EAACI/ENDA position paper on drug provocation testing.

In drug hypersensitivity, drug provocation testing (DPT), also called drug challenge, is the gold standard for investigation. In recent years, risk stratification has become an important tool for adjusting the diagnostic strategy to the perceived risk, whilst still maintaining a high level of safety for the patient. Skin tests are recommended before DPT but may be omitted in low-risk patients. The task force suggests a strict definition of such low-risk patients in children and adults. Based on experience and evidence from studies of allergy to beta-lactam antibiotics, an algorithm on how to adjust DPT to the risk, and when to omit skin tests before DPT, is presented. For other antibiotics, non-steroidal anti-inflammatory drugs and other drugs, skin tests are poorly validated and DPT is frequently necessary. We recommend performing DPT with chemotherapeutics and biologicals to avoid unnecessary desensitization procedures and DPT with skin tests negative contrast media. We suggest DPT with anesthetics only in highly specialized centers. Specifics of DPT to proton pump inhibitors, anticonvulsants and corticosteroids are discussed. This position paper provides general recommendations and guidance on optimizing use of DPT, whilst balancing benefits with patient safety and optimizing the use of the limited available resources.

Topical eye medications causing allergic contact dermatitis.

BACKGROUND: Allergic contact dermatitis (ACD) in the eye region caused by topical eye medications is difficult to diagnose and may be overlooked. OBJECTIVE: To study the characteristics and causative agents in patients with ACD caused by topical eye medications in a Danish tertiary dermatology department. METHODS: A retrospective study of 318 patients, patch tested between 2013 and 2021 due to suspected ACD to topical eye medications. All patients were tested with a locally developed eye medication series, some were additionally tested with suspected eye medications. Medical records were studied in patch test positive patients. RESULTS: Contact allergy to a topical eye allergen/medication was found in 12.9% (n = 41) of 318 patients, and culprit allergens were phenylephrine (6.9%), timolol (2.5%) and ketotifen (1.6%). Patch test positive patients were often previously diagnosed with cataract (29.3%) or glaucoma (24.4%), and the majority reported more than one previous reaction. Initial symptoms were oedema (56.0%), erythema (48.8%) and dermatitis (31.7%) in the eye region, and facial dermatitis was also seen. CONCLUSIONS: Patients with symptoms from the eye region who have been using topical eye medications should be patch tested with ingredients from commonly used eye medications supplemented by the products tested 'as is'.

Optimizing investigation of suspected allergy to polyethylene glycols.

BACKGROUND: Polyethylene glycols (PEGs) are polymers of varying molecular weight (MW) used widely as excipients in drugs and other products, including the mRNA vaccines against coronavirus disease 2019. Allergy to PEGs is rare. Skin testing and graded challenge carries a high risk of inducing systemic reactions. OBJECTIVE: We evaluated skin prick test (SPT) results and in vitro reactivity over time to different MW PEGs and assessed cross-sensitization patterns in PEG allergy. METHODS: Ten patients with previously diagnosed PEG allergy underwent SPT twice with PEGs 26 months apart. Lower MW (PEG 300, 3000, 6000) were tested, followed by PEG 20,000, in stepwise, increasing concentrations. Cross-sensitization to polysorbate 80 and poloxamer 407 was assessed. SPT was performed in 16 healthy controls. In vitro basophil histamine release (HR) test and passive sensitization HR test were performed in patients and controls. RESULTS: Patients previously testing positive on SPT to PEG 3000 and/or 6000 also tested positive to PEG 20,000. Patients with a longer interval since diagnosis tested negative to lower MW PEGs and positive mainly to higher concentrations of PEG 20,000. Three patients developed systemic urticaria during SPT. Eight patients showed cross-sensitization to poloxamer 407 and 3 to polysorbate 80. All controls tested negative. In vitro tests showed limited usefulness. CONCLUSIONS: Skin test reactivity to PEG can decrease over time, but titrated SPT with increasing concentrations of PEG 20,000 can be diagnostic when lower MW PEGs test negative. To avoid systemic reactions, stepwise SPT is mandatory.

EAACI guidelines: Anaphylaxis (2021 update).

