Tezepelumab in patients with allergic and eosinophilic asthma.

Asthma is a heterogeneous disease commonly driven by allergic and/or eosinophilic inflammation, both of which may be present in severe disease. Most approved biologics for severe asthma are indicated for specific phenotypes and target individual downstream type 2 components of the inflammatory cascade. Tezepelumab, a human monoclonal antibody (immunoglobulin G2λ), binds specifically to thymic stromal lymphopoietin (TSLP), an epithelial cytokine that initiates and sustains allergic and eosinophilic inflammation in asthma. By blocking TSLP, tezepelumab has demonstrated efficacy across known asthma phenotypes and acts upstream of all current clinically used biomarkers. In a pooled analysis of the phase 2b PATHWAY (NCT02054130) and phase 3 NAVIGATOR (NCT03347279) studies, compared with placebo, tezepelumab reduced the annualized asthma exacerbation rate over 52 weeks by 62% (95% confidence interval [CI]: 53, 70) in patients with perennial aeroallergen sensitization (allergic asthma); by 71% (95% CI: 62, 78) in patients with a baseline blood eosinophil count ≥300 cells/µL; and by 71% (95% CI: 59, 79) in patients with allergic asthma and a baseline blood eosinophil count ≥300 cells/µL. This review examines the efficacy and mode of action of tezepelumab in patients with allergic asthma, eosinophilic asthma and coexisting allergic and eosinophilic phenotypes.

The Polysorbate containing AstraZeneca COVID-19 vaccine is tolerated by polyethylene glycol (PEG) allergic patients.

BACKGROUND: Polyethylene glycol (PEG) is the excipient found in the mRNA COVID-19 vaccines. We previously demonstrated PEG allergy was a cause of severe anaphylaxis to the Pfizer/BioNTech COVID-19 vaccine. PEG is widely used in many household products, cosmetics and medicines. However PEG allergy is rare, there have been few confirmed cases of PEG allergy. The excipient of potential concern in the AstraZeneca COVID-19 vaccine is polysorbate 80 (PS80). Cross-reactivity between PEG and polysorbate has been suggested, based on their composition and skin-test data. The aim of this study was to determine whether PEG-allergic patients could be vaccinated with the PS80 containing AstraZeneca COVID-19 vaccine. METHOD: Eight patients with PEG allergy were identified by the allergy clinic at Cambridge University Hospital. Patients underwent skin prick testing to PS80 (20%) and to the AstraZeneca COVID-19 vaccine prior to vaccination. RESULTS: All eight patients allergic to PEG tolerated the AstraZeneca COVID-19 vaccine, even in 2 patients where the PS80 skin prick test was positive and 1 with a positive skin prick test to the AstraZeneca COVID-19 vaccine. CONCLUSION: Patients allergic to PEG, previously denied COVID vaccination, may now be safely vaccinated with the PS80 containing AstraZeneca vaccine and need only avoid the PEG-containing mRNA COVID-19 vaccines. This opens up the possibility that these patients will also tolerate other vaccines containing PS80 such as the Janssen/Johnson and Johnson COVID-19 vaccine. Clinical cross-reactivity between PEG and PS80 did not occur in this vaccine setting.

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.

Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial.

BACKGROUND: Patients with eosinophilic nasal polyposis frequently require surgery, and recurrence rates are high. OBJECTIVE: We sought to assess the efficacy and safety of mepolizumab versus placebo for severe bilateral nasal polyposis. METHODS: This randomized, double-blind, placebo-controlled trial recruited patients aged 18 to 70 years with recurrent nasal polyposis requiring surgery. Patients received 750 mg of intravenous mepolizumab or placebo every 4 weeks for a total of 6 doses in addition to daily topical corticosteroid treatment. The primary end point was the number of patients no longer requiring surgery at Week 25 based on a composite end point of endoscopic nasal polyp score and nasal polyposis severity visual analog scale (VAS) score. Secondary end points included change in nasal polyposis severity VAS score, endoscopic nasal polyp score, improvement in individual VAS symptoms (rhinorrhea, mucus in throat, nasal blockage, and sense of smell), patient-reported outcomes, and safety. RESULTS: One hundred five patients received mepolizumab (n = 54) or placebo (n = 51). A significantly greater proportion of patients in the mepolizumab group compared with the placebo group no longer required surgery at Week 25 (16 [30%] vs 5 [10%], respectively; P = .006). There was a significant improvement in nasal polyposis severity VAS score, endoscopic nasal polyp score, all individual VAS symptom scores, and Sino-Nasal Outcome Test patient-reported outcome score in the mepolizumab compared with placebo groups. Mepolizumab's safety profile was comparable with that of placebo. CONCLUSION: In patients with recurrent nasal polyposis receiving topical corticosteroids who required surgery, mepolizumab treatment led to a greater reduction in the need for surgery and a greater improvement in symptoms than placebo.

