Advances in the Understanding of Drug Hypersensitivity: 2012 Through 2022.

Over the last decade there have been key advances in understanding mechanisms, risk, and consequences of both true immunological drug hypersensitivity and unverified drug allergy labels that have changed clinical practice. This has been facilitated by the widespread adoption of electronic health records (EHRs). The vast majority of EHR drug allergy labels are unverified and cause significant morbidity from unnecessary avoidance of optimal drug therapy. There has also been significant movement in our understanding of mechanisms of drug hypersensitivity that, in addition to advancing our understanding of the pathogenesis of immediate and delayed reactions, have guided preventive efforts, diagnostic procedures, and clinical management. More widespread adoption, including scale-up of "allergy" delabeling and appropriate management, specifically for antibiotics, opiates, radiocontrast, chemotherapeutics, biologics, and nonsteroidal anti-inflammatory medications, will be necessary to improve patient outcomes over the next decade. This will require further engagement and collaboration between primary care health care providers, allergists, and other specialists.

The Evolution of Our Understanding of Penicillin Allergy: 1942-2022.

This article reviews our evolving understanding of penicillin hypersensitivity at the 80th anniversary of penicillin's clinical introduction. Penicillin breakdown products covalently bond to serum proteins, leading to classic drug hypersensitivity. Penicillin remains the most frequently reported drug "allergy." Adverse reactions were presumed, in retrospect incorrectly, to implicate a risk for anaphylaxis, and therefore skin testing for IgE became the focus. Skin test positivity may wane over time. This insight has led to the radical conclusion that penicillin hypersensitivity may not be "forever." Atopic background, other drug allergies, family history, gender, and race are apparently not risk factors for penicillin hypersensitivity. Confirmed penicillin hypersensitivity has declined since the 1960s, potentially due to "cleaner" penicillin products and lower dose oral, instead of parenteral, use. Avoiding penicillins, without evaluation, caused unanticipated problems that have been appreciated only recently including longer hospital stays, increased cost of care, suboptimal outcomes from serious infections, and greater toxicities and costs with alternative antibiotics. There are personal and public health advantages with broadly implemented penicillin allergy delabeling based on a reaction history-based risk assessment. Limited skin testing followed by an oral challenge, if negative, for higher-risk histories, and direct oral challenges in lower-risk individuals are currently the reference standard tests to confirm current tolerance.

Allergy Electronic Health Record Documentation: A 2022 Work Group Report of the AAAAI Adverse Reactions to Drugs, Biologicals, and Latex Committee.

The allergy section of the electronic health record (EHR) is ideally reviewed and updated by health care workers during routine outpatient visits, emergency room visits, inpatient hospitalizations, and surgical procedures. This EHR section has the potential to help proactively and comprehensively avoid exposures to drugs, contact irritants, foods, and other agents for which, based on an individual's medical history and/or genetics, there is increased risk for adverse outcomes with future exposures. Because clinical decisions are made and clinical decision support is triggered based on allergy details from the EHR, the allergy module needs to provide meaningful, accurate, timely, and comprehensive allergy information. Although the allergy section of the EHR must meet these requirements to guide appropriate clinical decisions and treatment plans, current EHR allergy modules have not achieved this standard. We urge EHR vendors to collaborate with allergists to optimize and modernize allergy documentation. A work group within the Adverse Reactions to Drugs, Biologicals, and Latex Committee of the American Academy of Allergy, Asthma & Immunology was formed to create recommendations for allergy documentation in the EHR. Whereas it is recognized that the term "allergy" is often used incorrectly because most adverse drug reactions (ADRs) are not true immune-mediated hypersensitivity reactions, "allergy" in this article includes allergies and hypersensitivities as well as side effects and intolerances. Our primary objective is to provide guidance for the current state of allergy documentation in the EHR. This guidance includes clarification of the definition of specific ADR types, reconciliation of confirmed ADRs, and removal of disproved or erroneous ADRs. This document includes a proposal for the creation, education, and implementation of a drug allergy labeling system that may allow for more accurate EHR documentation for improved patient safety.