Anaphylaxis is a clinical emergency which all healthcare professionals need to be able to recognize and manage. The European Academy of Allergy and Clinical Immunology Anaphylaxis multidisciplinary Task Force has updated the 2014 guideline. The guideline was developed using the AGREE II framework and the GRADE approach. The evidence was systematically reviewed and recommendations were created by weighing up benefits and harms. The guideline was peer-reviewed by external experts and reviewed in a public consultation. The use of clinical criteria to identify anaphylaxis is suggested with blood sampling for the later measurement of tryptase. The prompt use of intramuscular adrenaline as first-line management is recommended with the availability of adrenaline autoinjectors to patients in the community. Pharmacokinetic data should be provided for adrenaline autoinjector devices. Structured, comprehensive training for people at risk of anaphylaxis is recommended. Simulation training and visual prompts for healthcare professionals are suggested to improve the management of anaphylaxis. It is suggested that school policies reflect anaphylaxis guidelines. The evidence for the management of anaphylaxis remains mostly at a very low level. There is an urgent need to prioritize clinical trials with the potential to improve the management of patients at risk of anaphylaxis.

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.

Diagnosing, managing and preventing anaphylaxis: Systematic review.

BACKGROUND: This systematic review used the GRADE approach to compile evidence to inform the European Academy of Allergy and Clinical Immunology's (EAACI) anaphylaxis guideline. METHODS: We searched five bibliographic databases from 1946 to 20 April 2020 for studies about the diagnosis, management and prevention of anaphylaxis. We included 50 studies with 18 449 participants: 29 randomized controlled trials, seven controlled clinical trials, seven consecutive case series and seven case-control studies. Findings were summarized narratively because studies were too heterogeneous to conduct meta-analysis. RESULTS: It is unclear whether the NIAID/FAAN criteria or Brighton case definition are valid for immediately diagnosing anaphylaxis due to the very low certainty of evidence. There was also insufficient evidence about the impact of most anaphylaxis management and prevention strategies. Adrenaline is regularly used for first-line emergency management of anaphylaxis but little robust research has assessed its effectiveness. Newer models of adrenaline autoinjectors may slightly increase the proportion of people correctly using the devices and reduce time to administration. Face-to-face training for laypeople may slightly improve anaphylaxis knowledge and competence in using autoinjectors. We searched for but found little or no comparative effectiveness evidence about strategies such as fluid replacement, oxygen, glucocorticosteroids, methylxanthines, bronchodilators, management plans, food labels, drug labels and similar. CONCLUSIONS: Anaphylaxis is a potentially life-threatening condition but, due to practical and ethical challenges, there is a paucity of robust evidence about how to diagnose and manage it.

Perioperative anaphylaxis in children: Etiology, time sequence, and patterns of clinical reactivity.

BACKGROUND: Perioperative anaphylaxis (PA) in children is an uncommon but potentially life-threatening complication associated with anesthesia. Early identification and management of PA is essential to optimize clinical outcomes. METHODS: We performed a retrospective study of anesthesia records from pediatric patients with PA from centers in the United Kingdom, France, and the United States over a period of 10 years. Time sequence of clinical signs and physiological variables during PA were collected, along with results of allergy testing. RESULTS: Twenty-nine children with PA were included. Median age was 11 years. Based on the modified Ring and Messmer Grading Scale, severe reactions were seen in 25 (86%) members of this cohort, with 4 (14%) experiencing cardiac arrest. Life-threatening hypotension was the first clinical sign of PA in 59% of cases, followed by tachycardia and bronchospasm. In 16 (55%) cases, the initial signs of PA involved multiple organ systems. When the initial signs of PA were cardiovascular and/or respiratory, more epinephrine doses were administered. Average time from initial sign of PA to treatment with epinephrine was 6 minutes (SD: 6, range: 1-25). The causative allergen was identified in 15 patients. CONCLUSION: Severe hypotension is the most common presenting sign of PA in children. Initial cardiovascular and/or respiratory signs are associated with the need for increased epinephrine doses. Further studies should optimize the prediction, identification, and early management of PA in children.

Perioperative anaphylaxis: diagnostic challenges and management.