An imperfect "PAST" Lessons learned from the National Review of Asthma Deaths (NRAD) UK.

Asthma deaths are a barometer of the quality of asthma care. The principal care for patients with severe asthma is often a joint partnership between primary and secondary services. Communication between the two services determines the effectiveness of treatment. Undertaking an audit on asthma in either primary or separately in secondary care is a relatively straightforward process. However, when the audit spans both primary and secondary care in a country as large as the United Kingdom which is further sub-divided into the separate healthcare systems of England, Wales, Scotland, and Northern Island, then the audit becomes considerably more challenging. The National Review of Asthma Deaths (NRAD) reported in May 2014 was a confidential enquiry tasked with identifying circumstances surrounding asthma deaths across the whole of the UK, in order to ascertain avoidable factors and make recommendations to improve care and reduce future asthma deaths (Why asthma still kills: the National Review of Asthma Deaths (NRAD) Confidential Enquiry report, 2014, http://www.rcplondon.ac.uk/sites/default/files/why-asthma-still-kills-full-report.pdf ). The idea for NRAD arose from a longstanding East of England confidential enquiry started in 1988 by Dr Brian Harrison and then handed onto me in 2001 until funding for the national review of asthma deaths was secured in 2010.

The incidence and features of systemic reactions to skin prick tests.

BACKGROUND: Skin prick testing (SPT) has been regarded as a safe procedure with few systemic reactions. OBJECTIVE: To evaluate the rate of systemic reactions and their associations after SPT in the largest population to date. METHODS: In this study reactions were recorded prospectively in a specialist UK allergy clinic for 6 years (2007-2013). An estimated 31,000 patients underwent SPT. RESULTS: Twenty-four patients (age range 7 months to 56 years, mean 23.5 years, 17 female patients, 12 with asthma) had systemic reactions. The rate of systemic reactions to SPT was 0.077%. The likely allergens causing the reaction were foods (18; peanut, 7; walnut, 1; Brazil nut, 2; pistachio, 1; lupin, 1; cow's milk, 2; shrimp, 1; spinach, 1; legume, 1; soy, 1), aeroallergens (4; rabbit, 1; rat, 1; ragwort, 1; grass pollen, 1), wasp venom (1), and Tazocin (1). The causative SPT wheal was larger than 8 mm in 75%. The reaction to Tazocin was severe, with anaphylaxis occurring minutes after SPT. Reactions were treated immediately in the clinic and did not require further medical care. CONCLUSION: In this largest single-center study, the rate of systemic reactions after SPT was 77 per 100,000 patients. It is the first study to identify foods as a common and important cause (75%), with nuts posing the highest risk. This study reports the first systemic reaction to venom SPT and the first anaphylactic reaction after drug SPT. There was an association with a history of severe reactions and large skin test reaction. There are risks, albeit small, when undertaking SPT.

Impact of penicillin allergy labels on surgical site infections in a large UK cohort of gastrointestinal surgery patients.

Objectives: Studies in the USA, Canada and France have reported higher surgical site infection (SSI) risk in patients with a penicillin allergy label (PAL). Here, we investigate the association between PALs and SSI in the UK, a country with distinct epidemiology of infecting pathogens and range of antimicrobial regimens in routine use. Methods: Electronic health records and national SSI surveillance data were collated for a retrospective cohort of gastrointestinal surgery patients at Cambridge University Hospitals NHS Foundation Trust from 1 January 2015 to 31 December 2021. Univariable and multivariable logistic regression were used to examine the effects of PALs and the use of non-ß-lactam-based prophylaxis on likelihood of SSI, 30 day post-operative mortality, 7 day post-operative acute kidney injury and 60 day post-operative infection/colonization with antimicrobial-resistant bacteria or Clostridioides difficile. Results: Our data comprised 3644 patients and 4085 operations; 461 were undertaken in the presence of PALs (11.3%). SSI was detected after 435/4085 (10.7%) operations. Neither the presence of PALs, nor the use of non-ß-lactam-based prophylaxis were found to be associated with SSI: adjusted OR (aOR) 0.90 (95% CI 0.65-1.25) and 1.20 (0.88-1.62), respectively. PALs were independently associated with increased odds of newly identified MRSA infection/colonization in the 60 days after surgery: aOR 2.71 (95% CI 1.13-6.49). Negative association was observed for newly identified infection/colonization with third-generation cephalosporin-resistant Gram-negative bacteria: aOR 0.38 (95% CI 0.16-0.89). Conclusions: No evidence was found for an association between PALs and the likelihood of SSI in this large UK cohort, suggesting significant international variation in the impact of PALs on surgical patients.