Population-Based Incidence, Severity, and Risk Factors Associated with Treated Acute-Onset COVID-19 mRNA Vaccination-Associated Hypersensitivity Reactions.

BACKGROUND: COVID-19 mRNA vaccination-associated acute-onset hypersensitivity reactions have caused anxiety and may be contributing to vaccine hesitancy. OBJECTIVE: To determine the incidence, severity, and risk factors for treated acute-onset COVID-19 mRNA vaccination-associated hypersensitivity reactions in a well-characterized population. METHODS: All Kaiser Permanente Southern California (KPSC) members who received COVID-19 mRNA vaccinations between December 15, 2020, and March 11, 2021, at a KPSC facility were identified and characterized, along with all treated acute-onset vaccination-associated hypersensitivity events. RESULTS: We identified 391,123 unique vaccine recipients (59.18% female, age 64.19 ± 17.86 years); 215,156 received 2 doses (53.54% Moderna), 157,615 only a first dose (50.13% Moderna) (1961 [1.46%] >2 weeks late getting a second dose), and 18,352 (74.43% Moderna) only a second dose. Only 104 (0.028%) (85.58% female, age 53.18 ± 15.96 years) had treated first dose events, 68 (0.030%) Moderna. Only 32 (0.014%) (93.75% female, age 57.28 ± 17.09 years) had treated second dose events, 21 (0.016%) Moderna. Only 2 (0.00033%) vaccinations resulted in anaphylaxis. Only 27 (20.77%) of those with treated first dose reactions failed to get a second dose. Only 6 of 77 (7.8%) with first dose reactions also had second dose reactions. Individuals with treated events were more likely to be female (P < .0001), younger (P < .0001), and had more pre-existing drug "allergies" (2.11 ± 2.12 vs 1.02 ± 1.41 [P < .0001] for average recipients). CONCLUSIONS: Treated acute-onset hypersensitivity events were mostly benign, more common with first COVID-19 mRNA vaccine doses, more likely to occur in younger females with typical risk factors associated with multiple drug intolerance syndrome, and very unlikely to be primarily immunologically mediated.

Population-Based Incidence of New Ampicillin, Cephalexin, Cefaclor, and Sulfonamide Antibiotic "Allergies" in Exposed Individuals with and without Preexisting Ampicillin, Cephalexin, or Cefaclor "Allergies".

BACKGROUND: There is a theoretical concern, unconfirmed by population-based challenge data, that clinically significant, immunologically mediated hypersensitivity occurs among ß-lactams sharing side chains. OBJECTIVE: To determine the population-based allergy incidence associated with the use of ß-lactams sharing exact R1 side chains (ampicillin, cephalexin, and cefaclor [ACC]), with or without a current ACC allergy or a sulfonamide antibiotic allergy for comparison. METHODS: All courses of ACC and trimethoprim-sulfamethoxazole used by any Kaiser Permanente California members in 2017 and 2018, with follow-up through January 2019, were identified along with their preexisting antibiotic allergy status and all new antibiotic-specific allergies reported within 30 days of course initiation. RESULTS: A total of 1,167,713 courses of ACC were administered to individuals with no sulfonamide antibiotic or ACC allergy and 4,771 new ACC allergies (0.41%) were reported. Moreover, 130,032 courses of ACC were administered to individuals with a sulfonamide antibiotic allergy and no ACC allergy, and 904 new ACC allergies (0.70%) were reported. There were 5,958 courses of ACC administered to individuals with an ACC allergy, 2,341 who also had sulfonamide antibiotic allergy, and 52 new ACC allergies (0.87%) were reported. CONCLUSIONS: The incidence of new ACC allergy reports is minimally and non-specifically increased among individuals with a preexisting ACC or sulfonamide antibiotic allergy compared to the baseline incidence in the population. This argues against clinically significant, immunologically mediated cross-reactivity among ß-lactams sharing exact side chains in individuals with preexisting but unconfirmed ß-lactam allergy. Any previously reported, even unrelated antibiotic allergy appears to be a risk factor for reporting a new antibiotic allergy.

Why Was There Ever a Warning Not to Use Cephalosporins in the Setting of a Penicillin "Allergy"?

