Citations

Abstract Eosinophils and cytokines active on eosinophils, especially IL-5, are believed to be critically involved in chronic allergic diseases. IL-5 activates eosinophils and enhances their survival in vitro by delaying apoptosis. In this study, we found that lidocaine and six analogues blunt responses of eosinophils to IL-5. Lidocaine and its derivatives inhibit IL-5-mediated eosinophil survival in a concentration-dependent manner (IC50 = 110 μM for 30 pg/ml IL-5). At suboptimal lidocaine concentrations, the eosinophil survival response to IL-5 shifts and more IL-5 is required to maintain survival. The inhibitory effect requires at least 24-h exposure of eosinophils to lidocaine, and the protein kinase C activator, PMA, completely reverses the inhibition. A multiparameter flow-cytometric analysis shows that lidocaine hastens the apoptosis of eosinophils normally delayed by IL-5. Lidocaine does not affect IL-5R expression or IL-5-induced protein tyrosine phosphorylation. Lidocaine also inhibits eosinophil survival mediated by IL-3 or granulocyte-macrophage CSF, although less potently than that mediated by IL-5. Furthermore, lidocaine inhibits eosinophil superoxide production stimulated by IL-5, granulocyte-macrophage CSF, or IL-3, but not that stimulated by platelet-activating factor, immobilized IgG, or PMA. Lidocaine and its derivatives show novel immunomodulatory properties and are able to blunt eosinophil responses to cytokines in addition to their local anesthetic or antiarrhythmic properties. Thus, lidocaine and its derivatives may represent a new class of therapeutic agents to treat patients with allergic diseases.

ObjectivesUrine leukotriene E4 (uLTE4) is a biomarker of leukotriene synthesis and is elevated in patients with aspirin‐exacerbated respiratory disease (AERD). It can also be useful to help delineate aspirin‐tolerant chronic rhinosinusitis with nasal polyposis (CRSwNP) patients from AERD patients. The purpose of this study is to determine if uLTE4 biomarker levels are associated with objective and subjective markers of disease severity in patients with CRSwNP.MethodsA retrospective analysis of CRSwNP patients who underwent uLTE4 testing was completed to determine the association of uLTE4 levels to markers of disease severity. uLTE4 levels, as well as presenting subjective (Sinonasal Outcome Test 22 [SNOT22] scores, asthma control test [ACT] scores) and objective data (Lund‐Mackay CT score, spirometry and lab values) were collected.ResultsAmong the 157 CRSwNP patients who met inclusion criteria, uLTE4 levels were associated with history of asthma (P< .001), aspirin sensitivity (P< .001), worse Lund‐Mackay CT scores (P= .002) and other objective markers of disease severity including serum IgE (P= .05), presenting blood eosinophil level (P< .001), and the highest recorded eosinophil level (P< .001). In subgroup analysis, associations of uLTE4 to disease markers had stronger correlations in the aspirin sensitive CRSwNP group (Rrange 0.31–0.52) than the aspirin tolerant CRSwNP group (Rrange −0.30–0.24). uLTE4 levels were not associated with subjective symptom scores (SNOT22 and ACT scores).ConclusionElevated uLTE4 biomarker levels are associated with worsened objective markers of disease severity in CRSwNP patients but not patient‐reported symptom measures.Level of Evidence3Laryngoscope, 131:961–966, 2021

SummaryBackgroundThe mechanisms and immune pathways associated with chronic rhinosinusitis (CRS) are not fully understood. Immunological changes during acute exacerbation of CRS may provide valuable clues to the pathogenesis and perpetuation of the disease.ObjectiveTo characterize local and systemic immune responses associated with acute worsening of sinonasal symptoms during exacerbation in CRS with nasal polyps (CRSwNP) compared to controls.MethodsThis was a non‐interventional prospective study of individuals with CRSwNP and normal controls. Subjects underwent a baseline visit with collection of nasal secretions, nasal washes, and serum specimens. Within 3 days of acute worsening of sinonasal symptoms, subjects underwent a study visit, followed by a post‐visit 2 weeks later. The sinonasal outcome test‐22 (SNOT‐22) scores and immunological parameters in the specimens were analysed using a novel, unsupervised learning method and by conventional univariate analysis.ResultsBoth CRSwNP patients and control subjects showed a significant increase in SNOT‐22 scores during acute exacerbation. Increased nasal levels of IL‐6, IL‐5, and eosinophil major basic protein were observed in CRSwNP patients. A network analysis of serum specimens revealed changes in a set of immunological parameters, which are distinctly associated with CRSwNP but not with controls. In particular, systemic increases in VEGF and GM‐CSF levels were notable and were validated by a conventional analysis.ConclusionsCRSwNP patients demonstrate distinct immunological changes locally and systemically during acute exacerbation. Growth factors VEGF and GM‐CSF may be involved in the immunopathogenesis of subjects with CRS and nasal polyps experiencing exacerbation.

