Rechallenges without desensitization following platinum-based chemotherapy reactions.

BACKGROUND: There is increasing interest in non-desensitization protocols as a potential way to reintroduce chemotherapy following hypersensitivity reactions (HSR). OBJECTIVE: To provide insight into the potential utility of non-desensitization reintroduction, particularly at institutions where allergy consultation may not be available. METHODS: For 70 patients with platinum HSR who underwent rechallenge with standard (≤2 hours), extended (1-bag, 1-step, 4-6 hours), or titrated (4-to-5-bag and -step, 6-7.5 hours) infusions between 1/2014 and 7/2019, demographics and clinical characteristics were reviewed and initial and breakthrough reactions (BTR) were graded using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Tolerance (no BTR) and completion (dose completed despite BTR) were compared using Fisher's exact test. RESULTS: Patients (mean [standard deviation] age 57 [13] years, initial HSR grade 2 [1]), were rechallenged with standard (n = 8), extended (n = 23), or titrated (n = 22) infusions after oxaliplatin HSR; and standard (n = 5) or titrated (n = 12) after carboplatin HSR. Tolerance and completion were higher for extended versus (vs) standard (tolerance-87%-vs-8%, p < 0.005; completion-96%-vs-38%, p < 0.005) and titrated versus standard (tolerance-76%-vs-8%, p < 0.005; completion-79%-vs-38%, p < 0.05) infusions. CONCLUSIONS: Extended and titrated infusions may increase reintroduction safety compared to standard infusions. Further investigation into extended infusions may provide a safe alternative to standard infusions in patients who may not have access to desensitization at their institution.

United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions.

BACKGROUND: There is no accepted grading system classifying the severity of immediate reactions to drugs. OBJECTIVE: The purpose of this article is to present a proposed grading system developed through the consensus of drug allergy experts from the United States Drug Allergy Registry (USDAR) Consortium. METHODS: The USDAR investigators sought to develop a consensus severity grading system for immediate drug reactions that is applicable to clinical care and research. RESULTS: The USDAR grading scale scores severity levels on a scale of 0 to 4. A grade of no reaction (NR) is used for patients who undergo challenge without any symptoms or signs, and it would confirm a negative challenge result. A grade 0 reaction is indicative of primarily subjective complaints that are commonly seen with both historical drug reactions and during drug challenges, and it would suggest a low likelihood of a true drug allergic reaction. Grades 1 to 4 meet the criteria for a positive challenge result and may be considered indicative of a drug allergy. Grade 1 reactions are suggestive of a potential immediate drug reaction with mild symptoms. Grade 2 reactions are more likely to be immediate drug reactions of moderate severity. Grade 3 reactions have features suggestive of a severe allergic reaction, whereas grade 4 reactions are life-threatening reactions such as anaphylactic shock and fatal anaphylaxis. CONCLUSION: This proposed grading schema for immediate drug reactions improves on prior schemata by being developed specifically for immediate drug reactions and being easy to implement in clinical and research practice.

Drug allergy in older adults: A study from the United States Drug Allergy Registry.

BACKGROUND: Older adults have an increased risk of adverse drug reactions and negative effects associated with alternative antibiotic use. Although the number of antibiotic allergies reported increases with age, the characteristics and outcomes of older adults receiving drug allergy assessment are unknown. OBJECTIVE: To assess the characteristics and outcomes of drug allergy evaluations in older adults. METHODS: We considered patients aged above or equal to 65 years enrolled in the United States Drug Allergy Registry (USDAR), a US multisite prospective cohort (January 16, 2019 to February 28, 2022). Data were summarized using descriptive statistics. RESULTS: Of 1678 USDAR participants from 5 sites, 406 older adults aged above or equal to 65 years (37% 65-69 years, 37% 70-74 years, 16% 75-79 years, and 10% ≥80 years) received 501 drug allergy assessments. USDAR older adults were primarily of female sex (69%), White (94%), and non-Hispanic (98%). Most USDAR older adults reported less than or equal to 1 infections per year (64%) and rated their general health as good, very good, or excellent (80%). Of 296 (59%) penicillin allergy assessments in USDAR older adults, 286 (97%) were disproved. Other drug allergy assessments included sulfonamide (n = 41, 88% disproved) and cephalosporin (n = 20, 95% disproved) antibiotics. All 41 drug allergy labels in USDAR participants aged above or equal to 80 years and all 80 penicillin allergy labels in USDAR men aged above or equal to 65 years were disproved. CONCLUSION: Older adults represented a quarter of USDAR participants but were neither racially nor ethnically diverse and were generally healthy without considerable antibiotic need. Most older adults presented for antibiotic allergy assessments, the vast majority of which were disproved. Drug allergy assessments may be underutilized in the older adults who are most vulnerable to the harms of unconfirmed antibiotic allergy labels.

Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.

Coronavirus disease 2019 vaccine administration in patients with reported reactions to polyethylene glycol- and polysorbate-containing therapeutics.

BACKGROUND: Polyethylene glycol (PEG) and polysorbate reactions were initially implicated as a likely risk factor for reacting to coronavirus disease 2019 (COVID-19) vaccines and remain a source of vaccine hesitancy despite increasing evidence that they do not pose an increased risk for COVID-19 vaccine reactions. OBJECTIVE: To investigate COVID-19 vaccine safety outcomes in patients with reported reactions to PEG- and polysorbate-containing medications and vaccines. METHODS: COVID-19 vaccine safety was reviewed in patients with PEG or polysorbate reactions documented in their electronic medical records at a tertiary academic medical center (cohort 1) and patients referred to Allergy and Immunology with reported PEG or polysorbate reactions (cohort 2). COVID-19 vaccine safety was also reviewed following reported symptoms (onset ≤ 12 hours) to first-dose PEG-containing messenger RNA (mRNA) COVID-19 vaccine (cohort 3). RESULTS: Of 252 patients in cohort 1 (n = 202) and cohort 2 (n = 50), 236 (94%) received mRNA COVID-19 vaccines (106 Pfizer, 130 Moderna); 235 received both doses. Only 3 patients from cohort 2 developed mild rash following vaccination. None of the 44 patients in cohort 3 with acute symptoms following first-dose mRNA COVID-19 vaccine (27 Pfizer, 17 Moderna) had previously reported PEG or polysorbate reactions. Of these 44 patients, 43 received the second dose and all 3 who developed symptoms following the second dose (1 required epinephrine) had negative PEG skin testing. CONCLUSION: Patients with reported reactions to PEG and polysorbate safely received COVID-19 vaccines. PEG and polysorbate skin testing did not identify patients at risk for first dose or recurrent reactions to COVID-19 vaccines. Screening for PEG and polysorbate allergy may only increase vaccine hesitancy without identifying patients at risk for COVID-19 vaccine reactions.

Enabling antibiotic allergy evaluations and reintroduction of first-line antibiotics for patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) often have a history of antibiotic adverse drug reactions (ADRs) that pose a barrier to receiving recommended first-line treatment. Targeted antibiotic allergy evaluations are increasingly recognized as an important strategy for optimization of antimicrobial stewardship. OBJECTIVE: To improve first-line antibiotic use in patients with CF with antibiotic ADRs by streamlining access to antibiotic allergy evaluations and standardizing documentation of plans for antibiotic reintroduction. METHODS: We incorporated allergy evaluations into a multidisciplinary CF clinic and used telemedicine when allergy evaluations could not be performed during CF clinic. Standard documentation of antibiotic allergy plans was used to enable safe reintroduction of first-line antibiotics by CF providers. RESULTS: Strategies used in this study allowed 81.3% (26 of 32) of patients with CF to receive allergy evaluations and antibiotic allergy plans for prioritized antibiotics (penicillin, cephalosporin, sulfonamide), with removal of 41.0% (16 of 39) of prioritized antibiotic ADRs. Only 5.1% (2 of 39) of prioritized antibiotic ADRs evaluated required strict avoidance after evaluation. There were 9 patients who received at least 1 prioritized antibiotic, with 66.6% (6 of 9) of these patients given the antibiotic after only 1 allergy evaluation visit. Furthermore, these strategies allowed allergy evaluations of 23 nonprioritized antibiotics to occur, with removal of the ADR in 39.1% (9 of 23) and use of 77.8% (7 of 9) of nonprioritized antibiotics after removal. CONCLUSION: Incorporating allergy evaluations into a multidisciplinary CF clinic can liberalize first-line antibiotic use in patients with CF. Standard documentation of antibiotic allergy plans allowed antibiotic reintroduction to occur even before complete removal of documented antibiotic ADRs.

Cutaneous Manifestations of Reactions to Biologics.