It is now well-established that avoiding ß-lactam antibiotics, when they are the drugs of choice, results in significantly worse long-term global outcomes for patients. Much of this avoidable morbidity has been caused by widespread warnings in electronic health care record systems not to use cephalosporins in the setting of penicillin allergy. High rates, up to 1000-fold higher than now seen, of immunologically mediated reactions were associated with early impure penicillin preparations. This instilled a rational fear of ß-lactam-associated anaphylaxis in generations of physicians. In the late 1970s, several editorial comments regarding a potential increased risk to patients given cephalosporins who had a history of a penicillin allergy resulted in the warning that became imbedded in the culture of medicine. Over the past 40 years, compelling data have been developed that refute this warning and showed that the risks of avoiding cephalosporins outweighed the benefits. In late 2017, Kaiser Permanente Southern California completely removed all warnings not to use cephalosporins in the setting of a penicillin allergy. The results have recently been published in JAMA Network Open. This Rostrum article provides some of the backstory on the establishment and removal of this warning for physicians who trained over the past 30 years.

Association Between Removal of a Warning Against Cephalosporin Use in Patients With Penicillin Allergy and Antibiotic Prescribing.

Importance: Electronic health records (EHRs) often include default alerts that can influence physician selection of antibiotics, which in turn may be associated with a suboptimal choice of agents and increased antibiotic resistance. Objective: To examine whether removal of a default alert in the EHR to avoid cephalosporin use in patients with penicillin allergies is associated with changes in cephalosporin dispensing or administration in these patients. Design, Setting, and Participants: This retrospective cohort study of a natural experiment included data on patients who had received antibiotic treatment in the hospital or outpatient setting in 2 regions of a large, integrated health system in California from January 1, 2017, to December 31, 2018. Of 4 398 792 patients, 4 206 480 met the eligibility criteria: enrollment in the health system during antibiotic use, availability of complete demographic data, and use of antibiotics outside of the washout period. Interventions or Exposures: Oral or parenteral antibiotics dispensed or administered after removal of an EHR alert to avoid cephalosporin use in patients with a recorded penicillin allergy. Main Outcomes and Measures: Probability that an antibiotic course was a cephalosporin. A multinomial logistic regression model was used to examine the change in rates of cephalosporin use before and after an EHR penicillin allergy alert was removed in 1 of the study regions. Temporal changes in use rates were controlled for by comparing changes in cephalosporin use among patients with or without a penicillin allergy at the site that removed the warning and among patients at a comparison site that retained the warning. Regression models were used to examine adverse events. Results: Of the 4 206 480 patients who met all inclusion criteria, 2 465 849 (58.6%) were women; the mean (SD) age was 40.5 (23.2) years. A total of 10 652 014 antibiotic courses were administered or dispensed, divided approximately evenly between the period before and after removal of the warning. Before removal of an alert in the electronic health record system to avoid prescribing of cephalosporins to patients with a penicillin allergy at 1 of the 2 sites, 58 228 courses of cephalosporins (accounting for 17.9% of all antibiotic use at the site) were used among patients with a penicillin allergy; after removal of the alert, administration or dispensing of cephalosporins increased by 47% compared with cephalosporin administration or dispensing among patients without a penicillin allergy at the same site and patients at the comparison site that retained the warning (ratio of ratios of odds ratios [RROR], 1.47; 95% CI, 1.38-1.56) . No significant differences in anaphylaxis (9 total cases), new allergies (RROR, 1.02; 95% CI, 0.93-1.12), or treatment failures (RROR, 1.02; 95% CI, 0.99-1.05) were found at the course level. No significant differences were found in all-cause mortality (ratio of ratios of rate ratios [RRRR], 1.03; 95% CI, 0.94-1.13), hospital days (RRRR, 1.04; 95% CI, 0.99-1.10), and new infections (Clostridioides difficile: RRRR, 1.02; 95% CI, 0.84-1.22; methicillin-resistant Staphylococcus aureus: RRRR, 0.87; 95% CI, 0.75-1.00; and vancomycin-resistant Enterococcus: RRRR, 0.82; 95% CI, 0.55-1.22) at the patient level. Conclusions and Relevance: In this cohort study, removal of a warning in the electronic health record to avoid cephalosporin use in patients with penicillin allergies was associated with increased administration and dispensing of cephalosporin. This simple and rapidly implementable system-level intervention may be useful for improvement in antibiotic stewardship.

