Allergies and COVID-19 vaccines: An ENDA/EAACI Position paper.

BACKGROUND: Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized. METHOD: Members of the European Network for Drug Allergy and the European Academy of Allergy and Clinical Immunology interested in drug allergy participated in an online questionnaire on pre-vaccination screening and management of allergic reactions to COVID-19 vaccines, and literature was analysed. RESULTS: No death due to anaphylaxis to COVID-19 vaccines has been confirmed in scientific literature. Potential allergens, polyethylene glycol (PEG), polysorbate and tromethamine are excipients. The authors propose allergy evaluation of persons with the following histories: 1-anaphylaxis to injectable drug or vaccine containing PEG or derivatives; 2-anaphylaxis to oral/topical PEG containing products; 3-recurrent anaphylaxis of unknown cause; 4-suspected or confirmed allergy to any mRNA vaccine; and 5-confirmed allergy to PEG or derivatives. We recommend a prick-to-prick skin test with the left-over solution in the suspected vaccine vial to avoid waste. Prick test panel should include PEG 4000 or 3500, PEG 2000 and polysorbate 80. The value of in vitro test is arguable. CONCLUSIONS: These recommendations will lead to a better knowledge of the management and mechanisms involved in anaphylaxis to COVID-19 vaccines and enable more people with history of allergy to be vaccinated.

Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis.

A mechanistic understanding of the relationship between the chemistry of drug Ag formation and immune function is lacking. Thus, mass spectrometric methods were employed to detect and fully characterize circulating Ags derived from piperacillin in patients undergoing therapy and the nature of the drug-derived epitopes on protein that can function as an Ag to stimulate T cells. Albumin modification with piperacillin in vitro resulted in the formation of two distinct haptens, one formed directly from piperacillin and a second in which the dioxopiperazine ring had undergone hydrolysis. Modification was time and concentration dependent, with selective modification of Lys(541) observed at low concentrations, whereas at higher concentrations, up to 13 out of 59 lysine residues were modified, four of which (Lys(190), Lys(195), Lys(432), and Lys(541)) were detected in patients' plasma. Piperacillin-specific T lymphocyte responses (proliferation, cytokines, and granzyme B release) were detected ex vivo with cells from hypersensitive patients, and analysis of incubation medium showed that modification of the same lysine residues in albumin occurred in situ. The antigenicity of piperacillin-modified albumin was confirmed by stimulation of T cells with characterized synthetic conjugates. Analysis of minimally modified T cell-stimulatory albumin conjugates revealed peptide sequences incorporating Lys(190), Lys(432), and Lys(541) as principal functional epitopes for T cells. This study has characterized the multiple haptenic structures on albumin in patients and showed that they constitute functional antigenic determinants for T cells.

International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency.

BACKGROUND: There are a limited number of publications on the management of gynecologic/obstetric events in female patients with hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH). OBJECTIVE: We sought to elaborate guidelines for optimizing the management of gynecologic/obstetric events in female patients with HAE-C1-INH. METHODS: A roundtable discussion took place at the 6th C1 Inhibitor Deficiency Workshop (May 2009, Budapest, Hungary). A review of related literature in English was performed. RESULTS: Contraception: Estrogens should be avoided. Barrier methods, intrauterine devices, and progestins can be used. Pregnancy: Attenuated androgens are contraindicated and should be discontinued before attempting conception. Plasma-derived human C1 inhibitor concentrate (pdhC1INH) is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis. Tranexamic acid or virally inactivated fresh frozen plasma can be used for long-term prophylaxis if human plasma-derived C1-INH is not available. No safety data are available on icatibant, ecallantide, or recombinant human C1-INH (rhC1INH). Parturition: Complications during vaginal delivery are rare. Prophylaxis before labor and delivery might not be clinically indicated, but pdhC1INH therapeutic doses (20 U/kg) should be available. Nevertheless, each case should be treated based on HAE-C1-INH symptoms during pregnancy and previous labors. pdhC1INH prophylaxis is advised before forceps or vacuum extraction or cesarean section. Regional anesthesia is preferred to endotracheal intubation. Breast cancer: Attenuated androgens should be avoided. Antiestrogens can worsen angioedema symptoms. In these cases anastrozole might be an alternative. Other issues addressed include special features of HAE-C1-INH treatment in female patients, genetic counseling, infertility, abortion, lactation, menopause treatment, and endometrial cancer. CONCLUSIONS: A consensus for the management of female patients with HAE-C1-INH is presented.

