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Beta-lactam antibiotics are the most commonly reported drug allergy in adults and children. More than 95% of those with reported allergy labels to beta lactams are not confirmed when subjected to allergy testing. Beta lactam antibiotics are associated with a wide spectrum of immediate and delayed drug hypersensitivity reactions. The latency period to symptoms and clinical presentation aids in the causality assessment. Risk stratification based on diagnosis and timing then allows for appropriate management and evaluation. Skin prick testing, intradermal testing and oral challenge are well established for evaluation of immediate reactions. Delayed intradermal testing, patch testing and oral challenge can also be considered for evaluation of mild to moderate delayed reactions. Cross-reactivity between beta-lactams appears to be driven most commonly by a shared R1 side-chain. Standardized algorithms, protocols and pathways are needed for widespread implementation of a pragmatic and effective approach to patients reporting beta lactam allergy.

Objective To review the relevant literature related to children with reported penicillin allergy and highlight the different ways in which children could be delabeled and to evaluate the public health impact that a penicillin allergy has for children. Data Sources Data for this review were obtained via PubMed searches and then retrieval of articles from their respective journals for further review. Study Selections Studies regarding the safety of different ways to evaluate penicillin allergy in children were identified via PubMed searches. Any study that reported different ways of testing (3-tier, direct oral challenge, 5-day oral challenges) were included. This same format was used when selecting relevant articg:les related to the costs, prescription patterns, and stewardship trends associated with a penicillin allergy label. Results This review found that penicillin allergy testing is a safe and effective way to delabel those with reported allergy. In children with low-risk allergy symptoms, a direct oral challenge approach may be optimal. In those children with a history of high-risk allergy symptoms, a 3-tiered approach is ideal. The review also found that there is a significant cost associated with reported penicillin allergy and that there are increased negative health benefits to those children with reported allergy. Conclusion Penicillin allergy is overdiagnosed, often incorrectly, and the label is frequently first applied during childhood. Targeting children for the removal of the incorrect penicillin allergy label provides a mechanism to reduce the use of broader-spectrum and less effective antibiotics.

Anaphylaxis to vaccines is historically a rare event. The coronavirus disease 2019 pandemic drove the need for rapid vaccine production applying a novel antigen delivery system: messenger RNA vaccines packaged in lipid nanoparticles. Unexpectedly, public vaccine administration led to a small number of severe allergic reactions, with resultant substantial public concern, especially within atopic individuals. We reviewed the constituents of the messenger RNA lipid nanoparticle vaccine and considered several contributors to these reactions: (1) contact system activation by nucleic acid, (2) complement recognition of the vaccine-activating allergic effector cells, (3) preexisting antibody recognition of polyethylene glycol, a lipid nanoparticle surface hydrophilic polymer, and (4) direct mast cell activation, coupled with potential genetic or environmental predispositions to hypersensitivity. Unfortunately, measurement of anti–polyethylene glycol antibodies in vitro is not clinically available, and the predictive value of skin testing to polyethylene glycol components as a coronavirus disease 2019 messenger RNA vaccine-specific anaphylaxis marker is unknown. Even less is known regarding the applicability of vaccine use for testing (in vitro/vivo) to ascertain pathogenesis or predict reactivity risk. Expedient and thorough research-based evaluation of patients who have suffered anaphylactic vaccine reactions and prospective clinical trials in putative at-risk individuals are needed to address these concerns during a public health crisis.

