyp tissues and primary epithelial cells from nasal polyps of patients with CRSwNP compared with control tissues or cells from control subjects. The level of expression of OSMRß in tissue was correlated with levels of both IL-4Rα and TSLP. OSM stimulation of NECs increased the expression of OSMRß and IL-4Rα. Stimulation with IL-4 plus OSM augmented the production of TSLP; the response was suppressed by a signal transducer and activator of transcription 6 inhibitor. Stimulation of NECs with IL-4 plus OSM increased the expression of proprotein convertase subtilisin/kexin 3, an enzyme that truncates and activates TSLP. CONCLUSIONS: OSM increases the expression of IL-4Rα and synergizes with IL-4 to induce the synthesis and release of TSLP in NECs. Because the combination of IL-4 and OSM also augmented the expression of proprotein convertase subtilisin/kexin 3, these results suggest that OSM can induce both synthesis and posttranslational processing/activation of TSLP, promoting type 2 inflammation.


Subject(s)
Interleukin-4 , Nasal Polyps , Oncostatin M , Rhinitis , Sinusitis , Humans , Chronic Disease , Cytokines/metabolism , Inflammation/metabolism , Interleukin-4/metabolism , Nasal Mucosa/metabolism , Nasal Polyps/metabolism , Oncostatin M/metabolism , Proprotein Convertases/metabolism , Rhinitis/metabolism , Sinusitis/metabolism , Subtilisins/metabolism , Thymic Stromal Lymphopoietin
4.
Int Forum Allergy Rhinol ; 13(1): 15-24, 2023 01.
Article in English | MEDLINE | ID: mdl-35670482

ABSTRACT

BACKGROUND: Patients with chronic rhinosinusitis (CRS) may have persistence of polyps, discharge, or edema after endoscopic sinus surgery (ESS). Inflammation in CRS can be classified into three endotypes, with the presence of polyps associated with the type 2 endotype. Here, we evaluate the endotypic underpinnings of discharge or edema without polyps after ESS. METHODS: At a visit 6-12 months post ESS, patients underwent endoscopy and completed the CRS-PRO and SNOT-22. Luminex analysis of middle meatal mucus obtained at that visit was performed for IFN-γ, ECP, and IL-17a. Type 1, 2, and 3 endotypes were defined as greater than the 90th percentile expression of each marker, respectively, in controls. Wilcoxon rank-sum and chi-squared tests were used to compare cytokine levels and endotype prevalence between those with and without endoscopic findings. RESULTS: A total of 122 CRS patients completed a clinical exam (median: 8.2 months post ESS). Of the 122 patients, 107 did not have polyps on endoscopy. Of these 107 patients, 48 had discharge, 44 had edema, and 46 had neither discharge nor edema. Compared with those patients without any findings, patients with discharge or edema reported significantly worse severity as measured by CRS-PRO (10.5 vs. 7.0, p = 0.009; 12.0 vs. 7.0, p < 0.001; respectively), and had higher post-ESS IFN-γ, ECP, and IL-17a. Patients with discharge had higher prevalence of only T1 and T3 endotypes, while patients with edema had higher prevalence of only the T3 endotype. CONCLUSIONS: Post-ESS discharge or edema in the absence of polyps was associated with higher patient-reported outcome severity and was more strongly associated with type 1 or 3 inflammation.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Humans , Interleukin-17 , Patient Discharge , Rhinitis/epidemiology , Nasal Polyps/epidemiology , Sinusitis/epidemiology , Inflammation , Chronic Disease , Endoscopy , Edema
5.
J Am Coll Radiol ; 19(11S): S266-S303, 2022 11.
Article in English | MEDLINE | ID: mdl-36436957

ABSTRACT

Cranial neuropathy can result from pathology affecting the nerve fibers at any point and requires imaging of the entire course of the nerve from its nucleus to the end organ in order to identify a cause. MRI with and without intravenous contrast is often the modality of choice with CT playing a complementary role. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer-reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer-reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.


Subject(s)
Cranial Nerve Diseases , Humans , Cranial Nerve Diseases/diagnostic imaging , Peer Review , Systems Analysis
6.
J Allergy Clin Immunol ; 150(5): 1114-1124.e3, 2022 11.
Article in English | MEDLINE | ID: mdl-35728655

ABSTRACT

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells. OBJECTIVES: This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD. METHODS: NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours. RESULTS: This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13-induced attenuation of tPA expression in cultured cells (P < .01). CONCLUSIONS: RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13-induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.


