Browsing by Subject "Anaphylaxis"
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Item Diabetic ketoacidosis after the treatment of anaphylaxis(Bioscientifica, 2022) Brenner, Daniel S.; Kleinman, Keith; Manzo, Amy; Bembea, Melania M.; Cook, David W.; Emergency Medicine, School of MedicineSummary: Anaphylaxis is a rapidly progressive potentially lethal condition, and epinephrine is the most crucial medication in its treatment. In this study, we present a case of diabetic ketoacidosis in a young woman that was precipitated by the administration of epinephrine to treat anaphylaxis. This patient had diabetes mellitus and poor glycemic control and developed ketoacidosis despite having evidence of ongoing endogenous insulin production and having been treated with exogenous long-acting insulin less than 24 h prior to the event. This is a rare, serious, adverse side effect of life-saving medication. This report demonstrates that the risk of diabetic ketoacidosis should be considered when administering epinephrine to patients with diabetes, even in the absence of complete insulin deficiency. Learning points: Epinephrine directly suppresses insulin secretion, stimulates lipolysis, and causes ketone body generation. High-dose catecholamine administration can cause unexpected diabetic ketoacidosis in patients with risk factors. Early administration of insulin may not protect patients from developing ketoacidosis in the setting of high-dose catecholamine administration.Item Evidence that High Affinity IgE Can Develop in the Germinal Center in the Absence of an IgG1-switched Intermediate(American Association of Immunologists, 2023) Chen, Qiang; Liu, Hong; Luling, Noelle; Reinke, Julia; Dent, Alexander L.; Microbiology and Immunology, School of MedicineHigh affinity allergen-specific IgE is essential for the severe allergic anaphylaxis response. High affinity antibodies (Abs) are formed by successive rounds of selection of Ag-specific B cells in the germinal center (GC), however several studies have shown that IgE+ GC B cells are impaired in their ability to undergo selection in the GC. A pathway, known as the “indirect switching pathway” for IgE, has been described whereby Ag-specific B cells initially switch to the IgG1 isotype and undergo affinity selection in the GC, with a secondary switch to the IgE isotype after affinity selection. In previous work, using a food allergy model in mice, we investigated how high affinity IgE develops in the GC but we did not test the indirect switching model. Here we analyzed the importance of the indirect switching pathway by constructing IgG1-cre Bcl6-fl/fl mice. In these mice, once B cells switch to IgG1, they delete Bcl6 and thus cannot enter or persist in the GC. When we tested IgG1-cre Bcl6-fl/fl mice with our food allergy model, we found that as expected, IgG1 Abs had decreased affinity, but unexpectedly the affinity of IgE for allergen was unchanged. IgG1-cre Bcl6-fl/fl mice underwent anaphylaxis in response to allergen, consistent with the formation of high affinity IgE. Thus, in a food allergy response, high affinity IgE can be efficiently formed in the absence of indirect switching to IgG1, either by direct selection of IgE+ GC B cells or indirect selection of IgM+ GC B cells that later switch to IgE.Item Factor IX administration in the skin primes inhibitor formation and sensitizes hemophilia B mice to systemic factor IX administration(Elsevier, 2023-11-04) Sherman, Alexandra; Bertolini, Thais B.; Arisa, Sreevani; Herzog, Roland W.; Kaczmarek, Radoslaw; Pediatrics, School of MedicineBackground: Factor IX inhibitor formation is the most serious complication of replacement therapy for the bleeding disorder hemophilia B, exacerbated by severe allergic reactions occurring in up to 60% of patients with inhibitors. Low success rates of immune tolerance induction therapy in hemophilia B necessitate the search for novel immune tolerance therapies. Skin-associated lymphoid tissues have been successfully targeted in allergen-specific immunotherapy. Objectives: We aimed to develop a prophylactic immune tolerance protocol based on intradermal administration of FIX that would prevent inhibitor formation and/or anaphylaxis in response to replacement therapy. Methods: We measured FIX inhibitor, anti-FIX immunoglobulin G1, and immunoglobulin E titers using the Bethesda assay and enzyme-linked immunosorbent assay after 4 weeks of twice-weekly intradermal FIX or FIX-Fc administration followed by 5 to 6 weeks of weekly systemic FIX injections in C3H/HeJ hemophilia B mice. We also measured skin antigen-presenting, follicular helper T, and germinal center B cell frequencies in skin-draining lymph nodes after a single or repeat intradermal FIX administration. Results: Intradermal administration enhanced FIX inhibitor formation in response to systemic administration. We further found that intradermal administration alone triggers inhibitor formation, even at a low dose of 0.4 IU/kg, which is 100-fold lower than the