Drug hypersensitivity, in vitro tools, biomarkers, and burden with COVID-19 vaccines.

Hypersensitivity reactions to drugs are increasing worldwide. They display a large degree of variability in the immunological mechanisms involved, which impacts both disease severity and the optimal diagnostic procedure. Therefore, drug hypersensitivity diagnosis relies on both in vitro and in vivo assessments, although most of the methods are not well standardized. Moreover, several biomarkers can be used as valuable parameters for precision medicine that provide information on the endotypes, diagnosis, prognosis, and prediction of drug hypersensitivity development, as well on the identification of therapeutic targets and treatment efficacy monitoring. Furthermore, in the last 2 years, the SARS-CoV-2 (severe acute respiratory syndrome-coronavirus) pandemic has had an important impact on health system, leading us to update approaches on how to manage hypersensitivity reactions to drugs used for its treatment and on COVID-19 (Coronavirus disease) vaccines used for its prevention. This article reviews recent advances in these 3 areas regarding drug hypersensitivity: in vitro tools for drug hypersensitivity diagnosis, recently identified biomarkers that could guide clinical decision making and management of hypersensitivity reactions to drugs and vaccines used for COVID-19.

Simplifying the drug provocation test in non-immediate hypersensitivity reactions to amoxicillin in children: The experience of a tertiary care allergy unit.

BACKGROUND: Mild non-immediate reactions (NIR) to beta-lactams (ßLs) are the most common manifestation of adverse drug reactions in children, and the drug provocation test (DPT) remains the gold standard for diagnosis. However, there are still controversies about the protocol that should be used, especially regarding the administration of doses and the DPT length. OBJECTIVE: This study aimed to evaluate a pediatric population with a history of mild NIR to amoxicillin (AMX) or to amoxicillin-clavulanic acid (AMX/CL) who underwent a diagnostic workup including a DPT with the culprit drug, to understand if a graded DPT or, instead, a single full dose could be the most appropriate way of administration in clinical practice. METHODS: The data of children were retrospectively analyzed for a 5-year period, with demographic and clinical characteristics collected. We reported the allergy workup and the results of the DPT performed with the administration of incremental doses and a prolonged DPT at home for a total of 5 days. RESULTS: Three hundred fifty-four patients were included. Overall, 23/354 (6.5%) DPTs were positive: 11/23 patients showed a reaction after 2-8 h after the last dose on the 1st or 2nd day (1 reacted 30 min after the last dose), 1/23 reacted with urticaria 30 min after the first dose, 11/23 reacted at home on the 5th day of the DPT. CONCLUSION: This paper indirectly suggests that a single therapeutic dose administered on the 1st day of a DPT could be safe in the diagnostic workup of mild NIR to AMX/CL. Moreover, this could be less time-consuming as patients would spend less time in the hospital, also considering the public health restrictions imposed during the COVID-19 pandemic.

Iodinated contrast media shortage: Insights and guidance from two major public hospitals.

Global shortage of iodinated contrast medium (ICM) is the latest health care ripple-effect from the COVID-19 pandemic. Some public hospitals in Australia have less than a week's supply. Strategies are, therefore, urgently needed to conserve ICM for those diagnostic tests and interventions, which are time-critical, and without which patients would suffer death or significant morbidity. A plan is also required to continue providing best possible care to patients in the worst-case scenario of exhausted ICM supplies. This document, by representatives from two major public hospitals, will provide some guidance that is tailored to the Australian context.

Evaluation of chlorhexidine sensitization amongst healthcare workers.