Subject(s)
Asthma, Aspirin-Induced , Nasal Polyps , Rhinitis , Sinusitis , Humans , Nasal Polyps/metabolism , Rhinitis/metabolism , Tissue Plasminogen Activator , Interleukin-13 , Fibrinolysis , Tretinoin/pharmacology , Endothelial Cells/metabolism , Sinusitis/metabolism , Asthma, Aspirin-Induced/complications , Chronic Disease , Fibrin
7.
Int Forum Allergy Rhinol ; 12(11): 1330-1339, 2022 11.
Article in English | MEDLINE | ID: mdl-35362251

ABSTRACT

BACKGROUND: Mometasone-eluting stents (MES) have demonstrated improvement in short-term endoscopic outcomes and reduce short- to medium-term rescue interventions. Their effect on the local inflammatory environment, longer-term patient-reported outcomes, and radiographic severity have not been studied. METHODS: Middle meatal mucus and validated measures of disease severity were collected before and 6 to 12 months after endoscopic surgery in 52 patients with chronic rhinosinusitis with nasal polyps (CRSwNPs). Operative findings, type 2 mediator concentrations, intraoperative variables, and disease severity measures were compared between those who did and those who did not receive intraoperative frontal MES. RESULTS: A total of 52 patients with CRSwNPs were studied; 33 received frontal MES and were compared with 19 who did not. Pre-endoscopic sinus surgery (ESS) middle meatus (MM) interleukin (IL) 13 and eosinophil cationic protein (ECP) were higher in the stented group (p < 0.05), but pre-ESS clinical measures of disease severity were similar as were surgical extent and post-ESS medical management. Intraoperative eosinophilic mucin was more frequent in the stented group (58% vs 11%, p = 0.001). IL-5 (p < 0.05) and IL-13 (p < 0.001) decreased post-ESS in the stented group, but this was not observed in the nonstented group. Post-ESS IL-4 and IL-13 were higher in the nonstented vs stented group (p < 0.05 for both). CONCLUSION: Although patients who received intraoperative frontal MES had significantly higher pre-ESS MM IL-13 and ECP, patients who received frontal MES had lower concentrations of IL-4 and IL-13 than those who did not at a median of 8 months post-ESS. However, these changes did not correspond to significantly different measures of symptomatic or radiographic disease severity.


Subject(s)
Drug-Eluting Stents , Frontal Sinus , Nasal Polyps , Rhinitis , Sinusitis , Humans , Nasal Polyps/surgery , Interleukin-5 , Interleukin-13 , Mometasone Furoate/therapeutic use , Rhinitis/surgery , Interleukin-4 , Sinusitis/surgery , Endoscopy , Chronic Disease
8.
Int Forum Allergy Rhinol ; 12(11): 1377-1386, 2022 11.
Article in English | MEDLINE | ID: mdl-35363947