International audience

Objective This article reviews the latest science and epidemiologic studies related to drug allergy in children and adults to explore possible mechanisms related to female propensity for drug allergy. Data Sources PubMed literature review, focusing primarily on the last 5 years. Study Selections Articles reviewing the science behind female predisposition to atopic and asthmatic conditions and epidemiologic studies reviewing drug allergy and drug-induced anaphylaxis. Results Despite adult female predilection for atopic conditions, few laboratory studies explore sex-specific mechanisms in atopic/allergic diseases, and most are focused on autoimmunity and asthma. Drug allergy is more frequently reported in adult females compared with adult males. Adult females are also more likely to have drug-induced anaphylaxis (DIA), although no clear sex predominance has been reported in fatal or severe DIA. Studies in children suggest the reverse picture, with prepubertal males more likely to have drug allergy and DIA than prepubertal girls. Conclusion Possible explanations for female predisposition for drug allergy are multifactorial and include disproportionate utilization of health care with more exposure to antibiotics or medications, genetic factors related to the X chromosome, epigenetic changes, and discrepant hormonal interactions with immune cells.

Pediatric drug hypersensitivity is a rapidly evolving field. The purpose of this paper is to review the current state of pediatric drug hypersensitivity and highlight new developments in diagnosis and management. This paper will discuss the safety and use of risk stratification to proceed directly to oral challenge without prior skin testing for β-lactam reactions. We review unique aspects of pediatric drug challenges and desensitizations. It is important to accurately diagnose pediatric drug hypersensitivity reactions through a detailed history, physical examination, and available diagnostic testing. Understanding of the underlying mechanism leads to appropriate classification which is necessary to direct management. The decision to perform drug challenge, desensitization, or recommend avoidance of a medication can have a significant impact on a patient’s treatment. Utilization of weight-based dose and infusion rate adjustments for current drug challenge and desensitization protocols optimize success.

The overlabeling of pediatric antibiotic allergy represents a huge burden in society. Given that up to 10% of the US population is labeled as penicillin allergic, it can be estimated that at least 5 million children in this country are labeled with penicillin allergy. We now understand that most of the cutaneous symptoms that are interpreted as drug allergy are likely viral induced or due to a drug–virus interaction, and they usually do not represent a long-lasting, drug-specific, adaptive immune response to the antibiotic that a child received. Because most antibiotic allergy labels acquired in childhood are carried into adulthood, the overlabeling of antibiotic allergy is a liability that leads to unnecessary long-term health care risks, costs, and antibiotic resistance. Fortunately, awareness of this growing burden is increasing and leading to more emphasis on antibiotic allergy delabeling strategies in the adult population. There is growing literature that is used to support the safe and efficacious use of tools such as skin testing and drug challenge to evaluate and manage children with antibiotic allergy labels. In addition, there is an increasing understanding of antibiotic reactivity within classes and side-chain reactions. In summary, a better overall understanding of the current tools available for the diagnosis and management of adverse drug reactions is likely to change how pediatric primary care providers evaluate and treat patients with such diagnoses and prevent the unnecessary avoidance of antibiotics, particularly penicillins.

Proper management of drug allergy in children is based on a thorough history, in vitro testing (if available), in vivo testing, and drug challenge. This approach has been well developed with beta-lactam drugs but not with non-beta-lactam drugs and monoclonal antibodies. Children commonly develop rashes during an antibiotic course, which can lead to misdiagnosis of drug allergy. Clinical reactions to monoclonal antibodies vary and are managed depending on the type. A better knowledge of drug reactions that can occur in antibiotic allergy and monoclonal allergy can aid a provider in better management of their drug-allergic pediatric patients.