Drug Allergy Labels Lost in Translation: From Patient to Charts and Backwards.

The current method of defining, reporting, assessment, labeling, delabeling, and reconciliation of adverse drug reactions (ADRs), and specifically immunologically mediated drug hypersensitivity reactions (HSRs), in electronic health records (EHRs) is inadequate and compromises care quality and safety. It is critical to accurately and succinctly report the signs and symptoms associated with ADRs and suspected HSRs to enable clinicians to determine the plausible reaction type and help guide appropriate future management plans. Despite the current limitations of the EHR allergy module, we must encourage improved clinical documentation and demand technological improvements. Telehealth methods have been shown to be valuable in the assessment of ADRs and HSRs, particularly in the case of penicillin allergy evaluation and delabeling. The implementation, assessment, and refinement of advanced technologies, including clinical informatics and artificial intelligence, along with continued education of health care providers have potential to improve EHR documentation and communication, thereby advancing patient safety efforts.

Penicillin Allergy Testing Is Cost-Saving: An Economic Evaluation Study.

BACKGROUND: Having a penicillin allergy label is associated with the use of less appropriate and more expensive antibiotics and increased healthcare utilization. Penicillin allergy testing results in delabeling most allergy claimants and may be cost-saving. This study aimed to project whether penicillin allergy testing in patients reporting a penicillin allergy is cost-saving. METHODS: In this economic evaluation study, we built decision models to project the economic impact of 2 strategies for a patient with a penicillin allergy label: (1) perform diagnostic testing (drug challenges, with or without skin tests); and (2) do not perform diagnostic testing. The health service perspective was adopted, considering costs with penicillin allergy tests, and with hospital bed-days/outpatient visits, antibiotic use, and diagnostic testing. Twenty-four base case decision models were built, accounting for differences in the diagnostic workup, setting (inpatient vs outpatient) and geographic region. Uncertainty was explored via probabilistic sensitivity analyses. RESULTS: Penicillin allergy testing was cost-saving in all decision models built. For models assessing the performance of both skin tests and drug challenges, allergy testing resulted in average savings (in United States [US] dollars) of $657 for inpatients (US: $1444; Europe: $489) and $2746 for outpatients (US: $256; Europe: $6045). 75% of simulations obtained through probabilistic sensitivity analysis identified testing as the less costly option. CONCLUSIONS: Penicillin allergy testing was projected to be cost-saving across different scenarios. These results are devised to inform guidelines, supporting the adoption of policies promoting widespread testing of patients with a penicillin allergy label.

Practical Management of New-Onset Urticaria and Angioedema Presenting in Primary Care, Urgent Care, and the Emergency Department.

A new episode of urticaria and/or angioedema can be an anxiety-inducing event for both the patient and the physician(s) seeing them in primary care, urgent care, or the emergency department. These events are commonly mistaken for "allergic" reactions and often mistreated. The most common causes of new onset urticaria in older children and adults, with or without angioedema, and normal vital signs or hypertension, are post-infection or acute idiopathic urticaria. These patients are not helped by systemic steroids, which may cause morbidity. An IgE-mediated allergy is almost never the cause. These episodes are easy to manage and virtually never life-threatening. Acute idiopathic urticaria is treated with high-dose nonsedating antihistamines acute avoidance of alcohol and nonsteroidal anti-inflammatory drugs, and time. An epinephrine prescription is not indicated for onset acute urticaria or angioedema, unless there is a strong suspicion of anaphylaxis, and they have been acutely treated with epinephrine. When anaphylaxis is suspected, because of hypotension or hypoxia, the treatment of choice is intramuscular epinephrine and supportive care. An acute tryptase then needs to be obtained within 1 to 3 hours of symptom onset, prior to a referral to Allergy. Most angioedema, without itching or hives, is idiopathic. Treatment is supportive care and time. Antihistamines, epinephrine, and systemic corticosteroids are completely ineffective in treating idiopathic or bradykinin-mediated angioedema. Suspect hereditary or acquired angioedema if there is recurrent non-itchy swelling with abdominal pain triggered by mechanical trauma. Only check a C4 prior to a referral to Allergy for a formal diagnosis and long-term management.