Characterizing Antibiotic Allergy Labels in a Large UK Hospital Population to Inform Antimicrobial Stewardship and Delabeling Assessment Strategy.

BACKGROUND: Antibiotic allergy labels are important barriers to treatment and antimicrobial stewardship, but their prevalence in UK hospitals is poorly described. OBJECTIVE: To ascertain the prevalence and characteristics of antibiotic allergy labels in a large UK hospital setting and estimate the proportion of penicillin allergy labels for which point-of-care (POC) delabeling assessment would be appropriate. METHODS: Electronic health records data were analyzed from all patients treated at Cambridge University Hospitals NHS Foundation Trust in 2019. Validated POC delabeling risk stratification criteria were retrospectively applied to penicillin allergy labels. RESULTS: Recorded reactions to antibiotics were present in 11.8% of all patients (32,148 of 273,216), 16.3% of inpatients (13,874 of 85,230), and 9.7% of outpatients (18,274 of 187,986). Penicillins were the commonest reaction precipitant described (9.0% of patients; 24,646 of 273,216), followed by sulfonamides/trimethoprim (1.4%; 3869 of 273,216) and macrolides/lincosamides (1.3%; 3644 of 273,216). A total of 3.9% of inpatients had recorded reactions to >1 antibiotic class (3348 of 85,230). Cutaneous manifestations were the most commonly described reaction features (40.7% of labels; 15,821 of 38,902). Of 15,949 labels describing probable or possible penicillin "allergy" with sufficient detail to allow for the retrospective assessment of POC delabeling suitability, 1702 were deemed suitable for removal or downgrading of the label to "intolerance" without further investigation (10.7%), 11,887 were appropriate for POC assessment using an oral penicillin challenge (OPC) or OPC with prior bedside skin testing (74.5%), and 2360 were identified as unsuitable for any form of POC assessment (14.8%). CONCLUSIONS: Antibiotic allergy labels are highly prevalent in a UK hospital setting. A large proportion of penicillin allergy labels may be suitable for POC delabeling assessment.

Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients.

BACKGROUND: Divergence between deterioration to life-threatening COVID-19 or clinical improvement occurs for most within the first 14 days of symptoms. Life-threatening COVID-19 shares clinical similarities with Macrophage Activation Syndrome, which can be driven by elevated Free Interleukin-18 (IL-18) due to failure of negative-feedback release of IL-18 binding protein (IL-18bp). We, therefore, designed a prospective, longitudinal cohort study to examine IL-18 negative-feedback control in relation to COVID-19 severity and mortality from symptom day 15 onwards. METHODS: 662 blood samples, matched to time from symptom onset, from 206 COVID-19 patients were analysed by enzyme-linked immunosorbent assay for IL-18 and IL-18bp, enabling calculation of free IL-18 (fIL-18) using the updated dissociation constant (Kd) of 0.05 nmol. Adjusted multivariate regression analysis was used to assess the relationship between highest fIL-18 and outcome measures of COVID-19 severity and mortality. Re-calculated fIL-18 values from a previously studied healthy cohort are also presented. RESULTS: Range of fIL-18 in COVID-19 cohort was 10.05-1157.7 pg/ml. Up to symptom day 14, mean fIL-18 levels increased in all patients. Levels in survivors declined thereafter, but remained elevated in non-survivors. Adjusted regression analysis from symptom day 15 onwards showed a 100 mmHg decrease in PaO2/FiO2 (primary outcome) for each 37.7 pg/ml increase in highest fIL-18 (p < 0.03). Per 50 pg/ml increase in highest fIL-18, adjusted logistic regression gave an odds-ratio (OR) for crude 60-day mortality of 1.41 (1.1-2.0) (p < 0.03), and an OR for death with hypoxaemic respiratory failure of 1.90 [1.3-3.1] (p < 0.01). Highest fIL-18 was associated also with organ failure in patients with hypoxaemic respiratory failure, with an increase of 63.67 pg/ml for every additional organ supported (p < 0.01). CONCLUSIONS: Elevated free IL-18 levels from symptom day 15 onwards are associated with COVID-19 severity and mortality. ISRCTN: #13450549; registration date: 30/12/2020.

Identifying and Managing Those at Risk for Vaccine-Related Allergy and Anaphylaxis.