PURPOSE OF REVIEW: Perioperative hypersensitivity reactions can pose diagnostic and management challenges for the anaesthetist. Difficulties in diagnosing hypersensitivity reactions in the perioperative setting are highlighted and recommendations from recent guidelines on the acute management of life-threatening anaphylaxis are presented. RECENT FINDINGS: Anaesthetists play a key role in investigating perioperative hypersensitivity reactions. During a suspected perioperative hypersensitivity event, a serum tryptase level should be measured to help with subsequent allergy investigation. Moreover, anaesthetists can ensure that a high-quality referral is made to allergy clinics by providing thorough documentation of the events, detailing symptoms, treatments, and the chronology of drug administrations. SUMMARY: Perioperative hypersensitivity reactions are rare but can be life-threatening. A high index of suspicion should be maintained for their successful management. Whenever a perioperative hypersensitivity reaction is suspected, close collaboration between anaesthetist and the allergy team investigating the patient is paramount, in order for the patient to be appropriately investigated and have an uneventful anaesthetic in the future.

An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions.

Perioperative immediate hypersensitivity reactions are rare. Subsequent allergy investigation is complicated by multiple simultaneous drug exposures, the use of drugs with potent effects and the many differential diagnoses to hypersensitivity in the perioperative setting. The approach to the investigation of these complex reactions is not standardized, and it is becoming increasingly apparent that collaboration between experts in the field of allergy/immunology/dermatology and anaesthesiology is needed to provide the best possible care for these patients. The EAACI task force behind this position paper has therefore combined the expertise of allergists, immunologists and anaesthesiologists. The aims of this position paper were to provide recommendations for the investigation of immediate-type perioperative hypersensitivity reactions and to provide practical information that can assist clinicians in planning and carrying out investigations.

A EAACI drug allergy interest group survey on how European allergy specialists deal with ß-lactam allergy.

An accurate diagnosis of ß-lactam (BL) allergy can reduce patient morbidity and mortality. Our aim was to investigate the availability of BL reagents, their use and test procedures in different parts of Europe, as well as any differences in the diagnostic workups for evaluating subjects with BL hypersensitivity. A survey was emailed to all members of the EAACI Drug Allergy Interest Group (DAIG) between February and April 2016, and the questionnaire was meant to study the management of suspected BL hypersensitivity. The questionnaire was emailed to 82 DAIG centres and answered by 57. Amoxicillin alone or combined to clavulanic acid were the most commonly involved BL except in the Danish centre, where penicillin V was the most frequently suspected BL. All centres performed an allergy workup in subjects with histories of hypersensitivity to BL: 53 centres (93%) followed DAIG guidelines, two national guidelines and two local guidelines. However, there were deviations from DAIG recommendations concerning allergy tests, especially drug provocation tests. A significant heterogeneity exists in current practice not only among countries, but also among centres within the same country. This suggests the need to re-evaluate, update and standardize protocols on the management of patients with suspected BL allergy.

The Clinical Relevance of Natural Rubber Latex-Specific IgE in Patients Sensitized to Timothy Grass Pollen.

BACKGROUND: In pollen-allergic patients, cross-reacting allergens including cross-reactive carbohydrate determinants (CCDs) and profilins may result in positive natural rubber latex (NRL)-specific IgE (sIgE) antibody tests but the relationship between this sensitization and clinical NRL type 1 allergy is poorly described. OBJECTIVE: The aims of this study were to determine the frequency and clinical relevance of NRL sIgE in grass pollen-sensitized individuals and to investigate which NRL allergen components these individuals were sensitized to. METHODS: A total of 383 grass-sensitized patients answered questions about NRL allergy symptoms and their stored sera from previous investigations were analyzed for NRL sIgE. Patients with NRL sIgE (n = 32) underwent further investigations comprising medical history, skin prick test with NRL and inhalational allergens, and an additional blood sample. The additional blood samples were analyzed for total IgE and sIgE against NRL, timothy grass, birch, rHev b 1, 3, 5, 6.01, 6.02, 8, 9, 11, rPhl p 12, and MUXF3, which was used as a marker of CCD sensitization. RESULTS: Overall, 9.4% of all grass pollen-sensitized individuals showed IgE sensitization to NRL but only 1.6% had a confirmed type I NRL allergy. CCD and Hev b 8 explained the clinically irrelevant NRL IgE sensitization in 65% of the cases. We found a highly significant correlation between NRL profilin (Hev b 8) sensitization and grass profilin (Phl p 12) sensitization (p < 0.0001). CONCLUSIONS: Data from this study support the hypothesis that in patients with grass pollen sensitization, Hev b 8 mono-sensitization has little or no clinical relevance and is caused by cross sensitization from grass profilin (Phl p 12).