Immune-Related Adverse Drug Reactions and Immunologically Mediated Drug Hypersensitivity.

Biologic and other therapies used for the treatment of immune-mediated hypersensitivity conditions, and in people with immune-mediated hypersensitivity, can trigger a wide variety of immune-related adverse drug reactions and immunologically mediated drug hypersensitivities. These range from acute-onset immunoglobulin E-mediated allergies to delayed-onset T-cell-mediated hypersensitivities. Certain therapeutic and diagnostic agents can directly activate mast cells. Biologic agents used to treat immune-mediated hypersensitivity can also globally upregulate or downregulate the immune system leading to pathologic reactions, including cytokine storm and hypogammaglobulinemia.

Tackling the Patient with Multiple Drug "Allergies": Multiple Drug Intolerance Syndrome.

As populations age, the prevalence of reported drug "allergy" increases, often leading to suboptimal care and increased morbidity because of unnecessary avoidance of safe and effective medications. Evaluation by a drug allergy specialist is often warranted when a patient has more than 2 unrelated drug "allergies" listed in the medical record. In this commentary, we clarify and propose standard terminology to use when evaluating patients with multiple drug allergy labels including and more specifically when diagnosing multiple drug intolerance syndrome and the much rarer multiple drug hypersensitivity syndrome. We review epidemiology and key features of multiple drug intolerance syndrome and multiple drug hypersensitivity syndrome. We summarize the methodologic and practical diagnostic workup and management of individuals with MDIS to assist with the accurate delabeling of drug "allergies" in the electronic health record.

Addressing the epidemic of antibiotic "allergy" over-diagnosis.

OBJECTIVE: An epidemic of antibiotic allergy is occurring. DATA SOURCES: Articles published since 2008. STUDY SELECTIONS: Articles on antibiotic allergy and stewardship. RESULTS: A number of overlapping factors contribute. The most important factor is antibiotic overuse. Antibiotics are commonly used in situations in which no antibiotics are indicated. Thirty percent to 50% of ambulatory antibiotic use may be inappropriate. The duration of indicated antibiotic use is often excessive, which leads to more side effects. All antibiotic use can result in adverse reactions, and a fraction of these will be dutifully recorded as an allergy in the electronic health record (EHR). Most EHRs are not well structured to accurately convey information on expected side effects that have occurred, metabolic or other contraindications, dose-related or situational toxicities, personal preferences, clinically significant immunologically mediated hypersensitivity, and other reasons a particular patient may not want or should not be given a specific drug or type of drug in the future. As populations age, their accumulated baggage of reported antibiotic allergies increase. Suspected antibiotic allergy is rarely confirmed with appropriate testing or rechallenge. Patients then receive suboptimal antibiotic therapy and experience more side effects, treatment failures, and serious antibiotic-resistant infections. Reporting an antibiotic allergy in the EHR is nominally done to improve patient safety, but unfortunately, this is often not the actual result. CONCLUSION: Audit and feedback, to help ensure adherence to Choosing Wisely recommendations and good antibiotic stewardship practices, can help reduce inappropriate antibiotic use. Restructuring EHRs to facilitate correct drug intolerance reporting, along with active antibiotic allergy delabeling programs, can help stem this epidemic.

Adverse Reactions Associated with Penicillins, Carbapenems, Monobactams, and Clindamycin: A Retrospective Population-based Study.

