Protein misfolding in the endoplasmic reticulum (ER) contributes to the pathogenesis of many diseases. Although oxidative stress can disrupt protein folding, how protein misfolding and oxidative stress impact each other has not been explored. We have analyzed expression of coagulation factor VIII (FVIII), the protein deficient in hemophilia A, to elucidate the relationship between protein misfolding and oxidative stress. Newly synthesized FVIII misfolds in the ER lumen, activates the unfolded protein response (UPR), causes oxidative stress, and induces apoptosis in vitro and in vivo in mice. Strikingly, antioxidant treatment reduces UPR activation, oxidative stress, and apoptosis, and increases FVIII secretion in vitro and in vivo. The findings indicate that reactive oxygen species are a signal generated by misfolded protein in the ER that cause UPR activation and cell death. Genetic or chemical intervention to reduce reactive oxygen species improves protein folding and cell survival and may provide an avenue to treat and/or prevent diseases of protein misfolding.factor VIII ͉ oxidative stress ͉ unfolded protein response A lthough endoplasmic reticulum (ER) stress and oxidative stress are closely linked events, the molecular pathways that couple these processes are poorly understood (1). Reactive oxygen species (ROS) originate during oxygen-using cellular metabolic processes, such as oxidative phosphorylation within mitochondria. The ER provides a unique oxidizing environment for protein folding and disulfide bond formation before transit to the Golgi compartment. During disulfide bond formation ROS are formed as a product of electron transport from thiol groups in proteins through protein disulfide isomerase (PDI) and ER oxidoreductase 1 (ERO1) to reduce molecular oxygen to form the oxidant hydrogen peroxide. It has been suggested that oxidation of cysteine residues during disulfide bond formation in the ER may significantly contribute to oxidative stress (2, 3). The unfolded protein response (UPR) is an adaptive signaling pathway designed to prevent the accumulation of misfolded proteins in the ER lumen. Studies also suggest the UPR is designed to minimize the stress of oxidative protein folding (2). The UPR is signaled through the protein kinases inositolrequiring protein 1␣ and PKR-related ER kinase and the activating transcription factor 6␣ (4, 5). Chronic unresolved accumulation of unfolded proteins in the ER leads to apoptosis. To elucidate the relationship between unfolded protein accumulation in the ER lumen, oxidative stress, and apoptosis, we have analyzed the secretion of coagulation factor VIII (FVIII), a large glycoprotein that is deficient in the X chromosome-linked bleeding disorder hemophilia A. As FVIII is prone to misfolding in the ER lumen, FVIII expression provides a unique approach to manipulate the ER stress response that does not rely on pharmacological intervention, where any connection between ER stress and ROS would be difficult to dissect.FVIII is comprised of three domains in the ord...

The U.S. Food and Drug Administration (FDA) has recently issued an Emergency Use Authorization (EUA) for 2 highly effective coronavirus disease 2019 (COVID-19) vaccines from Pfizer-BioNTech and Moderna. This has brought hope to millions of Americans in the midst of an ongoing global pandemic. The FDA EUA guidance for both vaccines is to not administer the vaccine to individuals with a known history of a severe allergic reaction (eg, anaphylaxis) to any component of the COVID-19 vaccine. The Centers for Disease Control and Prevention (CDC) additionally advises individuals with a history of an immediate allergic reaction to a vaccine or injectable or any history of anaphylaxis be observed for 30 minutes after COVID-19 vaccination. All other individuals should be observed for 15 minutes after COVID-19 vaccination. Staff at vaccine clinics must be able to identify and manage anaphylaxis. Post–FDA EUA, despite very strong safety signals in both phase 3 trials, reports of possible allergic reactions have raised public concern. To provide reassurance and support during widespread global vaccination, allergists must offer clear guidance to individuals based on the best information available, but also in accordance with the broader recommendations of regulatory agencies. This review summarizes vaccine allergy epidemiology and proposes drug and vaccine allergy expert opinion informed risk stratification for Allergy specialist use in conjunction with guidance of public health and regulatory authorities. The risk stratification schema guide care for (1) individuals with different allergy histories to safely receive their first mRNA COVID-19 vaccine and (2) individuals who develop a reaction to their first dose of mRNA COVID-19 vaccine.

