Prophylaxis in hereditary angioedema: a United Kingdom Delphi consensus.

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.

BSACI guideline for the set-up of penicillin allergy de-labelling services by non-allergists working in a hospital setting.

The Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI) and a committee of experts and key stakeholders have developed this guideline for the evaluation and testing of patients with an unsubstantiated label of penicillin allergy. The guideline is intended for UK clinicians who are not trained in allergy or immunology, but who wish to develop a penicillin allergy de-labelling service for their patients. It is intended to supplement the BSACI 2015 guideline "Management of allergy to penicillin and other beta-lactams" and therefore does not detail the epidemiology or aetiology of penicillin allergy, as this is covered extensively in the 2015 guideline (1). The guideline is intended for use only in patients with a label of penicillin allergy and does not apply to other beta-lactam allergies. The recommendations include a checklist to identify patients at low risk of allergy and a framework for the conduct of drug provocation testing by non-allergists. There are separate sections for adults and paediatrics within the guideline, in recognition of the common differences in reported allergy history and likelihood of true allergy.

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.

Impact of high baseline Aspergillus-specific IgG levels on weight and quality-of-life outcomes of patients with chronic pulmonary aspergillosis.

This study aimed to evaluate the impact of quantitative baseline Aspergillus-specific immunoglobulin G (IgG) serum levels on weight changes of patients with chronic pulmonary aspergillosis (CPA) under antifungal treatment. We retrospectively reviewed data of patients diagnosed with CPA between April 2015 and March 2018 at the National Aspergillosis Centre (Manchester, UK). All patients were on continued antifungal treatment for 12 months. Data on Aspergillus-specific IgG levels, St George's quality of life (SGQoL) variables and weight at baseline, 6 months and 12 months were extracted. We defined a high serum Aspergillus-specific IgG as ≥ 200 mg/l (Group A) and low level < 200 mg/l (Group B). Forty-nine patients (37 male; 12 female), median age 65 years (range: 29-86) were studied. Overall, 33% (n = 16) of the patients were in Group A. The baseline characteristics between the two groups were similar. The median Charlson comorbidity index was 4 (range: 0-5) and 3 (range: 0-9) for Group A and Group B, respectively (P = .543). There was a sustained decline in median Aspergillus IgG levels from baseline, through 6 month to 12 months of continues therapy from 170 (range: 20-1110) to 121 (range: 20-1126), and finally 107 (15-937) mg/l, respectively (P < .001). Group A patients gained more weight at 6 months (9/15 [60%] vs. 7/33 [21%], P = .012) and at 12 months of treatment (9/15 [60%] vs. 7/33 [22%]), and more patients in Group B lost weight ((13/33 [41%] vs. 1/15 [7%]), P = .015). However, there was no difference in QoL outcomes across groups at 6 (P = .3) and 12 (P = .7) months. A very high Aspergillus IgG may confer a higher likelihood of weight gain as a key, objective marker of clinical response, if patients can tolerate 12 months of antifungal therapy.

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.

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.

Suspected perioperative allergic reactions: nomenclature and terminology.

Standardising nomenclature facilitates diagnostic and therapeutic algorithms, improves comparisons of data in scientific research and reduces misunderstanding. Here, we propose a nomenclature for suspected perioperative allergic reactions.

The use of drug provocation testing in the investigation of suspected immediate perioperative allergic reactions: current status.

Suspected perioperative allergic reactions are often severe. To avoid potentially life-threatening re-exposure to the culprit drug, establishing a firm diagnosis and identifying the culprit is crucial. Drug provocation tests are considered the gold standard in drug allergy investigation but have not been recommended in the investigation of perioperative allergy, mainly because of the pharmacological effects of drugs such as induction agents and neuromuscular blocking agents. Some specialised centres have reported benefits of provocation testing in perioperative allergy investigation, but the literature on the subject is limited. Here we provide a status update on the use of drug provocation testing in perioperative allergy, including its use in specific drug groups. This review is based on a literature search and experiences of the authors comprising anaesthesiologists and allergists with experience in perioperative allergy investigation. In addition, 19 participating centres in the International Suspected Perioperative Allergic Reaction Group were surveyed on the use of provocation testing in perioperative allergy investigation. A response was received from 13 centres in eight European countries, New Zealand, and the USA. Also, 21 centres from the Australian and New Zealand Anaesthetic Allergy Group were surveyed. Two centres performed provocation routinely and seven centres performed no provocations at all. Nearly half of the centres reported performing provocations with induction agents and neuromuscular blocking agents. Drug provocation testing is being used in perioperative allergy investigation in specialised centres, but collaborations between relevant specialties and multicentre studies are necessary to determine indications and establish common testing protocols.

Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations.

Suspected perioperative allergic reactions are rare but can be life-threatening. The diagnosis is difficult to make in the perioperative setting, but prompt recognition and correct treatment is necessary to ensure a good outcome. A group of 26 international experts in perioperative allergy (anaesthesiologists, allergists, and immunologists) contributed to a modified Delphi consensus process, which covered areas such as differential diagnosis, management during and after anaphylaxis, allergy investigations, and plans for a subsequent anaesthetic. They were asked to rank the appropriateness of statements related to the immediate management of suspected perioperative allergic reactions. Statements were selected to represent areas where there is a lack of consensus in existing guidelines, such as dosing of epinephrine and fluids, the management of impending cardiac arrest, and reactions refractory to standard treatment. The results of the modified Delphi consensus process have been included in the recommendations on the management of suspected perioperative allergic reactions. This paper provides anaesthetists with an overview of relevant knowledge on the immediate and postoperative management of suspected perioperative allergic reactions based on current literature and expert opinion. In addition, it provides practical advice and recommendations in areas where consensus has been lacking in existing guidelines.

Comparative epidemiology of suspected perioperative hypersensitivity reactions.

Suspected perioperative hypersensitivity reactions are rare but contribute significantly to the morbidity and mortality of surgical procedures. Recent publications have highlighted the differences between countries concerning the respective risk of different drugs, and changes in patterns of causal agents and the emergence of new allergens. This review summarises recent information on the epidemiology of perioperative hypersensitivity reactions, with specific consideration of differences between geographic areas for the most frequently involved offending agents.

Prescribing Immunoglobulin Replacement Therapy for Patients with Non-classical and Secondary Antibody Deficiency: an Analysis of the Practice of Clinical Immunologists in the UK and Republic of Ireland.

BACKGROUND: Immunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled. METHODS: Under the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers. RESULTS: In order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 µg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months. CONCLUSIONS: There was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination.

Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012.

BACKGROUND: The incidence of anaphylaxis might be increasing. Data for fatal anaphylaxis are limited because of the rarity of this outcome. OBJECTIVE: We sought to document trends in anaphylaxis admissions and fatalities by age, sex, and cause in England and Wales over a 20-year period. METHODS: We extracted data from national databases that record hospital admissions and fatalities caused by anaphylaxis in England and Wales (1992-2012) and crosschecked fatalities against a prospective fatal anaphylaxis registry. We examined time trends and age distribution for fatal anaphylaxis caused by food, drugs, and insect stings. RESULTS: Hospital admissions from all-cause anaphylaxis increased by 615% over the time period studied, but annual fatality rates remained stable at 0.047 cases (95% CI, 0.042-0.052 cases) per 100,000 population. Admission and fatality rates for drug- and insect sting-induced anaphylaxis were highest in the group aged 60 years and older. In contrast, admissions because of food-triggered anaphylaxis were most common in young people, with a marked peak in the incidence of fatal food reactions during the second and third decades of life. These findings are not explained by age-related differences in rates of hospitalization. CONCLUSIONS: Hospitalizations for anaphylaxis increased between 1992 and 2012, but the incidence of fatal anaphylaxis did not. This might be due to increasing awareness of the diagnosis, shifting patterns of behavior in patients and health care providers, or both. The age distribution of fatal anaphylaxis varies significantly according to the nature of the eliciting agent, which suggests a specific vulnerability to severe outcomes from food-induced allergic reactions in the second and third decades.

Addressing the Challenges of Penicillin Allergy Delabeling With Electronic Health Records and Mobile Applications.

Allergy labels are common, often incorrect, and potentially harmful. There are many opportunities for clinical decision support (CDS) tools integrated in the electronic health record (EHR) and mobile apps to address the challenges with drug allergy management, including penicillin allergy delabeling (PADL). Effective delabeling solutions must consider multidisciplinary clinical workflow and multistep processes, including documentation, assessment, plan (eg, allergy testing and referral), record update, drug allergy alert management, and allergy reconciliation over time. Developing a systematic infrastructure to manage allergies across the EHR is critical to improve the accuracy and completeness of a patient's allergy and avoid inadvertently relabeling. Improving the appropriateness and relevancy of drug allergy alerts is important to reduce alert fatigue. Using alerts to guide clinicians on appropriate antibiotic use may reduce unnecessary ß-lactam avoidance. To date, EHR CDS tools have facilitated non-allergists to provide PADL at the point of care. A mobile app was shown to support PADL and provide specialist support and education. Future research is needed to standardize, integrate, and evaluate innovative CDS tools in the EHR to demonstrate patient safety and clinical utility and facilitate wider adoption.

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom.

BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.