PURPOSE OF REVIEW: The goal of this paper is to review the major adverse cutaneous reactions that have been reported to the most commonly used biologics. RECENT FINDINGS: Anti-TNF agents and immune checkpoint inhibitors have significant, immune-mediated cutaneous manifestations that can necessitate discontinuation. Anti-TNF agents, IL-6 inhibitors, and IL-12/23 inhibitors can paradoxically cause psoriasis flares or unmask previously undiagnosed psoriasis. IL-17 inhibitors are unique in increasing risk for Candida infections. Benign injection site reactions, non-specific rash, cellulitis, and hypersensitivity reactions are relatively common adverse events. A wide variety of cutaneous reactions caused by biologics have been reported, ranging from benign injection site reactions to life-threatening cutaneous reactions necessitating discontinuation of the implicated biologic agent.

Gastrointestinal Manifestations in X-linked Agammaglobulinemia.

PURPOSE: X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in X-linked agammaglobulinemia (XLA), the spectrum of gastrointestinal manifestations has not previously been fully explored. METHODS: We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the United States Immunodeficiency Network, a national registry of primary immunodeficiencies. RESULTS: In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide ranging, and management strategies were diverse and mainly experimental. CONCLUSIONS: Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.

Immediate and Delayed Hypersensitivity Reactions to Corticosteroids: Evaluation and Management.

Corticosteroids are anti-inflammatory medications used widely to treat allergic inflammation. Although the endocrine and gastrointestinal side effects of corticosteroids have been described, the occurrence of immediate hypersensitivity reactions and delayed contact dermatitis due to corticosteroids remains under-recognized. Hypersensitivity reactions can occur to a corticosteroid itself, or to the additives and vehicles in corticosteroid preparations. Skin testing and oral graded challenge can help confirm the suspected culprit agent in immediate hypersensitivity reactions and help identify an alternative tolerated corticosteroid. Patch testing can help identify the culprit agents in delayed hypersensitivity contact dermatitis. Cross-reactivity patterns have not been observed for immediate hypersensitivity reactions as they have been for delayed contact dermatitis. Sensitization in contact dermatitis exhibits cross-reactivity patterns based on corticosteroid structure. We review the current understanding regarding the clinical presentation, evaluation, and management of immediate and delayed hypersensitivity reactions to corticosteroids.

Immediate and Delayed Hypersensitivity Reactions to Proton Pump Inhibitors: Evaluation and Management.

PPIs are among the most commonly administered medications in the USA and are generally well tolerated. Immediate and delayed immune-mediated hypersensitivity reactions are rare but increasingly recognized adverse effects of proton pump inhibitors (PPIs). Immediate hypersensitivity reactions can occur due to IgE-mediated hypersensitivity to PPIs and can be evaluated by immediate hypersensitivity skin testing and oral provocation challenge testing. A desensitization protocol can be used when PPI use cannot be avoided in an allergic patient. Delayed hypersensitivity reactions to PPIs have also been reported. Occupational exposures causing cutaneous reactions to PPIs are the most commonly reported delayed hypersensitivity reaction, followed by drug-induced subacute cutaneous lupus erythematosus. This review presents a summary of the clinical presentation, diagnostic evaluation, and management of immune-mediated hypersensitivity reactions to PPIs.

Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a clinicopathologic entity of increasing worldwide prevalence. IL-5 is essential for eosinophil trafficking, and anti-IL-5 therapy decreases esophageal eosinophilia. EoE is associated with prominent mast cell infiltration. OBJECTIVE: We investigated whether anti-IL-5 (mepolizumab) treatment reduced esophageal mast cell accumulation in biopsy specimens from pediatric patients with EoE from a previous randomized anti-IL-5 trial. METHODS: A subanalysis was completed for children treated with 0.55, 2.5, or 10 mg/kg mepolizumab monthly for 12 weeks followed by no treatment until week 24. Quantitative immunochemistry was used to assess the numbers of eosinophils, tryptase-positive mast cells, IL-9(+) cells, and mast cell-eosinophil couplets before and after treatment. RESULTS: Forty-three biopsy specimens had adequate tissue for paired analysis. Forty percent of subjects responded to anti-IL-5 (defined as <15 eosinophils per high-power field [hpf] after mepolizumab therapy), and 77% of all subjects had decreased numbers of mast cells after anti-IL-5. In responders epithelial mast cell numbers decreased from 62 to 19 per hpf (P < .001), were significantly lower than in nonresponders after therapy (P < .05), and correlated with eosinophil numbers (r = 0.75, P < .0001). Mast cells and eosinophils were found in couplets before therapy, and these were significantly decreased only in responders after anti-IL-5 (P < .001). Esophageal eosinophils comprised the majority of cells that made the mast cell growth factor IL-9. IL-9(+) cell numbers decreased from 102 to 71 per hpf (P < .001) after anti-IL-5. CONCLUSIONS: Pediatric patients with EoE had significantly fewer mast cells, IL-9(+) cells, and mast cell-eosinophil couplets in the esophageal epithelium after anti-IL-5 therapy. Because eosinophils were one source of IL-9, they might support esophageal mastocytosis.