ABSTRACT

The 22-item Sino-Nasal Outcome Test (SNOT-22) and 12-item Patient Reported Outcomes in Chronic Rhinosinusitis (CRS-PRO) instrument are validated patient-reported outcomes measures in CRS. In this study we assess the correlation of these with type 2 (T2) biomarkers before and after endoscopic sinus surgery (ESS). METHODS: Middle meatal mucus data were collected and the SNOT-22 and CRS-PRO were administered to 123 patients (71 CRS without nasal polyps [CRSsNP], 52 CRS with nasal polyps [CRSwNP]) with CRS before and 6 to 12 months after undergoing ESS. Interleukin (IL)-4, IL-5, IL-13, and eosinophilic cationic protein (ECP) were measured using a multiplexed bead assay and enzyme-linked immunoassay. Pre- and post-ESS SNOT-22 and CRS-PRO were compared with T2 biomarkers. RESULTS: Before ESS neither PROM correlated with any biomarker. After ESS, CRS-PRO showed a correlation with 2 mediators (IL-5 and IL-13: p = 0.012 and 0.003, respectively) compared with none for the SNOT-22. For CRSwNP patients, pre-ESS CRS-PRO and SNOT-22 correlated with IL-4 (p = 0.04 for both). However, after ESS, CRS-PRO correlated with 3 biomarkers (IL-5, IL-13, and ECP: p = 0.02, 0.024, and 0.04, respectively) and SNOT-22 with 2 biomarkers (IL-5 and IL-13: p = 0.038 and 0.02, respectively). There were no significant relationships between any of the T2 biomarkers pre- or post-ESS among patients with CRSsNP. Exploratory analyses of the subdomains showed the SNOT-22 rhinologic and CRS-PRO rhinopsychologic subdomains correlated better with the T2 biomarkers. On individual item analysis, IL-13 correlated significantly post-ESS with 8 of 12 items on the CRS-PRO vs 6 of 22 items on the SNOT-22. CONCLUSION: The CRS-PRO total score showed a significant correlation with T2 biomarkers especially when assessed post-ESS and among CRSwNP patients.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Humans , Nasal Polyps/surgery , Sino-Nasal Outcome Test , Rhinitis/surgery , Interleukin-13 , Inflammation Mediators , Interleukin-5 , Sinusitis/surgery , Endoscopy , Chronic Disease , Biomarkers
9.
J Allergy Clin Immunol ; 150(2): 467-476.e1, 2022 08.
Article in English | MEDLINE | ID: mdl-35271862

ABSTRACT

BACKGROUND: Increased activation of the coagulation cascade and diminished fibrinolysis combine to promote fibrin deposition and polyp formation in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). More information is needed concerning mechanisms of coagulation in CRSwNP. OBJECTIVE: We investigated the mechanisms as well as the initiation and regulation of coagulation cascade activation in CRS. METHODS: Samples were collected from 135 subjects with CRSwNP, 80 subjects with chronic CRS without nasal polyps (NP), and 65 control subjects. The levels of activated factor X (FXa), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex, tissue factor (TF), and TF pathway inhibitor (TFPI) were monitored in CRS by real-time PCR, ELISA, immunohistochemistry, or immunofluorescence. Heteromeric complexes of TF with activated factor VII (FVII) and TF with activated FVII and FXa were assessed by coimmunoprecipitation and Western blotting. RESULTS: Increased levels of FXa, F1+2, and thrombin-antithrombin complex were detected in NP tissue compared to uncinate tissue from CRS and control subjects. Although free TF protein levels were not increased in NP, immunoprecipitation of TF in NP tissue revealed increased complexes of TF with FVII. Local expression of FVII was detected in sinonasal mucosa, and the ratio of TFPI to FXa was lower in NP tissue. CONCLUSION: The coagulation cascade is associated with NP compared to control and uncinate tissue from CRS patients, and TF and FVII are produced locally in sinonasal mucosa in patients. TF and FVII can activate the extrinsic coagulation pathway, suggesting that this pathway may activate fibrin deposition in CRSwNP. Reduced formation of the complex of FXa and TFPI in NP may reduce natural suppression of the extrinsic coagulation pathway in CRSwNP.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Blood Coagulation , Chronic Disease , Fibrin , Humans , Nasal Polyps/metabolism , Rhinitis/metabolism , Sinusitis/metabolism , Thromboplastin
10.
J Allergy Clin Immunol ; 150(2): 352-361.e7, 2022 08.
Article in English | MEDLINE | ID: mdl-35305978