There is growing evidence that the mouse allergen is a major causative factor for allergic rhinitis, conjunctivitis, and asthma in children and adults of urban and rural populations.1 Furthermore, exposure to mice by laboratory animal workers is associated with a high risk of developing occupational allergies.2 Our Allergy practice at Vanderbilt University has recognized a number of patients with poorly controlled allergies to the mice that they work with. This clinical observation prompted an investigation for a better diagnostic and therapeutic option for our patients. The major mouse allergens belong to the lipocalin family of proteins that are synthesized in the mouse liver and secreted in the urine. The major mouse allergen is known as Mus m 1 in the allergen nomenclature. Although detectable in serum and pelt extracts, Mus m 1 concentration is 10 times greater in mouse urine than serum.3 Yet, currently the only commercially available mouse extracts are mouse epithelial extracts which contain varying low concentrations of the major mouse allergen Mus m 1 (0.5–8 µg/mL).4 We hypothesized that a highly concentrated major mouse allergen extract suitable for mouse allergy testing in humans could be isolated from mouse urine. The purpose of the study was to develop a new method for preparing mouse urine allergen extract and assess its diagnostic properties in humans. Volunteers underwent skin prick testing and intranasal challenge with the mouse urine extract to determine the diagnostic performance. To our knowledge, this is the first study to determine the diagnostic performance of mouse urine extract. We asked ALK-Abello Laboratory (Round Rock, TX) to prepare a new mouse urine extract to use in our investigation. Mouse urine collected from male laboratory mice was stored frozen until tested for Mus m 1 (Indoor Biotechnologies, Charlottesville, NC). Urine, containing 2,000 to 3,000 µg/mL of Mus m 1 was dialyzed using 0.4% phenol in normal saline, and then diluted to a concentration of 100 µg/ml. The final extract contained 100 µg/mL of Mus m 1 in 50% glycerin, 0.9% NaCl and 0.4% phenol. Qualitative analysis of protein content in the new mouse urine extract and the commercial mouse epithelial extract (ALK-Abello) were analyzed by reversed-phase liquid chromatography-tandem mass spectrometry.5 Thirty nine healthy individuals (32 women, 7 men, age 18–60 years) with a history of mouse exposure were recruited from Vanderbilt University by means of mass e-mail and advertisement. Volunteers consented verbally and in writing to the protocol that was approved by the Vanderbilt University Committee for the Protection of Human Subjects. An Investigational New Drug agreement with the U.S. Food and Drug Administration for the use of mouse urine extract for skin testing and nasal provocations in humans was in place prior to initiation of the study. Subjects discontinued any medications that could interfere with testing at least 5 days prior to the study. Patients completed a questionnaire to assess mouse-related allergic symptoms and exposure. Volunteers then underwent skin prick testing with common aeroallergens (cat and dog hair, mixed mites, German cockroach, alternaria, cladosporium, Bermuda grass, Johnson grass, pecan pollen, oak, cedar, ragweed, mixed lambs quarter) and the commercial mouse epithelial extract (ALK-Abello). Subsequently, volunteers underwent titrated skin prick testing to the new mouse urine extract. Normal saline was added to the mouse urine extract containing 100 µg/mL of Mus m 1 to produce concentrations of extract ranging from 0.33 µg/mL to 100 µg/mL. Skin prick testing to the new mouse urine extract started at 0.33 µg/mL if positive to the commercial mouse epithelial extract or 1 µg/mL if the subject was negative to the commercial mouse epithelial extract in prior testing. Regardless of the starting point, the dose was then increased by ½ log increments until the subject was considered positive or reached the maximum concentration of 100 µg/mL. Allergy testing was performed using standard guidelines and was considered positive if the wheal was ≥3 mm than negative control at 15 min post-exposure.6 Intradermal testing was not done. In addition, all volunteers, regardless of symptoms, underwent nasal challenge to the new mouse urine extract using the procedure described by Bousquet and colleagues.7 The starting point for the nasal challenge depended on the titrated skin test results and clinical symptoms to mice, as evaluated by the mouse symptom and exposure survey. Each challenge was 0.1mL of full strength mouse extract diluted with 0.9% NaCl beginning with glycerin control followed by increases in concentration of mouse allergen extract until a positive challenge or maximum dose (100 µg/mL) was reached. A positive challenge was determined by using a 13-point symptom score of sneezing, pruritis, rhinorrhea, nasal blockage