intravenous dose of 40 IU/kg typically required to induce inhibitor development in hemophilia B mice. Also, intradermal administration triggered germinal center formation in skin-draining lymph nodes and sensitized mice to systemic administration. Factor IX-Fc fusion protein did not modulate inhibitor formation. Conclusion: Intradermal FIX administration is highly immunogenic, suggesting that the skin compartment is not amenable to immune tolerance induction or therapeutic delivery of clotting factors.Item Peanut Allergen-specific Inhibition of Anaphylaxis in a Humanized Mouse Model(American Association for the Advancement of Science, 2023) Alakhras, Nada S.; Shin, Jaeho; Smith, Scott A.; Sinn, Anthony L.; Zhang, Wenwu; Hwang, Gyoyeon; Sjoerdsma, Jenna; Bromley, Emily K.; Pollok, Karen E.; Bilgicer, Basar; Kaplan, Mark H.; Biochemistry and Molecular Biology, School of MedicinePeanut-induced allergy is an immunoglobulin E (IgE)-mediated type I hypersensitivity reaction that manifests symptoms ranging from local edema to life-threatening anaphylaxis. Although there are treatments for symptoms in patients with allergies resulting from allergen exposure, there are few preventive therapies other than strict dietary avoidance or oral immunotherapy, neither of which are successful in all patients. We have previously designed a covalent heterobivalent inhibitor (cHBI) that binds in an allergen-specific manner as a preventive for allergic reactions. Building on previous in vitro testing, here, we developed a humanized mouse model to test cHBI efficacy in vivo. Nonobese diabetic-severe combined immunodeficient γc-deficient mice expressing transgenes for human stem cell factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3 developed mature functional human mast cells in multiple tissues and displayed robust anaphylactic reactions when passively sensitized with patient-derived IgE monoclonal antibodies specific for peanut Arachis hypogaea 2 (Ara h 2). The allergic response in humanized mice was IgE dose dependent and was mediated by human mast cells. Using this humanized mouse model, we showed that cHBI prevented allergic reactions for more than 2 weeks when administered before allergen exposure. cHBI also prevented fatal anaphylaxis and attenuated allergic reactions when administered shortly after the onset of symptoms. cHBI impaired mast cell degranulation in vivo in an allergen-specific manner. cHBI rescued the mice from lethal anaphylactic responses during oral Ara h 2 allergen-induced anaphylaxis. Together, these findings suggest that cHBI has the potential to be an effective preventative for peanut-specific allergic responses in patients.Item Preclinical development of plant‐based oral immune modulatory therapy for haemophilia B(Wiley, 2021-10) Srinivasan, Aparajitha; Herzog, Roland W.; Khan, Imran; Sherman, Alexandra; Bertolini, Thais; Wynn, Tung; Daniell, Henry; Pediatrics, School of MedicineAnti‐drug antibody (ADA) formation is a major complication in treatment of the X‐linked bleeding disorder haemophilia B (deficiency in coagulation factor IX, FIX). Current clinical immune tolerance protocols are often not effective due to complications such as anaphylactic reactions against FIX. Plant‐based oral tolerance induction may address this problem, as illustrated by the recent first regulatory approval of orally delivered plant cells to treat peanut allergy. Our previous studies showed that oral delivery of plant cells expressing FIX fused to the transmucosal carrier CTB (cholera toxin subunit B) in chloroplasts suppressed ADA in animals with haemophilia B. We report here creation of the first lettuce transplastomic lines expressing a coagulation factor, in the absence of antibiotic resistance gene. Stable integration of the CTB‐FIX gene and homoplasmy (transformation of ˜10 000 copies in each cell) were maintained in both T1 and T2 generation marker‐free plants. CTB‐FIX expression in lyophilized leaves of T1 and T2 marker‐free plants was 1.0–1.5 mg/g dry weight, confirming that the marker excision did not affect antigen levels. Oral administration of CTB‐FIX to Sprague Dawley rats at 0.25, 1 or 2.5 mg/kg did not produce overt adverse effects or toxicity. The no‐observed‐adverse‐effect level (NOAEL) is at least 2.5 mg/kg for a single oral administration in rats. Oral administration of CTB‐FIX at 0.3 or 1.47 mg/kg either mixed in food or as an oral suspension to Beagle dogs did not produce any observable toxicity. These toxicology studies should facilitate filing of regulatory approval documents and evaluation in haemophilia B patients.Item Relationship between pre-existing allergies and anaphylactic reactions post mRNA COVID-19 vaccine administration(Elsevier, 2021-07) Desai, Aditya P.; Desai, Aryan P.; Loomis, Gregory J.; Department of Medicine, School of Medicine, IU West LafayetteTwo mRNA vaccines for COVID-19, Pfizer-BioNTech and Moderna, are approved for emergency use in the United States. After their approval and dosing in millions