Updated Guidance Regarding The Risk ofAllergic Reactions to COVID-19 Vaccines and Recommended Evaluation and Management: A GRADE Assessment, and International Consensus Approach

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against \u3e 15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Recent advances in understanding and managing IgG4-related disease [version 1; referees: 4 approved]

IgG4-related disease was only recently discovered, so its description, management, and new discoveries related to its etiology are rapidly evolving. Because IgG4 itself is a unique antibody which is intimately related to the diagnosis of the disease, the role of plasmablasts in the pathophysiology remains an active area of discussion. Recent studies have uncovered a possible role for CD4-positive cytotoxic T lymphocytes, T follicular helper cells, and M2 macrophages. The clinical presentation is variable and can be vague, as this disease affects many organs and new presentations are continuing to be described. The diagnosis depends on clinical and histopathological assessment. The mainstay of treatment is with glucocorticoids, but rituximab has recently shown promise. Monitoring disease activity using imaging modalities (including positron emission tomography) and serum markers is imperative, as relapses are common. IgG4-related disease spans many medical disciplines but is a treatable condition with which all clinicians should be familiar

Drug Allergy in Women

Across all settings, women self-report more drug allergies than do men. Although there is epidemiologic evidence of increased drug allergy labeling in postpubertal females, the evidence base for female sex as a risk factor for true immune-mediated drug hypersensitivity reactions (DHRs), particularly in fatal drug-induced anaphylaxis, is low. A focus on the known immunologic mechanisms described in immediate and delayed DHR, layered on known hormonal and genetic sex differences that drive other immune-mediated diseases, could be the key to understanding biological sex variations in DHR. Particular conditions that highlight the impact of drug allergy in women include (1) pregnancy, in which a drug allergy label is associated with increased maternal and fetal complications; (2) multiple drug intolerance syndrome, associated with anxiety and depression; and (3) female-predominant autoimmune medical conditions in the context of mislabeling of the drug allergy or increased underlying risk. In this review, we describe the importance of drug allergy in the female population, mainly focusing on the epidemiology and risk, the mechanisms, and the associated conditions and psychosocial factors. By performing a detailed analysis of the current literature, we provide focused conclusions and identify existing knowledge gaps that should be prioritized for future research

Arginyltransferase Is an ATP-Independent Self-Regulating Enzyme that Forms Distinct Functional Complexes In Vivo

Posttranslational arginylation mediated by arginyltransferase (ATE1) plays an important role in cardiovascular development, cell motility, and regulation of cytoskeleton and metabolic enzymes. This protein modification was discovered decades ago, however, the arginylation reaction and the functioning of ATE1 remained poorly understood because of the lack of good biochemical models. Here, we report the development of an in vitro arginylation system, in which ATE1 function and molecular requirements can be tested using purified recombinant ATE1 isoforms supplemented with a controlled number of components. Our results show that arginylation reaction is a self-sufficient, ATP-independent process that can affect different sites in a polypeptide and that arginyltransferases form different molecular complexes in vivo, associate with components of the translation machinery, and have distinct, partially overlapping subsets of substrates, suggesting that these enzymes play different physiological functions. ► ATE1 is ATP-independent and capable of self-arginylation ► ATE1 activity is modulated by intracellular cofactors ► ATE1 isoforms have different subsets of substrates, suggesting different functions ► ATE1 associates with the translation machinery and forms two distinct complexes in viv

Diagnostic accuracy of vaccine and vaccine excipient testing in the setting of allergic reactions to COVID-19 vaccines: A systematic review and meta-analysis