Immediate hypersensitivity reactions to vaccines, the most severe of which is anaphylaxis, are uncommon events occurring in fewer than 1 in a million doses administered. These reactions are infrequently immunoglobulin E-mediated. Because they are unlikely to recur, a reaction to a single dose of a vaccine is rarely a contraindication to redosing. This narrative review article contextualizes the recent knowledge we have gained from the coronavirus 2019 (COVID-19) pandemic rollout of the new mRNA platform with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines within the much broader context of what is known about immediate reactions to other vaccinations of routine and global importance. We focus on what is known about evidence-based approaches to diagnosis and management and what is new in our understanding of mechanisms of immediate vaccine reactions. Specifically, we review the epidemiology of immediate hypersensitivity vaccine reactions, differential diagnosis for immune-mediated and nonimmune reaction clinical phenotypes, including how to recognize immunization stress-related responses. In addition, we highlight what is known about mechanisms and review the rare but important contribution of excipient allergies and specifically when to consider testing for them as well as other key features that contribute to safe evaluation and management.

Anaphylaxis: current state of knowledge for the modern physician.

Anaphylaxis is a severe, potentially fatal, hypersensitivity reaction of rapid onset. It may trigger life-threatening cardiopulmonary compromise, often with skin and mucosal changes such as urticaria and angioedema. The prevalence of anaphylaxis is increasing and the number of cases of fatal anaphylaxis appears to be rising. Food, insect stings, and drugs are the most common triggers. Novel triggers are increasingly seen and include delayed anaphylaxis to red meat, food-dependent exercise-induced reactions and anaphylaxis to monoclonal antibodies. Anaphylaxis is usually IgE mediated, but other mechanisms also play a role for example direct mast cells activation. Differential diagnosis is discussed including asthma, syncope and shock; excessive endogenous histamine, food related syndromes, and some rare diagnoses. Intramuscular epinephrine is first line treatment. The role of other drugs is reviewed. Timed and serial serum tryptase measurements help to confirm the diagnosis. Long-term management is necessary to minimise the risk of recurrence and includes identification of the trigger(s), management of risk factors, education on avoidance and a formalised treatment plan with an epinephrine auto-injector if appropriate. Every patient who has experienced anaphylaxis should be referred to an allergy clinic for appropriate management. This is endorsed by many national guidelines (eg, UK NICE). Anaphylaxis is often misdiagnosed or miscoded as, for example, asthma or food allergy. Most doctors will encounter a patient with anaphylaxis in their career and should to be familiar with the clinical features, management and mechanisms of this potentially fatal condition.

Risk factors for childhood asthma deaths from the UK Eastern Region Confidential Enquiry 2001-2006.

BACKGROUND: Confidential enquiries into asthma deaths can identify inadequacies in medical management and factors which contribute to patients' death. AIMS: To identify risk factors for paediatric asthma deaths over a 6-year period. METHODS: Observational case-series study of paediatric asthma deaths between 2001-2006 in the UK Eastern Region. Hospital, primary care and post-mortem data were obtained for every child (≤17 yrs) with asthma recorded on the death certificate, and a detailed questionnaire was completed. Information was obtained on asthma severity, medications, hospital admissions, GP and hospital follow-up, adherence, psychosocial / behavioural factors, allergies, details of the terminal attack and precipitating factors. RESULTS: 20 children (10 male; 8-17 yrs; median: 11.5 yrs) died of asthma between 2001-2006. 9/20 had mild to moderate asthma (BTS/ SIGN criteria), 10/20 had severe asthma and 1 child was not known to have asthma. 13/20 were clinically atopic. Only 3 had undergone allergy assessment. 10/20 died between June and August. 12/20 children had adverse psychosocial and behavioural factors. 7/20 children were on non-combination long-acting ß2-agonist (LABA) treatment without inhaled corticosteroids (ICS). CONCLUSIONS: Almost half the deaths occurred in children with mild/moderate asthma. We recommend that allergic factors and seasonal allergy should be identified early, non-combination LABAs avoided, and speculate that overuse of short-acting ß2-agonists (SABAs) may indicate non-adherence with ICS. Asthma deaths in children can be avoided if risk factors are identified early.

Anaphylaxis to Excipients in Current Clinical Practice: Evaluation and Management.

Excipients are the inactive ingredients in a drug or product that help to stabilize, preserve, or enhance the pharmacokinetics and bioavailability of the active ingredients. Excipient allergy is rare and hence often missed or misdiagnosed due to lack of awareness of the need to carefully review all drug ingredients. For the patient, excipient allergy can be frightening and potentially disruptive to health care delivery. This narrative review provides a clinically oriented, international, collaborative perspective on excipient allergy testing, management of future health care safety, limitations in our testing modalities, and barriers to optimal care.