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Background CDC states that a severe or immediate allergic reaction to the first dose of an mRNA COVID-19 vaccine is a contraindication for the second dose. Objective To assess outcomes associated with excipient skin testing after a reported allergic reaction to mRNA COVID-19 vaccine dose one. Methods We identified a consecutive sample of patients with reported allergic reactions after the first dose of mRNA COVID-19 vaccine who underwent allergy assessment with skin testing to polyethylene glycol (PEG) and, if appropriate, polysorbate 80. Skin testing results in conjunction with clinical phenotyping of the first dose mRNA COVID-19 vaccine reaction guided second dose vaccination recommendation. Second dose mRNA COVID-19 vaccine reactions were assessed. Results 80 patients with reported first dose mRNA COVID-19 vaccine allergic reactions (n=65, 81% immediate onset) underwent excipient skin testing. 14 (18%) had positive skin tests to PEG (n=5) and/or polysorbate 80 (n=12). Skin testing result did not impact tolerance of second dose in patients with immediate or delayed reactions. Of 70 (88%) patients who received their second mRNA COVID-19 vaccine dose, 62 (89%) had either no reaction or a mild reaction managed with antihistamines, but two patients required epinephrine. Three patients with positive PEG-3350 intradermal (methylprednisolone) testing tolerated second dose mRNA COVID-19 vaccination. Refresh Tears caused non-specific irritation. Conclusion Most individuals with a reported allergic reaction to dose one of the mRNA COVID-19 vaccines, regardless of skin test result, received the second dose safely. More data are needed on the value of skin prick testing to PEG (Miralax) in evaluating patients with mRNA COVID-19 vaccine anaphylaxis. Refresh Tears should not be used for skin testing.

Addressing inaccurate penicillin allergies is encouraged as part of antibiotic stewardship in the inpatient setting. However, implementing interventions targeted at the 10–15% of inpatients reporting a prior penicillin allergy can pose substantial logistic challenges. We implemented a computerized guideline for patients with reported beta-lactam allergy at five hospitals within a single healthcare system in the Boston area. In this paper, we describe our implementation roadmap, including both successes achieved and challenges faced. We explain key implementation steps, including assembling a team, stakeholder engagement, developing or selecting an approach, spreading the change, establishing measures, and measuring impact. The objective is to detail the lessons learned while empowering others to be part of this important, multi-disciplinary work to improve the care of patients with reported beta-lactam allergies.

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IMPORTANCEVaccination against SARS-CoV-2 is a highly effective strategy to prevent infection and severe COVID-19 outcomes. The best strategy for a second dose of vaccine among persons who had an immediate allergic reaction to their first SARS CoV-2 vaccination is unclear.OBJECTIVE To assess the risk of severe immediate allergic reactions (eg, anaphylaxis) to a second dose of SARS-CoV-2 mRNA vaccine among persons with immediate allergic reactions to their first vaccine dose.DATA SOURCES MEDLINE, Embase, Web of Science, and the World Health Organization Global Coronavirus database were searched from inception through October 4, 2021.STUDY SELECTION Included studies addressed immediate allergic reactions of any severity to a second SARS-CoV-2 vaccine dose in persons with a known or suspected immediate allergic reaction (<4 hours after vaccination) after their first SARS-CoV-2 vaccine dose. Studies describing a second vaccine dose among persons reporting delayed reactions (>4 hours after vaccination) were excluded.DATA EXTRACTION AND SYNTHESIS Paired reviewers independently selected studies, extracted data, and assessed risk of bias. Random-effects models were used for meta-analysis. The GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) approach evaluated certainty of the evidence. MAIN OUTCOMES AND MEASURESRisk of severe immediate allergic reaction and repeated severe immediate allergic reactions with a second vaccine dose. Reaction severity was defined by the reporting investigator, using Brighton Collaboration Criteria, Ring and Messmer criteria, World Allergy Organization criteria, or National Institute of Allergy and Infectious Diseases criteria. RESULTS Among 22 studies of SARS-CoV-2 mRNA vaccines, 1366 individuals (87.8% women; mean age, 46.1 years) had immediate allergic reactions to their first vaccination. Analysis using the pooled random-effects model found that 6 patients developed severe immediate allergic reactions after their second vaccination (absolute risk, 0.16% [95% CI, 0.01%-2.94%]), 232 developed mild symptoms (13.65% [95% CI, 7.76%-22.9%]), and, conversely, 1360 tolerated the dose (99.84% [95% CI, 97.09%-99.99%]). Among 78 persons with severe immediate allergic reactions to their first SARS-CoV-2 mRNA vaccination, 4 people (4.94% [95% CI, 0.93%-22.28%]) had a second severe immediate reaction, and 15 had nonsevere symptoms (9.54% [95% CI, 2.18%-33.34%]). There were no deaths. Graded vaccine dosing, skin testing, and premedication as risk-stratification strategies did not alter the findings. Certainty of evidence was moderate for those with any allergic reaction to the first dose and low for those with severe allergic reactions to the first dose. CONCLUSIONS AND RELEVANCEIn this systematic review and meta-analysis of case studies and case reports, the risk of immediate allergic reactions and severe immediate reactions or anaphylaxis associated with a second dose of an SARS-CoV-2 mRNA vaccine was low among persons who experienced an immediate allergic reaction to their fir...

Using free-text search of the EHR allergy module identified a large US DRESS syndrome cohort. DRESS prevalence was 2.18 per 100,000 patients. Both liver and kidney injury were frequent, and vancomycin was the most common drug culprit. DRESS cases were morbid and resource-intensive.