Chlorhexidine Allergy: On the Rise and Often Overlooked.

PURPOSE OF REVIEW: In recent years, the risk of allergy to chlorhexidine is increasingly recognised. In this review, we discuss why the allergy is so easily overlooked and point out several preventative initiatives that can minimise the risk of both chlorhexidine sensitisation and allergy development and accidental re-exposure in patients with chlorhexidine allergy. Testing for chlorhexidine allergy is also discussed. RECENT FINDINGS: Numerous reports have been published from many different specialties. Symptoms range from mild skin symptoms to life-threatening anaphylaxis. Testing for chlorhexidine allergy is based on skin testing and in vitro testing. Recently, it was found that both skin prick testing and specific IgE have high sensitivities and specificities. This review gives an overview of chlorhexidine allergy with a special focus on preventative initiatives and testing.

Chlorhexidine allergy in the perioperative setting: a narrative review.

Chlorhexidine is an antiseptic with a broad spectrum of activity and a persistent effect on skin. Consequently, it has become an ubiquitous antiseptic in healthcare and the community. As use has become widespread, increasing numbers of cases of allergy have been reported in the literature, including cases of anaphylaxis to chlorhexidine gels used on mucous membranes, chlorhexidine-impregnated devices such as central venous catheters, chlorhexidine preparations used on wounds and broken skin, and cases after dental procedures. Numerous governmental warnings have been issued over recent decades to warn of the risk of allergy to chlorhexidine on mucosal surfaces or in medical devices. Whilst the number of published cases likely underestimates the true prevalence of reactions, we retrospectively surveyed clinics with experience in investigating perioperative chlorhexidine allergy. Despite differences in investigation practice before the survey took place, 13 clinics responded which together had diagnosed 252 cases of anaphylaxis to chlorhexidine, and cases of delayed allergy. In eight of 13 clinics, chlorhexidine was within the top four most commonly diagnosed causes of perioperative anaphylaxis. Despite this, the incidence of anaphylaxis to chlorhexidine is low given that patients are very commonly exposed. Sensitisation of healthcare workers can occur, but is uncommon. Before exposing patients to this antiseptic, consideration of the potential risk vs benefit should be undertaken, particularly for higher risk exposures, such as mucosal exposure or i.v. exposure via impregnated lines. Difficulties exist in protecting patients with known allergies from re-exposure to chlorhexidine, which would be improved with uniform labelling and chlorhexidine product registers.

Mast Cells and Anaphylaxis.

For half a century, it has been known that the mast cell is the cell responsible for the majority of anaphylactic events. Its mediators, taken as a whole, are capable of producing all of the clinical manifestations of these events. With the discovery of immunoglobulin E (IgE), it was originally felt that the vast majority of anaphylactic episodes were due to antigen coupling with two cell-bound IgE molecules. More recently it has been learned that many episodes are produced by direct activation of mast cells, not involving antigen binding to IgE, and that monomeric IgE under certain conditions can also cause degranulation. Of note--in regard to antigen independent degranulation--are recent reports that the human G-protein-coupled receptor, MRGPRX2, may be the receptor for many drugs and cationic proteins capable of producing direct mast cell degranulation and anaphylactic events.

Perioperative anaphylactic shock caused by propofol.

Perioperative anaphylaxis is rare and the diagnosis is difficult to distinguish from normal side effects from anaesthesia. Anaesthetists should be able to diagnose anaphylaxis and treat promptly with adrenaline and fluids. Allergy investigation should be performed subsequently. This is a case report of perioperative anaphylaxis to propofol. Propofol contains refined soya oil and egg lecithin, but no connection between allergy to soy, egg or peanut and allergy to propofol has been proven, and international guidelines recommend that propofol can be used in patients with these food allergies.