of recipients, reports of anaphylaxis began to appear in the Vaccine Adverse Reporting System (VAERS). Here we provide an analysis of the relationship between prior history of allergy and/or anaphylaxis and anaphylaxis rates following the administration of mRNA COVID-19 vaccines. Overall reported incidence of anaphylaxis was estimated to be rare at 4.2 cases per million doses. It appeared that the relative incidence of anaphylaxis following administration of these COVID-19 vaccines was two and seven times higher for recipients with a prior history of allergies and/or anaphylaxis, respectively. This report provides valuable metrics to make evidence-based decisions for subjects with pre-existing allergic conditions receiving a COVID-19 mRNA vaccine.Item T Follicular Regulatory Cells Promote the Germinal Center Reaction and Allergic IgE Response While Repressing Abnormal Differentiation of T Follicular Helper Cells(2019-05) Xie, Ming; Dent, Alexander L.; Dong, X. Charlie; Kaplan, Mark H.; Zhou, BaohuaFollicular T helper (TFH) and regulatory (TFR) cells are two key classes of CD4+ T cells found in germinal centers (GCs). The primary role of TFH cells is to help B cells form GCs to produce high-affinity antibodies during an infection while the role of TFR cells remains controversial. The transcriptional repressor Bcl6 is essential for the differentiation of TFH, TFR and GCB cells and understanding signaling pathways that induce Bcl6 and TFH cell differentiation are important. We observed that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation by a pathway involving the metabolic sensor AMP kinase. The transcription factor Blimp1 represses both TFH cell differentiation and Bcl6 expression, and we show the major role of Blimp1 on TFH cell differentiation is to repress Bcl6 expression and not other genes in the TFH differentiation pathway. We also found Bcl6 positively regulates expression of the key TFH cell receptor PD-1 by inhibiting the repression of PD-1 by the transcription factor Tbet. The roles of TFH and TFR cells in controlling allergen-specific IgE were investigated using a peanut allergy model and strains of mice with alterations in the TFH and TFR pathways. We found TFR cells unexpectedly play an essential role in promoting and maintaining IgE production and anaphylaxis, as well as the GC reaction. Compared to control mice, TFR-deficient mice lacked circulating peanut-specific IgE and anaphylactic responses were significantly weakened. Mechanistically, TFR cells require Blimp1 controlled IL-10 to promote GCB cell survival and IgE production. Blocking IL-10 signals mimicked the loss of IgE levels in TFR-deficient mice and rescued mice from anaphylaxis. Overall, these studies have defined novel roles of Bcl6, TFH and TFR cells in regulating antibody production by the GC reaction, and provide greater understanding of how allergic immune responses are controlled.Item Use of Epinephrine in Patients with Drug-Induced Anaphylaxis: An Analysis of the Beijing Pharmacovigilance Database(S. Karger AG, Basel, 2017) Wang, Tiansheng; Ma, Xiang; Xing, Yan; Sun, Shusen; Zhang, Hua; Stürmer, Til; Wang, Bin; Li, Xiaotong; Tang, Huilin; Jiao, Ligong; Zhai, Suodi; Epidemiology, School of Public HealthFew studies assessing the use of epinephrine in drug-induced anaphylaxis (DIA) in the hospital setting are available. We utilized the Beijing Pharmacovigilance Database (BPD) to evaluate the appropriateness of epinephrine for DIA management. METHODS: DIA cases collected in the BPD from January 2004 to December 2014 were adjudicated and analyzed for demographics, causative drugs, clinical signs, outcomes, initial treatment, route, dosing, and cardiovascular adverse events (CAE) of epinephrine. RESULTS: DIA was primarily caused by antibiotics (38.4%), radiocontrast agents (11.9%), traditional Chinese medicine injections (10.9%), and chemotherapeutic drugs (10.3%). Only 708 (59.5%) patients received epinephrine treatment. Patients who received epinephrine were more likely to experience wheezing (p < 0.001) and respiratory arrest (p < 0.001). Among 518 patients with a complete record of the epinephrine administration route, the percentage of patients receiving it by intramuscular (IM) injection, subcutaneous (SC) injection, intravenous (IV) bolus injection, or IV continuous infusion was 16.9, 31.5, 43.5, and 8.1%, respectively. Among the 427 patients with a record of both the administration route and the dosing, an overdose was more likely with IV bolus (94.1%) in contrast to IM injection (56.6%; p < 0.001) or SC injection (43.7%; p < 0.001). Among the patients analyzed for CAE (n = 349), 17 patients accounted for 19 CAE, and 13 (76.5%) of these patients were overdosed with epinephrine. CONCLUSION: Underuse, inappropriate IV bolus use, and overdosing were the 3 major problems with epinephrine use in DIA in China. Educational training for health care professionals on the appropriate use of epinephrine in managing anaphylactic reactions is suggested.