RATIONALE: Aspirin exacerbated respiratory disease (AERD) involves overproduction of cysteinyl-leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselectivecyclooxygenase inhibitors. The mechanistic basis for MC activation in this disorder is unknown, but can be inhibited by inhibition of cysLT synthesis, suggesting MC activation in AERD occurs by an idiosyncratic, cysLTsdependent mechanism. IL-33, a cytokine released by structural cells, can activate MCs. Previously we have demonstrated that ptges -/mice show increased bronchoconstriction in response to inhaled lysine-aspirin (Lys-ASA). We hypothesized that AERD involves a cysLTs-driven IL-33-mediated mast cell activation pathway. METHODS: Nasal polyps were collected from AERD patients and aspirin tolerant (AT) controls for IL-33 analysis. ptges -/and ltc4s -/mice were primed with dust-mite-extract, and then challenged with aerosol Lys-ASA or exogenous cysLTs to record airway resistance (R L ). Lung MC activation and eicosanoids production were measured by ELISA. IL-33 level was measured by ELISA and Western-Blot. RESULTS: AERD patients show increased IL-33 expression in nasal polyps, as compared to controls. The murine model of AERD (ptges -/mice), shows upregulated IL-33 protein level in the airway epithelium, along with marked eosinophilic bronchovascular inflammation. Deletion of LTC 4 -synthase attenuated the increased IL-33 content of the ptges -/lungs and reduced pulmonary eosinophilia and basal secretion of MC products. Challenges of dust mite-primed ptges -/mice with Lys-ASA induce IL-33-dependent MC activation and bronchoconstriction that were reproduced with LTE 4 challenges. CONCLUSIONS: IL-33 is a component of a cysLT-driven innate type-2 immune response that drives pathogenic MC activation and contributes substantially to AERD pathogenesis.
RATIONALE: The guidelines for safe subcutaneous immunotherapy administration put forth by AAAAI recommend a 30 minute in-office wait after injection, stating that the majority of serious systemic reactions occur within 30 minutes of receiving an injection. However, less is known about delayed systemic reactions occurring outside of a clinic setting. We wanted to determine what percent of reactions occurred after 30 minutes within in our practice. METHODS: We retrospectively evaluated all systemic reactions from November 1, 2004 to November 1, 2014 to determine time from injection to onset of symptoms. RESULTS: Of the 57,102 injections that were given over 10 years, there were 72 systemic reactions among 50 patients. Of the total number of reactions, 52.8% (38 instances) occurred after 30 minutes. Seven patients experienced symptom onset as late as 90 or more minutes post injection. The percentage of patients who required epinephrine did not differ based on reaction time (p50.65). This dataset was unable to determine any factors predicting the likelihood of a delayed reaction such as age, sex, allergen content or duration of successful immunotherapy. CONCLUSIONS: Our data suggest that even with a 30 minute in-office wait time, approximately half of systemic reactions occurred outside the clinic. Although in our series of patients there were few emergency treatments and no fatalities, the risk of severe reactions to allergy shots outside the clinic remains. The results underscore the importance of educating patients about the symptoms of systemic reactions, proper epinephrine self-administration, and the possibility of delayed onset of symptoms.
RATIONALE: Titers of anti-A and anti-B antibodies (isoagglutinins) in intravenous immunoglobulin (IVIG) products correlate with the risk of hemolysis. Therefore, it is hypothesized that reduction of anti-A/B may reduce this risk. METHODS: We tested the effect of a specific immunoaffinity chromatography (IAC) step, using a blood group A and B trisaccharides-coupled resin, added to the manufacturing process of an IVIG (Privigen Ò , CSL Behring). Anti-A/B in the final product was measured by the direct agglutination test (DAT). Historical Privigen Ò lots produced without the IAC step or other measures of isoagglutinin reduction (donor screening) were used as comparators. A fluorescence-activated cell sorting (FACS)-based anti-A/B binding assay was used to compare intermediate products before and after the IAC step.
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