ABSTRACT

BACKGROUND: Chronic rhinosinusitis with nasal polyps is frequently managed with endoscopic sinus surgery (ESS). Prior studies describe individual clinical variables and eosinophil density measures as prognostic for polyp recurrence (PR). However, the relative prognostic significance of these have not been extensively investigated. OBJECTIVES: We sought to evaluate the impact of PR on measures of disease severity post-ESS and quantify the prognostic value of various clinical variables and biomarkers. METHODS: Ninety-four patients with chronic rhinosinusitis with nasal polyps and prospectively biobanked polyp homogenates at the time of ESS were recruited 2 to 5 years post-ESS. Patients were evaluated with patient-reported outcome measures and endoscopic and radiographic scoring pre- and post-ESS. Biomarkers in polyp homogenates were measured with ELISA and Luminex. Relaxed least absolute shrinkage and selection operator regression optimized predictive clinical, biomarker, and combined models. Model performance was assessed using receiver-operating characteristic curve and random forest analysis. RESULTS: PR was found in 39.4% of patients, despite significant improvements in modified Lund-Mackay (MLM) radiographic and 22-item Sinonasal Outcomes Test scores (both P < .0001). PR was significantly associated with worse post-ESS MLM, modified Lund-Kennedy, and 22-item Sinonasal Outcomes Test scores. Relaxed least absolute shrinkage and selection operator identified 2 clinical predictors (area under the curve = 0.79) and 3 biomarkers (area under the curve = 0.78) that were prognostic for PR. When combined, the model incorporating these pre-ESS factors: MLM, asthma, eosinophil cationic protein, anti-double-stranded DNA IgG, and IL-5 improved PR predictive accuracy to area under the curve of 0.89. Random forest analysis identified and validated each of the 5 variables as the strongest predictors of PR. CONCLUSIONS: PR had strong associations with patient-reported outcome measures, endoscopic and radiographic severity. A combined model comprised of eosinophil cationic protein, IL-5, pre-ESS MLM, asthma, and anti-double-stranded DNA IgG could accurately predict PR.


Subject(s)
Asthma , Nasal Polyps , Rhinitis , Sinusitis , Biomarkers , Chronic Disease , DNA , Endoscopy , Eosinophil Cationic Protein , Humans , Immunoglobulin G , Interleukin-5 , Nasal Polyps/surgery , Prognosis , Rhinitis/surgery , Sinusitis/surgery
11.
Clin Exp Allergy ; 52(8): 954-964, 2022 08.
Article in English | MEDLINE | ID: mdl-35253284

ABSTRACT

BACKGROUND: Polyps from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) contain increased levels of autoreactive antibodies, B cells and fibrin deposition. Anti-phospholipid antibodies (APA) are autoantibodies known to cause thrombosis but have not been implicated in chronic rhinosinusitis (CRS). OBJECTIVE: To compare APA levels (anti-cardiolipin, anti-phosphatidylethanolamine (anti-PE), and anti-ß2 -glycoprotein (anti-B2GP)) in nasal polyp (NP) tissue with tissue from control and CRS without nasal polyp (CRSsNP) patients, we tested whether NP antibodies affect coagulation, and correlate APAs with anti-dsDNA IgG and markers of coagulation. METHODS: Patient specimens were assayed for APA IgG, anti-dsDNA IgG and thrombin-anti-thrombin (TaT) complex by ELISA. Antibodies from a subset of specimens were tested for modified activated partial thromboplastin time (aPTT) measured on an optical-mechanical coagulometer. RESULTS: Anti-cardiolipin IgG in NP was 5-fold higher than control tissue (p < .0001). NP antibodies prolonged aPTT compared to control tissue antibodies at 400 µg/mL (36.7 s vs. 33.8 s, p = .024) and 600 µg/mL (40.9 s vs. 34.7 s, p = .0037). Anti-PE IgG antibodies were increased in NP (p = .027), but anti-B2GP IgG was not significantly higher (p = .084). All APAs correlated with anti-dsDNA IgG levels, which were also elevated (R = .77, .71 and .54, respectively, for anti-cardiolipin, anti-PE, and anti-B2GP; all p < .001), but only anti-cardiolipin (R = .50, p = .0185) and anti-PE (R = 0.45, p = .037) correlated with TaT complex levels. CONCLUSIONS: APA IgG antibodies are increased in NP and correlate with autoreactive tissue antibodies. NP antibodies have in vitro anti-coagulant activity similar to those observed in anti-phospholipid syndrome, suggesting that they may have pro-coagulant effects in polyp tissue.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Chronic Disease , Humans , Immunoglobulin G , Nasal Polyps/complications
12.
J Allergy Clin Immunol ; 149(5): 1666-1674, 2022 05.
Article in English | MEDLINE | ID: mdl-34953792