BACKGROUND: Chlorhexidine is an antiseptic widely used in healthcare settings. There are increasing reports of significant hypersensitivity reactions associated with its use. Development of chlorhexidine allergy has been identified as an important occupational risk to healthcare workers (HCWs). AIMS: To evaluate the prevalence of sensitization to chlorhexidine amongst HCWs at a large tertiary hospital to assess the potential allergic safety risks associated with chlorhexidine exposure to staff. METHODS: Sensitization to chlorhexidine was evaluated by measurement of serum-specific immunoglobulin E (IgE) in samples collected from staff assessed after a sharps-injury incident and laboratory staff collected for quality assurance procedures. This test method has been shown to have high sensitivity and specificity in the diagnosis of chlorhexidine allergy. Prevalence of sensitization was additionally evaluated with reference to changes in exposure to chlorhexidine-based hand hygiene products because of infection control procedures and the coronavirus disease 2019 pandemic. RESULTS: A total of 320 samples were examined. The prevalence of positive chlorhexidine-specific IgE was 2%. Prevalence of sensitization in samples collected before and after increased chlorhexidine exposure was 1% and 3%. This did not represent a statistically significant difference. CONCLUSIONS: The prevalence figures for chlorhexidine sensitization in this study are higher than have been estimated previously for similar HCW cohorts. Increased exposure to chlorhexidine-based hand hygiene products was not demonstrated to increase sensitization in this group. Given the risk of severe reactions in sensitized individuals, this study indicates that evaluation of chlorhexidine allergy is important when investigating occupational allergy in HCWs.

Telemedicine in Drug Hypersensitivity.

This review focuses on the current applications of telemedicine for drug hypersensitivity reactions. Telemedicine holds promise as a tool to risk-stratify patients with drug hypersensitivity, for both evaluation of penicillin allergies and severe cutaneous adverse reactions. Although telemedicine may not fully replace in-person assessment owing to the need for testing, challenges, and in-person physical examination or skin biopsy, it may allow for risk stratification whereby some in-person visits may not be necessary. Electronic consults have also emerged along with telemedicine as a tool for drug allergy evaluations.

Promoting ß-lactam utilization through suppression of electronic medical record cross-allergy alerts.

PURPOSE: Current literature surrounding management of patients with reported ß-lactam allergies focuses on allergy delabeling. Standard clinical decision support tools have not been optimized to be compatible with the currently accepted cross-reaction rate of 1% to 2%. This potentially promotes use of non-ß-lactam antibiotics, which are often not first-line therapy and may carry increased risks. The impact of electronic medical record (EMR) clinical decision support tool optimization on utilization of ß-lactam antibiotics in ß-lactam-allergic patients was evaluated. METHODS: A retrospective pre-post ß-lactam cross-allergy EMR alert suppression quality improvement intervention cohort study of ß-lactam-allergic adult inpatients prescribed antibiotics was conducted. Preintervention baseline data were collected for an initial cohort admitted during September 2018. The intervention, in which clinical decision support rules were updated to display ß-lactam cross-sensitivity allergy alerts only for ß-lactam-allergic patients with documentation of organization-defined high-severity reactions of anaphylaxis, hives, and shortness of breath, was implemented August 20, 2019. The postintervention cohort included patients admitted during September 2019. RESULTS: A 91% increase in the percentage of ß-lactam-allergic patients who received a ß-lactam agent at any time during their admission was noted after the intervention (26.6% vs 51%, P < 0.001). Statistically significant decreases in prescribing of alternative antibiotic classes were seen for fluoroquinolones (decrease from 45.3% to 26%, P < 0.001), aminoglycosides (decrease from 9.4% to 2.9%, P = 0.002), and aztreonam (decrease from 30% to 16.7%, P < 0.001). CONCLUSION: EMR ß-lactam cross-allergy alert optimization consistent with current literature significantly improved the utilization of alternative ß-lactam subclasses, mostly through ß-lactam prescribing as initial therapy in ß-lactam-allergic patients.

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.

Allergic reactions against Covid-19 vaccines

Coronavirus Disease 2019 (COVID-19) affected the whole world in a short time. One of the most influential public health initiatives modern medicine has to offer, the vaccine has become even more important as the COVID-19 pandemic continues to worsen worldwide. Many vaccine trials were launched during the COVID-19 pandemic, and these vaccines were widely used around the world, offering realistic hope for ending the pandemic. Allergic reactions to vaccines were reported shortly after their approval. These reactions, in general, are rare, but, in some circumstances, they can be serious. Allergy to vaccines can occur because of either the active vaccine component or vaccine ingredients. The spectrum of the reactions may be just a local hypersensitiviy reaction or may be as severe as an anaphylaxis, which is an acute severe, life-threatening systemic hypersensitive reaction, and it requires quick intervention. If an allergy is suspected, a correct examination followed by algorithms is important for true diagnosis, treatment, and decision regarding revaccination. Patients who experience an allergic reaction with the first dose of covid 19 vaccine should be directed to the allergy-immunologist, and the evaluation of at-risk patients should be individualized. Finally, we should point out that the benefits of current COVID-19 vaccines go far beyond the side effects, and that the vaccine is the most important way to recover from the pandemic.