and ocular symptoms.8 Each symptom was graded by the participant and accumulated to give a total score for each incremental challenge, including the glycerin control.9 The nasal challenge was considered positive if the subject had a non65 cumulative symptom score of ≥5. All participants tolerated the experiments well. The primary statistical objective was to compare the results of the titrated skin prick testing and nasal challenge of the new mouse urine extract. The sensitivity, specificity, positive predictive value and negative predictive value of the titrated skin prick test were calculated using 95% confidence intervals for each of these values by employing the Wilson score-test-based method for calculating confidence intervals for binomial probabilities and R (www.r-project.org) software. Qualitative reversed-phase liquid chromatography-tandem mass spectrometry analysis of the mouse urine extract revealed approximately 26 mouse urine proteins and a minute amount of albumin. In contrast, the commercial mouse epithelial extract contained more than 267 proteins including high amounts of albumin, diverse bioactive proteins including heat shock proteins and other poorly characterized proteins with only small quantities of mouse urine proteins. The mouse exposure and symptom survey was completed by 39 volunteers. These volunteers were exposed to mice on average 14 hours per week. Ninety two percent of participants (36/39) handled mice as laboratory workers. Self diagnosis of allergy to mouse and other aeroallergens based on nasal, ocular, respiratory and skin symptoms was reported by 23/39 (59%) and 29/39 individuals (74%), respectively. Thirty seven had interpretable skin prick testing (2 individuals had dermatographism). Among these 37 patients, 28 (76%) had a positive test with at least one aeroallergen, 13 (35%) with the mouse epithelial extract, and 9 (24%) with the mouse urine extract. Nasal challenge with the mouse urine extract was completed in 35 participants. Two volunteers were excluded from the study because they developed reaction to glycerin control either on skin testing or nasal challenge. Out of the 9 subjects with positive skin test to the mouse urine extract, 8 reported symptoms on the survey, and 7 were positive to nasal challenge using mouse urine extract. All subjects with negative mouse symptom questionnaires had negative nasal challenges. The sensitivity of the new mouse urine extract was 70% (7/10), specificity 92% (23/25), positive predictive value 78% (7/9), and negative predictive value 88% (23/26). The most important characteristics of allergen extracts used for diagnostic challenges and immunotherapy include chemical purity and predictable concentration of the specific antigen. We describe a new mouse urine extract that has a greater concentration of the major mouse allergen Mus m 1 and chemical purity than the commercially available mouse epithelial extract. The urine extract contains mostly mouse urine proteins, whereas the epithelial extract is a mixture of albumin, nonspecific proteins including heat shock proteins with a small amount of Mus m 1. However, despite the improved purity, the mouse urine extract did not demonstrate a clear improvement in diagnostic performance over the previously published data of the diagnostic performance of the mouse epithelial extract.4 Comparative performance is revealed in table 1. Table 1 Comparative Performance of Mouse Urine Extract to Mouse Epithelia Extract These results may suggest that Mus m 1 is not the only allergen causing clinical symptoms to mice. There are studies suggesting that serum albumin may also play an etiologic role in mouse allergy in humans.10 Serum albumin is abundantly present in the mouse epithelial extract. Perhaps, the optimal diagnostic method for mouse allergy should include testing with both Mus m 1 and albumin proteins. Importantly, it is also possible, that the reaction to the highly impure epithelial extract is mediated by both IgE and non-IgE mediated inflammatory pathways, thus only in part assessing a true allergic response to mouse. Thus, we describe a new mouse allergen extract containing pure and highly concentrated mouse urine protein that is suitable for diagnostic purposes in humans. Therefore, in our opinion, despite comparable diagnostic efficacy, the newly described urine extract could be superior to the epithelial extract as a diagnostic and research tool for mouse allergy in humans. Furthermore, if we assume that human allergy to mice is similar to cat and dog in which there is a dose dependent response to the major allergen in immunotherapy, then in the future this new extract could be used to develop desensitization methods based on dose of major allergen.11,12 This could give laboratory workers as well as children and adults with severe allergy and asthma to mice an option for relief that was previously never available.