ABSTRACT

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is well characterized by type 2 (T2) inflammation characterized by eosinophilia in Western countries. However, the presence and roles of neutrophils in T2 CRSwNP are poorly understood. OBJECTIVE: We sought to clarify accumulation and inflammatory roles of neutrophils in CRSwNP in a Western population. METHODS: Sinonasal tissues and nasal lavage fluids were obtained from control patients and patients with CRS, and neutrophil markers were determined by ELISA. The presence of neutrophils in tissue was determined by flow cytometry. The gene expression profiles in neutrophils were determined by RNA sequencing. RESULTS: A neutrophil marker elastase was selectively elevated in nasal polyp (NP) tissue, whereas eosinophilic cationic protein (an eosinophil marker) was elevated in both uncinate and NP tissues of CRSwNP patients. Nasal lavage fluid myeloperoxidase (another neutrophil marker) was also significantly elevated in CRSwNP compared to control patients. Neutrophil markers were more greatly elevated in CRSwNP patients with recurrent disease. Flow cytometric analysis confirmed that neutrophil numbers were significantly elevated in NPs compared to control tissues. RNA sequencing analysis found that 344 genes were >3-fold and significantly elevated in NP neutrophils compared to peripheral blood neutrophils. Gene Ontology analysis suggested that the elevated genes in NP neutrophils were significantly associated with activation. Results suggest that neutrophils are accumulated in T2 NP tissues and that accumulated neutrophils are highly activated and contribute to inflammation in NPs. CONCLUSIONS: Neutrophils may play a heretofore unrecognized meaningful role in the pathogenesis of CRSwNP in Western countries and may be a potentially important therapeutic target in T2 CRSwNP.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Biomarkers , Chronic Disease , Humans , Inflammation/pathology , Nasal Polyps/pathology , Neutrophils/pathology , Rhinitis/pathology , Sinusitis/pathology
13.
BMJ Open ; 11(11): e054746, 2021 11 19.
Article in English | MEDLINE | ID: mdl-34799364

ABSTRACT

OBJECTIVES: To develop and evaluate a simulation-based mastery learning (SBML) curriculum for cricothyrotomy using wet towels to suppress aerosolisation during a pandemic. DESIGN: Quasi-experimental, pre-post study. SETTING: Tertiary care, academic medical centre in Chicago. PARTICIPANTS: Ear, nose and throat and general surgery residents, fellows and attendings. INTERVENTION: Cricothyroidotomy simulation-based mastery learning curriculum. OUTCOMES MEASURE: Pretest to posttest simulated cricothyrotomy skills checklist performance. RESULTS: 37 of 41 eligible surgeons participated in the curriculum. Median pretest score was 72.5 (IQR 55.0-80.0) and 100.0 (IQR 98.8-100.0) for the posttest p<0.001. All participants scored at or above a minimum passing standard (93% checklist items correct) at posttest. CONCLUSIONS: Using SBML is effective to quickly train clinicians to competently perform simulated cricothyrotomy during a pandemic.


Subject(s)
Internship and Residency , Pandemics , Academic Medical Centers , Clinical Competence , Cohort Studies , Curriculum , Humans
14.
OTO Open ; 5(4): 2473974X211049328, 2021.
Article in English | MEDLINE | ID: mdl-34661041

ABSTRACT

OBJECTIVE: To evaluate the utility of point-of-care COVID-19 testing for identifying infected patients in an otolaryngology practice. STUDY DESIGN: Retrospective review of 947 patients tested with a point-of-care nucleic acid amplification test for SARS-CoV-2 (Abbott ID Now). SETTING: Tertiary otolaryngology clinic setting from July to November 2020. METHODS: Tests were characterized by provider-specified indication (symptomatic, preprocedural, and universal), subspecialty, provider type, and contemporaneous regional COVID-19 positivity rate, defined as 12%. Positive results were further classified as true or false positive (TP or FP) based on repeat polymerase chain reaction testing wherever available, and true positivity rates were compared among groups by multiway chi-square and Fisher's exact tests. FP rates within 48 hours of a TP result were also evaluated to assess for batch contamination. RESULTS: A total of 947 SARS-CoV-2 nucleic acid amplification tests were performed, yielding 9 TPs (0.95%) and 5 FPs (0.53%). TP rates were significantly different by testing indication, with higher rates among symptomatic patients (P = .012; vs universal, odds ratio = 7.86 [95% CI, 1.27-83.52]; vs preprocedural, odds ratio = 4.91 [95% CI, 0.79-52.17]); by subspecialty (P = .011), as driven by higher positivity rates in laryngology; and by encounter, with higher rates among advanced practice practitioners than physicians (P = .002; odds ratio = 9.97 [95% CI, 2.11-51.16]). TP rates were not significantly different during periods of uncontrolled local outbreak (P = .660). FP rates were not significantly higher within a 48-hour window of a TP (P = .192). CONCLUSION: Point-of-care COVID-19 nucleic acid amplification tests in an outpatient otolaryngology clinic identified a low TP rate (<1%) with most cases being clinically suspected. Laryngology and advanced practice practitioner encounters may have higher positivity rates.Level of evidence: 3.