BACKGROUND: Limited population-based data on penicillin-, carbapenem-, monobactam-, and clindamycin-associated reported adverse reactions exist. OBJECTIVE: To collect data on penicillin, carbapenem, monobactam, and clindamycin usage and associated adverse reactions. METHODS: Data from January 1, 2009, to December 31, 2017, in Kaiser Permanente Southern California were collected. RESULTS: There were 6,144,422 unique individuals, mean age 33.6 ± 21.1 years, 52.2% females, with at least 1 health care visit during the 9-year study interval, for a total of 37,387,313 patient-years of follow-up. This population was exposed to 5,617,402 courses of oral penicillins, 370,478 courses of parenteral penicillins, 59,645 courses of parenteral carbapenems or monobactams, 817,232 courses of oral clindamycin, and 215,880 courses of parenteral clindamycin. New penicillin allergies were reported more commonly after parenteral (0.85%) compared with oral (0.74%) exposures (P < .0001). There were 22 cases (1 in 255,320) of oral penicillin-associated anaphylaxis and 3 cases (1 in 123,792) of parenteral penicillin-associated anaphylaxis (P < .001). There were 2 clindamycin-associated anaphylaxis cases, 1 (1 in 817,232) oral and 1 (1 in 215,880) parenteral. There were 2 (1 in 2,993,940) penicillin-associated serious cutaneous adverse reaction (SCAR) cases, but both also had co-trimoxazole coexposure within 45 days. There was 1 (1 in 1,033,112) clindamycin-associated SCAR. Clostridioides difficile infection was more common after parenteral exposures, and with extended-spectrum penicillins, beta-lactamase combinations, carbapenems, monobactam, and clindamycin exposures compared with oral penicillins or clindamycin. CONCLUSIONS: Only 1 of 1543 (0.065%) oral and 1 of 1030 (0.097%) parenteral penicillin-associated allergy reports were confirmed to be anaphylaxis. C. difficile was more common after parenteral versus oral penicillin, carbapenem, monobactam, and clindamycin exposures, and with broader spectrum antibiotic exposures.

Large Health System Databases and Drug Hypersensitivity.

Large health system databases have revolutionized our understanding of the epidemiology of adverse drug reactions and immunologically mediated drug hypersensitivity. Population-based background rates of newly reported drug intolerance with each therapeutic exposure could not have been determined without large health system databases. Large databases have increased our understanding of multiple drug intolerance syndrome. Large health care systems, such as Kaiser Permanente, with a single electronic medical record system that covers all inpatient, outpatient, and pharmacy interactions, are particularly valuable in understanding the population-based incidence of severe and nonsevere adverse drug reactions, the risks of delayed-onset adverse drug reactions, such as those caused by Clostridiodes difficile, which can occur months after antibiotic exposures, and the risks and benefits associated with "allergy" delabeling, specifically penicillin allergy delabeling, which may accrue in the years after the delabeling. There currently are limitations to using electronic data, specifically billing code data, when studying adverse drug reactions. It is critical to audit electronic health records, which have temporally associated the use of a drug and an adverse reaction because of high rates of miscoding or lack of true cause and effect. Pending improvements in drug hypersensitivity coding in International Classification of Diseases, Eleventh Revision may make large databases even more useful.

Self-reported beta-lactam intolerance: not a class effect, dangerous to patients, and rarely allergy.

Introduction: About 8% of the United States population carries an unconfirmed penicillin 'allergy' in their medical record. Many physicians needlessly avoid other beta-lactam use in individuals with unconfirmed penicillin allergies. There is a significantly increased risk of developing serious antibiotic-resistant infections, and increased morbidity and mortality in those who report penicillin allergy. Areas covered: Within this study, we reviewed the relevant literature on self-reported beta-lactam allergy. We discuss how the myth of serious allergy to penicillin developed and then discuss and in detail clinically significant immunologically mediated hypersensitivity reactions. Following this discussion, we delineate the risks of not using a beta-lactam when it is the drug of choice and then discuss the epidemiology of beta-lactam-associated anaphylaxis, serious cutaneous adverse reactions, and serious systemic immunologically mediated reactions. Following these topics, we further discuss the consensus current best practices to de-label patients with reported penicillin allergy. Expert opinion: An unconfirmed allergy to penicillin offers considerable harm to patients. Many patients have low-risk allergy symptoms to penicillin who could likely tolerate the medication without having an allergic reaction. The current best practices to de-label reported penicillin allergy is the utilization of a single dose oral challenge, with 1 h of observation, in low-risk patients.