Hagan, John B.

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.

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.

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.