15.
Laryngoscope Investig Otolaryngol ; 6(5): 924-931, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34667834

ABSTRACT

OBJECTIVES: Chronic rhinosinusitis (CRS) affects approximately 12% of the population and leads to increased health care utilization and indirect costs exceeding $20 billion annually in the United States. The Lund-Mackay score (LMS) measures radiographic disease severity for CRS but poorly correlates with symptom scores. The association between LMS and health care utilization in CRS patients has not yet been investigated. The study aimed to assess the association between health care utilization and CRS radiographic severity using LMS. METHODS: CRS patients enrolled in a clinical registry were evaluated. Nasal endoscopy findings and LMS were recorded for patients with sinus CT imaging. Patient symptom scores, demographic characteristics, and health care utilization measures were collected. The relationship between these factors and LMS was examined. RESULTS: A total of 556 patients met inclusion criteria. Mean age was 45.3 years, 53.4% were male, and 41.7% had nasal polyps. There was no difference in sex, smoking history, 22-item Sino-nasal Outcome Test scores, or past medical history factors between patients with high (≥8, n = 410) and low (<8, n = 146) LMS. Among high LMS patients, 73.7% underwent endoscopic sinus surgery (ESS) compared to 55.5% with low LMS (P < .01), and a greater percentage of patients had nasal polyps (49.3% vs 20.5%, P < .01). On multivariable logistic regression, high LMS patients used fewer antibiotic courses (OR: 0.68 [0.51-0.91]), but were more likely to be managed with ESS (OR: 2.28 [1.41-3.73]), and have nasal polyps (OR: 2.11 [1.16-3.93]) compared to low LMS patients. There was no significant difference in the number of steroid courses, over the counter pill use, provider visits, work/school days missed, or symptom duration between the two LMS groups. CONCLUSION: CRS patients with severe radiographic disease are more likely to have nasal polyps, undergo ESS, and take fewer antibiotic courses. However, there is no association between radiographic disease severity and other measures of health care utilization. LEVEL OF EVIDENCE: 2b, individual retrospective cohort study.

16.
J Allergy Clin Immunol Pract ; 9(8): 3188-3195.e2, 2021 08.
Article in English | MEDLINE | ID: mdl-33965595

ABSTRACT

BACKGROUND: Whereas chronic rhinosinusitis (CRS) is associated with asthma, and vice versa, the association between CRS and other lower respiratory conditions is not well-established. Bronchiectasis is characterized by permanent damage of the airways, and as many as 45% of bronchiectasis patients have CRS, but the prevalence of bronchiectasis among CRS patients is not known. OBJECTIVE: To determine the prevalence of bronchiectasis among CRS patients and to characterize demographic and clinical features of patients with bronchiectasis and CRS. METHODS: Electronic medical records of patients with rhinosinusitis were searched by computer algorithm supplemented with manual chart review to identify patients with CRS, asthma, and/or bronchiectasis. Demographic and clinical features and antibiotic courses for sinopulmonary infections 2 years before and after sinus surgery were obtained by manual chart review. RESULTS: The prevalence of bronchiectasis as determined by International Classification of Diseases, Ninth Revision code was significantly higher in CRS patients than in asthmatic patients (2.3% vs 1.7%; P < .003). Similarly, based on a text word search of "bronchiectasis" in the chest computed tomography (CT) scan reports, patients with CRS who had chest CT scans had a higher prevalence of bronchiectasis than did asthmatic patients with chest CT scans (24.3% vs 19.5%; P = .005). Patients with CRS and concurrent bronchiectasis did not have a reduction in the frequency of sinopulmonary infections after sinus surgery compared with patients with CRS without bronchiectasis (P < .05). CONCLUSIONS: Bronchiectasis is an important comorbidity in patients with CRS and may identify a severe phenotype of chronic sinonasal disease.