The value of the basophil activation test in the evaluation of patients reporting allergic reactions to the BNT162b2 mRNA COVID-19 vaccine.

BACKGROUND: mRNA-based COVID-19 vaccines have been reported to induce hypersensitivity reactions (HSR) in a small number of individuals. We aimed to evaluate the real-world incidence of the BNT162b2 mRNA COVID-19 vaccine HSR and to determine the value of the basophil activation test (BAT) in the allergological workup of patients reporting these reactions. METHODS: We prospectively enrolled patients with a clinical history indicative of HSR to the BNT162b2 mRNA COVID-19 vaccine. The allergological workup included skin testing (STs) and BAT with polyethylene glycol (PEG) and the vaccine. In those with negative allergy assessments, the administration of the second dose of the BNT162b2 mRNA COVID-19 vaccine was offered. RESULTS: Seventeen adults were included. Eleven cases (64.7%) tested negative in the allergological workup and tolerated the re-administration of the second dose of the vaccine and considered non-allergic. Six cases (35.3%) were considered allergic and classified into three groups: 2 subjects displayed positive STs and/or BAT to PEG (Group A), two individuals displayed positive BAT to the vaccine (Group B), and in 2 patients with moderate or severe reactions, the culprit was not identified, tested negative to STs and BAT to both PEG and vaccine (Group C). We further evaluated the value of BAT when the results were positive to the vaccine and negative to PEG by performing BAT in controls groups, finding positive BAT results in 50% of controls, all of them recovered from COVID-19 infection. In contrast, BAT was negative in patients who had not suffered from COVID-19 disease. CONCLUSIONS: BAT can be used as a potential diagnostic tool for confirming allergy to PEG excipient but not to the vaccine as a positive result in BAT may indicate a past COVID-19 infection instead of an allergy.

Drug allergy management in the elderly.

PURPOSE OF REVIEW: Drug allergy management has previously not been emphasized in the elderly. However, the geriatric population poses several unique characteristics, challenges for drug allergy testing and considerations in the management. Especially in the era of COVID-19, the elderly population is a vulnerable cohort and reviewing the management during this unprecedented time is both timely and relevant. RECENT FINDINGS: In recent years, larger scale studies focusing on the epidemiology and prevalence trends of drug allergies among older adults has been summarized in this review. Emphasis on anaphylaxis in the older adults has been studied. SUMMARY: There are many implications of these findings. Epidemiological studies are useful in realizing the burden and spectrum of drug allergies on our healthcare system. It has allowed us to identify certain barriers in drug allergy management and develop ways to overcome these challenges through. Lastly, we have proposed an approach to drug allergy management based on previous studies as well as from our perspective and local experience.

Vaccine allergy: evidence to consider for COVID-19 vaccines.

PURPOSE OF REVIEW: Whereas the COVID-19 pandemic has changed our lives worldwide, we hope that vaccination can combat the disease. We propose how to evaluate suspected severe allergic reactions to the vaccines so that as many as possible may be safely vaccinated. RECENT FINDINGS: Rare cases of severe allergic reactions after COVID-19 vaccination have been observed, seemingly at a higher frequency than for other vaccines. Few excipients are likely to have caused these reactions. IgE-mediated reactions to polyethylene glycol (PEG) and its derivatives are the most suspected, albeit hitherto unproven, causes. We suggest to make a diagnosis based on skin tests with PEG and PEG derivatives and that these be considered in relation to the decisions required before the first and the second vaccine dose. A vaccine without these excipients is available, but published data about its side effects are limited. SUMMARY: The underlying immunological mechanisms of the rare severe allergic reactions to the COVID-19 vaccines are poorly understood and need to be clarified. Identifying those who have an undiagnosed allergy to PEG and PEG derivatives is crucial before vaccination, and these substances are found in laxatives, cosmetics and in 30% of all our medications today.

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.