For persons with immediate allergic reactions to mRNA COVID-19 vaccines, skin testing (ST) to the vaccine/excipients (polyethylene glycol[PEG] and polysorbate 80 [PS]) has been recommended, but has unknown accuracy. To assess vaccine/excipient ST accuracy in predicting all-severity immediate allergic reactions upon re-vaccination, systematic review was performed searching Medline, EMBASE, Web of Science, and the WHO global coronavirus database (inception-Oct 4, 2021) for studies addressing immediate (≤4 h post-vaccination) all-severity allergic reactions to 2nd mRNA COVID-19 vaccination in persons with 1st dose immediate allergic reactions. Cases evaluating delayed reactions, change of vaccine platform, or revaccination without vaccine/excipient ST were excluded. Meta-analysis of diagnostic testing accuracy was performed using Bayesian methods. The GRADE approach evaluated certainty of the evidence, and QUADAS-2 assessed risk of bias. Among 20 studies of mRNA COVID-19 first dose vaccine reactions, 317 individuals underwent 578 ST to any one or combination of vaccine, PEG, or PS, and were re-vaccinated with the same vaccine. Test sensitivity for either mRNA vaccine was 0.2 (95%CrI 0.01–0.52) and specificity 0.97 (95%CrI 0.9–1). PEG test sensitivity was 0.02 (95%CrI 0.00–0.07) and specificity 0.99 (95%CrI 0.96–1). PS test sensitivity was 0.03 (95%CrI 0.00–0.0.11) and specificity 0.97 (95%CrI 0.91–1). Combined for use of any of the 3 testing agents, sensitivity was 0.03 (95%CrI 0.00–0.08) and specificity was 0.98 (95%CrI 0.95–1.00). Certainty of evidence was moderate. ST has low sensitivity but high specificity in predicting all-severity repeat immediate allergic reactions to the same agent, among persons with 1st dose immediate allergic reactions to mRNA COVID-19 vaccines. mRNA COVID-19 vaccine or excipient ST has limited risk assessment utility.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175406/1/all15571-sup-0003-supplementaryfigureE2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175406/2/all15571-sup-0002-supplementaryfigureE1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175406/3/all15571_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175406/4/all15571.pd

Beyond Sedlis: A novel, histology-based nomogram for predicting recurrence risk and need for adjuvant radiation in cervical cancer—A NRG/GOG ancillary analysis

6019 Background: In GOG 49, factors associated with a 3-year, 30% recurrence risk in squamous cell carcinoma of the cervix (SCC) after surgery alone were defined. These "intermediate" risk factors [tumor size (TS), depth of tumor invasion (DOI), and lymphvascular space invasion (LVSI)] were then studied in GOG 92, which demonstrated the utility of treating patients (pts) with ≥2 intermediate risk factors with adjuvant radiation (RT), Sedlis Criteria. However, pts with < 30% recurrence risk were not eligible and few pts with adenocarcinoma (AC) were included. Our study purpose was 1) to evaluate recurrence risk factors for AC vs SCC, and 2) to define contemporary nomograms for adjuvant treatment in pts with both histologies. Methods: We performed an ancillary analysis of GOG 49, 92, and 141, and included Stage I pts who received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were created separately for AC and SCC to evaluate independent risk factors for recurrence. Model accuracy was tested with ROC curves. Prognostic nomograms were generated for 2-year recurrence risk for AC and SCC. Results: We identified 715 with SCC and 105 pts with AC; 142 with SCC (19.9%) and 18 with AC 17.1%) recurred. For SCC, factors associated independently with recurrence were: LVSI [HR 1.58 (CI 1.12-2.22)], DOI [middle 1/3, HR 4.31 (CI 1.81-10.26); deep 1/3, HR 7.05 (CI 2.99-16.64)] and TS [≥4cm HR 2.67 (CI 1.67-4.29)]. In contrast, for AC, only TS ≥4cm was independently associated with recurrence [HR 4.69 (CI 1.25-17.63)]. At 3 years, ROC curves for these models predicted recurrence with 76% and 75% accuracy for SCC and AC, respectively. Utilizing a nomogram generated from these models, for SCC, DOI had the greatest impact on recurrence, with mid 1/3 conferring an 18% risk and deep 1/3 a 32% risk, while LVSI and TS increased risk by 4-10%, respectively. In contrast, for AC, TS alone had the greatest impact on recurrence risk with TS 2-4cm conferring a 20% risk over 3 years and TS ≥4cm, a 28% risk. Conclusions: Our nomogram differs from the Sedlis Criteria in demonstrating that single, as well as a combination of risk factors predict substantial 3-year recurrence rates in Stage I cervical cancer. Furthermore, these factors differ by AC and SCC subtypes, suggesting that distinct, histology-specific nomograms may have greater utility in identifying pts who will most benefit from adjuvant therapy