Subject(s)
Bronchiectasis , Nasal Polyps , Rhinitis , Sinusitis , Bronchiectasis/epidemiology , Chronic Disease , Humans , Prevalence , Rhinitis/epidemiology , Sinusitis/epidemiology , Tertiary Care Centers
17.
J Allergy Clin Immunol ; 148(2): 439-449.e5, 2021 08.
Article in English | MEDLINE | ID: mdl-33819512

ABSTRACT

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to cyclooxygenase-1 enzyme inhibitors. The underlying mechanisms contributing to AERD pathogenesis are not fully understood, but AERD is characterized by an enhanced type 2 inflammatory phenotype. Basophils are potent type 2 effector cells, but their involvement in AERD pathophysiology remains unclear. OBJECTIVE: We sought to characterize the systemic and local basophil responses in patients with AERD compared with patients with CRSwNP. METHODS: Sinonasal tissues including inferior turbinate and/or nasal polyps (NPs) and peripheral blood were collected from controls, patients with AERD, and patients with CRSwNP. Expression of cell surface (CD45, FcεRI, CD203c), activation (CD63), and intracellular (2D7) markers associated with basophils was characterized using flow cytometry. Clinical data including Lund-Mackay scores and pulmonary function were obtained. RESULTS: The mean number of basophils (CD45+CD203c+FcεRI+CD117-) detected in AERD NPs (147 ± 28 cells/mg tissue) was significantly elevated compared with that detected in CRSwNP NPs (69 ± 20 cells/mg tissue; P = .01). The number of circulating basophils was significantly elevated in patients with AERD (P = .04). Basophils in NPs had significantly higher CD203c and CD63 mean fluorescence intensity compared with blood in both conditions (P < .01). Basophils from AERD NPs had lower expression of the granule content marker 2D7 compared with those from matched blood (P < .01) or NPs of patients with CRSwNP (P = .06), suggesting ongoing degranulation. Basophil 2D7 mean fluorescence intensity significantly correlated with pulmonary function (r = 0.62; P = .02) and inversely correlated with sinonasal inflammation (r = -0.56; P = .004). CONCLUSIONS: Increased basophil numbers and extent of ongoing degranulation in NPs of patients with AERD compared with patients with CRSwNP may contribute to the exaggerated disease pathogenesis and severity unique to AERD.


Subject(s)
Asthma/immunology , Basophils/immunology , Cyclooxygenase Inhibitors/adverse effects , Nasal Polyps/immunology , Rhinitis/immunology , Sinusitis/immunology , Adult , Asthma/chemically induced , Asthma/pathology , Basophils/pathology , Chronic Disease , Cyclooxygenase Inhibitors/therapeutic use , Female , Humans , Male , Middle Aged , Nasal Polyps/chemically induced , Nasal Polyps/pathology , Rhinitis/chemically induced , Rhinitis/pathology , Sinusitis/chemically induced , Sinusitis/pathology
18.
Int Forum Allergy Rhinol ; 11(9): 1308-1320, 2021 09.
Article in English | MEDLINE | ID: mdl-33728827

ABSTRACT

BACKGROUND: The chronic rhinosinusitis patient-reported outcome (CRS-PRO) measure is a 12-item measure with previously demonstrated validity in chronic rhinosinusitis (CRS) patients receiving medical therapy. This study establishes the factor structure, responsiveness, and convergent validity of the CRS-PRO following endoscopic sinus surgery (ESS). METHODS: Northwestern CRS Subject Registry patients had pre-ESS, 3-month (n = 111; CRS without nasal polyps [CRSsNP] = 60, CRS with nasal polyps [CRSwNP] = 51), and 6-month (n = 86; CRSsNP = 47, CRSwNP = 39) post-ESS assessments where patients completed the CRS-PRO, 22-item Sino-Nasal Outcome Test (SNOT-22), and four Patient-Reported Outcomes Measurement (PROM) Information System (PROMIS) short forms (general health measures). Patients had pre-ESS objective testing (endoscopic and radiographic assessment). Factor analysis was conducted using principal axis factoring with varimax rotation on the baseline CRS-PRO. The clinically important difference (CID) was estimated using both distribution-based and anchor-based methods. RESULTS: Factor analysis found the CRS-PRO comprised the "rhino-psychologic," "facial discomfort," and "cough" factors, which were responsive to ESS and correlated with the other PROMs. The changes observed in the CRS-PRO at 3 months had strong correlation with the corresponding changes in SNOT-22 (r = 0.792, p < 0.0001) and moderate correlations with changes in PROMIS fatigue and sleep domains. These changes had a very large effect size (Cohen's d 1.44) comparable to the longer SNOT-22 (Cohen's d 1.41) with slightly larger effect sizes observed in CRSwNP compared to CRSsNP patients. Similar convergent validity and responsiveness were observed in the 6-month data. The CRS-PRO CID was estimated to be between 5.0 and 7.5 (midpoint 6.0) using distribution-based and anchor-based methods. CONCLUSION: This study demonstrates the validity and responsiveness of the CRS-PRO in subjects receiving ESS.


Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Chronic Disease , Endoscopy , Humans , Nasal Polyps/surgery , Patient Reported Outcome Measures , Rhinitis/surgery , Sinusitis/surgery
19.
J Allergy Clin Immunol ; 147(4): 1306-1317, 2021 04.
Article in English | MEDLINE | ID: mdl-33326802

ABSTRACT

BACKGROUND: Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) is a common disease that is characterized by multiple inflammatory endotypes. However, the molecular mechanisms in CRSsNP are poorly understood compared with those of polypoid CRS. OBJECTIVE: Our aim was to identify mechanisms and biomarkers associated with inflammatory endotypes underpinning CRSsNP. METHODS: Ethmoid tissues and nasal lavage fluids (NLFs) were obtained from control patients and patients with CRS. The gene expression profiles were determined by microarray analysis and quantitative RT-PCR, and expression of proteins was measured by ELISA and Luminex analysis. RESULTS: Microarray found that compared with their levels of expression in control tissue, the levels of expression of 126, 241, and 545 genes were more than 3-fold and significantly elevated in CRSsNP with type 1 (T1) endotype, type 2 (T2) endotype, and type 3 (T3) endotype, respectively. Selected identified genes were confirmed by RT-PCR. Gene set enrichment analysis suggested that T1 CRSsNP was associated with IFN-γ signaling and antiviral immunity controlled by T cells (TH1 and CD8+), natural killer cells, and antigen-presenting cells; T2 CRSsNP was associated with STAT6 signaling and IgE-mediated activation controlled by eosinophils, mast cells, TH2 cells, group 2 innate lymphoid cells, and antigen-presenting cells; and T3 CRSsNP was associated with IL-17 signaling, acute inflammatory response, complement-mediated inflammation, and infection controlled by neutrophils, TH17 cells, B cells, and antigen-presenting cells. The results suggest that T1 (CXCL9 and CXCL10), T2 (eosinophilic proteins and CCL26), and T3 (CSF3) endotypic biomarkers in NLF may be able to distinguish tissue endotypes in CRSsNP. CONCLUSIONS: Inflammatory endotypes in CRSsNP were controlled by different molecular mechanisms. NLF biomarker assays may allow for more precise and personalized medical treatments in CRS.


Subject(s)
Rhinitis/immunology , Sinusitis/immunology , Biomarkers , Chronic Disease , Ethmoid Sinus/immunology , Humans , Inflammation/genetics , Inflammation/immunology , Nasal Lavage Fluid/immunology , Nasal Polyps/genetics , Nasal Polyps/immunology , Rhinitis/genetics , Sinusitis/genetics , Transcriptome
20.
J Allergy Clin Immunol ; 147(2): 600-612, 2021 02.
Article in English | MEDLINE | ID: mdl-32371071

ABSTRACT

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD. OBJECTIVE: Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. METHODS: Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence. RESULTS: The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P < .05) or controls (P < .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r = 0.56; P < .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P < .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in NPs from patients with AERD. CONCLUSIONS: Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD.


Subject(s)
Arachidonate 15-Lipoxygenase/immunology , Asthma, Aspirin-Induced/immunology , Respiration Disorders/immunology , Adult , Arachidonate 15-Lipoxygenase/metabolism , Asthma, Aspirin-Induced/metabolism , Female , Humans , Male , Middle Aged , Respiration Disorders/metabolism
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