AbstractBackgroundAsthma guidelines suggest reducing controller medications when asthma is stable.MethodsThe purpose of the study is to estimate the risk of asthma exacerbation in stable asthmatics who reduce inhaled corticosteroids (ICS) compared to those who maintain a stable ICS dose. We identified articles from a systematic review of English and non‐English articles using MEDLINE, EMBASE, Web of Science, and CENTRAL (inception to May 25, 2013). We included randomized controlled trials (RCTs) with a stable asthma run‐in period of 4 weeks or more, an intervention to reduce ICS, and a follow‐up period of at least 3 months.ResultsThe search strategy identified 2253 potential articles, of which 206 were reviewed at the full‐text level and 6 met criteria for inclusion. The relative risk of an asthma exacerbation in individuals who reduced ICS compared to those who maintained the same ICS dose was 1.25 (95% CI 0.96, 1.62; P = 0.10; I2 = 0%) in studies with a mean follow‐up of 22 weeks. Individuals who reduced ICS had a decreased% predicted FEV1 of 0.87% (95% CI −1.58%,3.33%; P = 0.49, I2 = 58%) and a decreased mean morning peak expiratory flow of 9.57 l/min (95% CI 1.25, 17.90; P = 0.02; I2 = 74%) compared to those individuals who maintained a stable ICS dose.ConclusionsAsthma exacerbations were statistically no more likely among individuals who reduced ICS compared to those who maintained their ICS dose, supporting current guidelines which recommend decreasing ICS by 50% after a period of asthma stability.

BackgroundWe aimed to test the hypothesis that three‐dimensional (3D) volume‐based scoring of computed tomography (CT) images of the paranasal sinuses was superior to Lund‐Mackay CT scoring of disease severity in chronic rhinosinusitis (CRS). We determined correlation between changes in CT scores (using each scoring system) with changes in other measures of disease severity (symptoms, endoscopic scoring, and quality of life) in patients with CRS treated with triamcinolone.MethodsThe study group comprised 48 adult subjects with CRS. Baseline symptoms and quality of life were assessed. Endoscopy and CT scans were performed. Patients received a single systemic dose of intramuscular triamcinolone and were reevaluated 1 month later. Strengths of the correlations between changes in CT scores and changes in CRS signs and symptoms and quality of life were determined.ResultsWe observed some variability in degree of improvement for the different symptom, endoscopic, and quality‐of‐life parameters after treatment. Improvement of parameters was significantly correlated with improvement in CT disease score using both CT scoring methods. However, volumetric CT scoring had greater correlation with these parameters than Lund‐Mackay scoring.ConclusionVolumetric scoring exhibited higher degree of correlation than Lund‐Mackay scoring when comparing improvement in CT score with improvement in score for symptoms, endoscopic exam, and quality of life in this group of patients who received beneficial medical treatment for CRS.

Nonadherence with anti-inflammatory treatment is a frequent cause of continued symptoms in asthmatic patients. Clinical assessments including patient-reported medication administration may provide the asthma specialist incomplete information regarding actual adherence to anti-inflammatory medications. The objective of this report was to describe the first case where adherence to inhaled asthma therapy was assessed by direct analysis of glucocorticoids in induced sputum. The patient's blood, urine, and sputum were tested for synthetic corticosteroids using mass spectrometry. To evaluate a clinical suspicion of poor adherence, sputum, urine, and blood were used to assess for current compliance to medication use. We report a case where asthma specialists attributed poorly controlled asthma to nonadherence to medical therapy. After modification of the medical regimen, adherence with oral and inhaled steroids was assessed–via examination of the urine, blood, and sputum. Direct analysis of glucocorticoids in sputum is feasible and in theory could provide a novel tool to document current medication adherence. Concomitant assessment of glucocorticoids and eosinophils in the same induced sputum specimen could provide insight into possible steroid resistance in select referral patients with difficult asthma.

Background One way to gain insight into the pathophysiology of chronic rhinosinusitis (CRS) is to study the immunologic changes that occur with exacerbation. This study describes the immunologic changes during CRS exacerbation Methods We performed a prospective study to investigate the immunologic changes seen during exacerbation of CRS with nasal polyposis. We recruited adult subjects who met clinical criteria for CRS with sinus CT scan within the past 5 years with Lund-Mackay score of >5 and nasal polyps. Subjects underwent a baseline visit with collection of nasal secretion and nasal wash. With acute worsening of symptoms, subjects underwent 6 near-consecutive-day collections and one follow-up collection 2 weeks later. IL-6, IL-33, eosinophil major basic protein (MBP), eosinophil-derived neurotoxin (EDN), myeloperoxidase (MPO), and uric acid were measured on the nasal samples from each visit. Results A total of 10 subjects were recruited and 9 had acute worsening of CRS during the study period. Eight of the nine subjects were women and ages ranged from 26 to 56 years. At baseline, most inflammatory parameters were low and eight of the nine subjects were on intranasal corticosteroids. Compared with baseline measurements, IL-6, MBP, MPO, EDN, and uric acid were significantly elevated during CRS exacerbation. Levels of IL-6 and MBP (r = 0.47) levels as well as IL-6 and MPO (r = 0.75) were both significantly correlated (p < 0.01). Conclusion Prospective study of CRS exacerbations is feasible and provides insights into the immunologic mechanisms of CRS.