Healthcare professionals' attitudes to penicillin allergy labels.

INTRODUCTION: About 10% of hospital inpatients are labelled with penicillin allergy in their electronic medical record (EMR). However, allergy is confirmed in less than 10% of these records. Consequently, 90% of patients are treated with broad-spectrum antibiotics, contributing to antimicrobial resistance. We aimed to explore experiences and practices of healthcare professionals that may explain incorrect labelling of penicillin allergy in Denmark and elucidate any consequences hereof. METHODS: An electronic survey was distributed to physicians and nurses in six hospital units in Copenhagen and via social media. The survey was active from 19 March to 1 May 2020. Data were assessed using descriptive statistics and by thematic analysis. RESULTS: The response rate was 44.6%. The survey had 369 participants; 152 physicians and 217 nurses. Half of the physicians and one in every five nurses had experienced problems treating patients with a penicillin allergy label. Physicians reported limited trust in allergy labels, and labelling practices varied. The risk that patients may be truly allergic was the main reason for not removing labels (72%), and a precautionary principle was identified related to penicillin allergy labelling. CONCLUSIONS: The penicillin allergy label is an independent factor of medication errors. Solutions to enhance patient safety may include education of physicians in allergy labelling, decision support, standardisation of the allergy registration in the various EMR systems used, and ideally also a national drug allergy register, which is accessible from all sectors. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Perioperative Hypersensitivity Evaluation and Management: A Practical Approach.

Perioperative hypersensitivity (POH) is an uncommon, potentially life-threatening event. Identification of POH can be difficult given the lack of familiarity, physiological effects of anesthesia, draping of the patient during surgery, and potential nonimmunological factors contributing to signs and symptoms. Given the unique nature and large number of medications administered in the perioperative setting, evaluation of POH can be challenging. In this paper, we present a practical approach to management with an emphasis on understanding what happens in the operating room, the overlap of signs and symptoms between nonimmunological and immunological reactions, acute management, and subsequent evaluation. In addition, we provide a strategy for further review of an initially negative evaluation and emphasize the importance of establishing management plans for the patient as well as providing recommendations to the medical, anesthesia, and surgical teams for future surgeries. A critical factor for successful management at all points in the process is a close collaboration between the anesthesia and the allergy teams.

Allergy to polyethylene glycol and polysorbates in a patient cohort: Diagnostic work-up and decision points for vaccination during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic focus has been on polyethylene glycol (PEG) and polysorbate as these excipients are constituents in the first vaccines and possible elicitors of allergic reactions to the vaccines. We aimed to evaluate the possibility of vaccinating patients with PEG and/or polysorbate allergy against COVID-19. METHODS: Twenty-five patients with a history of an allergic reaction to drugs, vaccines and mouth hygiene products containing PEG or polysorbate and sensitization (skin test or in vitro test) or a positive challenge were included. We re-evaluated 19 of 21 patients diagnosed before 2021 and four new patients by skin prick tests (SPT) and Basophil Histamine Release (BaHR) for PEGs, polysorbates and approved COVID-19 vaccines as well as measurement of specific IgE (PEG 2000, 10,000). Patients were offered vaccination based on decision points from the primary diagnosis and re-evaluation. RESULTS: Most common primary elicitors were depot-steroids and laxatives. Most patients had experienced more than one reaction. SPT was superior to BaHR test although many SPTs became negative over time. After careful re-evaluation three patients were successfully vaccinated with the Pfizer/BioNTech vaccine. Three were vaccinated before referral. Eleven were offered the Johnson-Johnson vaccine; four were vaccinated successfully, seven abstained. Six patients could not be vaccinated with PEG or polysorbate containing vaccines. CONCLUSION: Hypersensitivity to excipients in COVID-19 vaccines constitutes a risk to patients with allergy to PEG or polysorbates. After diagnostic evaluation, a safe COVID-19 vaccine could be offered to most patients, the remainders will await new vaccines containing different excipients.