HAE international home therapy consensus document.

Hereditary angioedema (C1 inhibitor deficiency, HAE) is associated with intermittent swellings which are disabling and may be fatal. Effective treatments are available and these are most useful when given early in the course of the swelling. The requirement to attend a medical facility for parenteral treatment results in delays. Home therapy offers the possibility of earlier treatment and better symptom control, enabling patients to live more healthy, productive lives. This paper examines the evidence for patient-controlled home treatment of acute attacks ('self or assisted administration') and suggests a framework for patients and physicians interested in participating in home or self-administration programmes. It represents the opinion of the authors who have a wide range of expert experience in the management of HAE.

Intradermal Tests With Drugs: An Approach to Standardization.

Background: Intradermal tests (IDTs) are performed and interpreted differently in drug allergy centers making valid comparison of results difficult. Objective: To reduce method-related and intercenter variability of IDTs by the introduction of a standardized method. Materials and methods: In 11 centers of the European Network for Drug Allergy, IDTs were prospectively performed with saline and with amoxicillin (20 mg/ml) using (1) the local method and (2) the standardized European Network in Drug Allergy (ENDA) method (0.02 ml). The diameters of the initial injection wheal (Wi) for the different volumes and sites injected obtained from each center were analyzed. Results: The most reproducible method was to fill a syringe with test solution, then expel the excess fluid to obtain exactly 0.02 ml. The median Wi diameter with 0.02 ml injection using the standardized method was 5 mm [range 2-10 mm; interquartile range (IQR) 5-5 mm; n = 1,096] for saline and 5 mm (range 2-9 mm; IQR = 4.5-5 mm; n = 240) for amoxicillin. IDT injection sites did not affect the Wi diameter. Training improved precision and reduced the variability of Wi diameters. Conclusion: Using the standardized IDT method described in this multicenter study helped to reduce variability, enabling more reliable comparison of results between individuals and centers.

Complement membrane attack complex and hemodynamic changes during human orthotopic liver transplantation.

Hemodynamic changes and elevation of intracellular calcium following reperfusion in human liver transplantation occur rapidly and do not match the time course of cytokine expression, therefore, we postulate involvement of other, pre-formed substances, such as complement. We studied 40 adult patients undergoing liver transplantation. Blood was drawn for estimation of C3, C4, C3 degradation product, membrane attack complex, and CH100 levels and elastase (a marker of neutrophil activation) at induction of anesthesia, 5 minutes before reperfusion, 5 minutes and 60 minutes after reperfusion. Cardiac output was measured by thermodilution and systemic vascular resistance was calculated at these same time points. There was a significant rise in C5b-9 membrane attack complex (P =.0012) with a corresponding fall in C3 (P =.0013) and C4 (P =.0002) levels and a rise in C3 degradation product levels (P =.0006). There was no significant change in CH100. These changes very closely followed the hemodynamic changes of a significant fall in systemic vascular resistance index (P =.0024) and increase in cardiac index (P =.0005). Elastase rose from 356 +/- 53 to 557 +/- 40 microg/L (P <.0001). There is complement activation and neutrophil activation at reperfusion in liver transplantation. Dilution alone cannot explain the fall in C3 and C4 levels as there is a corresponding increase in membrane attack complex and C3 degradation product levels with time. As both C3 and C4 are consumed, the classical pathway must be active, though alternative and lectin activated pathways may also be involved. These findings may, at least in part, explain the hemodynamic changes typically seen at reperfusion in liver transplantation.