Impaired maintenance of naturally acquired T-cell memory to the meningococcus in patients with B-cell immunodeficiency.

The importance of T cells in the generation of antigen-specific B-cell immunity has been extensively described, but the role B cells play in shaping T-cell memory is uncertain. In healthy controls, exposure to Neisseria meningitidis in the upper respiratory tract is associated with the generation of memory T cells in the mucosal and systemic compartments. However, we demonstrate that in B cell-deficient subjects with X-linked agammaglobulinemia (XLA), naturally acquired T-cell memory responses to meningococcal antigens are reduced compared with healthy control patients. This difference is not found in T-cell memory to an obligate respiratory pathogen, influenza virus. Accordingly, we show that meningococcal antigens up-regulate major histocompatibility complex (MHC) class II, CD40, CD86/80 expression on mucosal and systemic associated B cells and that antigen presentation stimulates T-cell proliferation. A similar reduction in N meningitidis but not influenza antigen-specific T-cell memory was observed in subjects with X-linked hyper IgM syndrome (X-HIM), implicating the interaction of CD40-CD40L in this process. Together, these data implicate B cells in the induction and maintenance of T-cell memory to mucosal colonizing bacteria such as N meningitidis and highlight the importance of B cells beyond antibody production but as a target for immune reconstitution.

Paired sensitivity analysis of four SARS-CoV-2 serological immunoassays in a longitudinal cohort of convalescent hospital staff.

BACKGROUND: SARS-CoV-2 serological testing has seen extensive academic and clinical use from investigating correlates of immunity to seroprevalence, convalescent plasma and vaccine trials. Interpretation of these studies will depend on robust validation of the longitudinal sensitivities of these assays, especially in the context of mild disease which makes up the majority of the Coronavirus Disease 2019 (COVID-19) caseload. METHODS: Hospital staff (n = 94) returning to work following polymerase chain reaction confirmed COVID-19 were offered antibody testing to assist with laboratory verification. Initial specimens were collected at median 29 days post-symptom onset and run on the Roche, Abbott, Siemens and DiaSorin platforms. Re-sampling occurred at median 142 days from a subset of the initial cohort (n = 62) that had volunteered to provide further serum samples to assist in longitudinal sensitivity analysis. Samples that were not run across all four platforms were excluded from analysis. RESULTS: Comparative sensitivity analysis was conducted on 89/94 of the initial specimens and 55/62 of the repeat specimens. Sensitivity at initial sampling ranged from 78 to 87% across platforms. At re-sampling, sensitivities were: 100% (Roche), 45% (Abbott), 100% (Siemens), and 80% (DiaSorin). Paired analysis using the longitudinal cohort (n = 55) demonstrated stable or increasing median assay values on three platforms, with a clear reduction seen only on the Abbott platform (4.78 to 1.34) with corresponding sensitivity drop-off (81.8% to 45.4%). CONCLUSION: The Abbott assay demonstrated sensitivity drop-off and decrease in median assay signal below detection threshold at four to five months. This has implications on the interpretation and design of future studies.

Development and Validation of a Mobile Clinical Decision Support Tool for the Diagnosis of Drug Allergy in Adults: The Drug Allergy App.

BACKGROUND: Penicillin allergy overdiagnosis has been associated with inappropriate antibiotic prescribing, increased antimicrobial resistance, worse clinical outcomes, and increased health care costs. OBJECTIVE: To develop and validate a questionnaire-based algorithm built in a mobile application to support clinicians in collecting accurate history of previous reactions and diagnosing drug allergy appropriately. METHODS: A survey was completed by 164 medical and nonmedical prescribers to understand barriers to best practice. Based on the survey recommendations, we created a 10-item questionnaire-based algorithm to allow classification of drug allergy history in line with the National Institute for Health and Care Excellence guidelines on drug allergy. The algorithm was incorporated into a mobile application and retrospectively validated using anonymized clinical databases at regional immunology and dermatology centers in Manchester, United Kingdom. RESULTS: A total of 55.2% of prescribers (95% confidence interval, 47% to 63.4%) thought it impossible to draw a firm conclusion based on history alone and 59.4% (95% CI, 51.4% to 67.5%) believed that regardless of the details of the penicillin allergy history, they would avoid all ß-lactams. A drug allergy mobile application was developed and retrospectively validated, which revealed a low risk for misclassification of outcomes compared with reference standard drug allergy investigations in the allergy and dermatology clinics. CONCLUSIONS: Perceived lack of time and preparedness to collect an accurate drug allergy history appear to be important barriers to appropriate antimicrobial prescribing. The Drug Allergy App may represent a useful clinical decision support tool to diagnose drug allergy correctly and support appropriate antibiotic prescribing.