Impact of an Inpatient Allergy Guideline on ß-Lactam and Alternative Antibiotic Use.

BACKGROUND: A guideline identifying when inpatients with penicillin or cephalosporin antibiotic allergy labels (PCAAL) can receive ß-lactam antibiotics increased ß-lactam receipt at a large northeastern US health care system. OBJECTIVE: To report outcomes of implementing a similar guideline and electronic order set (OS) at an independent academic health care system. METHODS: Penicillin/cephalosporin receipt (percentage of inpatients receiving full doses) and alternative antibiotic use (days of therapy per 1000 patient-days [DOT/1000PD]) were compared over 3 periods before (February 1, 2017, to January 31, 2018) and after guideline implementation (February 1, 2018, to January 31, 2019), and after OS implementation (February 1, 2019, to January 31, 2020) among inpatients with PCAAL admitted on medical services with access to guideline/OS and education (Medical-PCAAL, n = 8721), surgical services with access to guideline/OS without education (Surgical-PCAAL, n = 5069), and obstetrics/gynecology services without interventions (Ob/Gyn-PCAAL, n = 798) and inpatients without PCAAL admitted on the same services (Medical-No-PCAAL, n = 50,840; Surgical-No-PCAAL, n = 29,845; Ob/Gyn-No-PCAAL, n = 6109). χ2 tests were used to compare categorical variables, and analysis of variance was used to compare continuous and interrupted time series analyses (ITSA) to investigate the guideline/OS implementation effect on penicillin/cephalosporin receipt. RESULTS: In the Medical-PCAAL group, penicillin/cephalosporin receipt increased (58%-68%, P < .001), specifically for cefazolin (8%-11%, P = .02) and third- to fifth-generation cephalosporins (43%-48%, P = .04), and aztreonam use decreased (12 DOT/1000PD, P = .03). In the Medical-No-PCAAL group, penicillin/cephalosporin receipt increased (88%-90%, P = .004), specifically for penicillin (40%-44%, P < .001), without changes in aztreonam use. Significant changes were not observed in these outcomes on surgical or obstetrics/gynecology services. Per ITSA, guideline/OS implementation was associated with increased penicillin/cephalosporin receipt in the Medical-PCAAL group only. CONCLUSION: Guideline and OS implementation was associated with improved antibiotic stewardship on inpatient services that also received allergy education.

Drug Allergy Delabeling Programs: Recent Strategies and Targeted Populations.

Drug allergy delabeling programs have become an essential element of antibiotic stewardship. Development of delabeling programs involves careful selection of target patient population, thoughtful design of delabeling approach, stakeholder engagement, assembly of key team members, implementation, and evaluation of clinical and safety outcomes. Recent programs have targeted patients thought to be most likely to benefit from removal of inaccurate antibiotic allergy labels, those with ß-lactam antibiotic allergies and high-risk populations likely to need ß-lactam antibiotics as first-line treatment. This review provides an overview of current risk stratification methods and ß-lactam cross-reactivity data and summarizes how different inpatient and outpatient delabeling programs have used these concepts in delabeling algorithms. ß-Lactam delabeling programs for inpatients, pediatric patients, and programs utilizing telehealth have been implemented with good outcomes. This review also focuses on delabeling programs for high-risk populations likely to benefit from first-line ß-lactam antibiotics. These populations include perioperative, prenatal, and immunocompromised patients. Delabeling programs have been successful in the inpatient and outpatient settings at enabling appropriate antibiotic use. This article reviews delabeling strategies utilized by these programs with a focus on highlighting elements key to their success and future areas for innovation.

Hypersensitivity Reactions to Platinum Agents and Taxanes.

Hypersensitivity reactions (HSRs) to chemotherapy agents can present a serious challenge to treating patients with preferred or first-line therapies. Allergic reactions through an immunologic mechanism have been established for platinum and taxane agents, which are used to treat a wide variety of cancers including gynecologic cancers. Platin HSRs typically occur after multiple cycles of chemotherapy, reflecting the development of drug IgE sensitization, while taxane HSRs often occur on first or second exposure. Despite observed differences between platin and taxane HSRs, drug desensitization has been an effective method to reintroduce both chemotherapeutic agents safely. Skin testing is the primary diagnostic tool used to risk-stratify patients after initial HSRs, with more widespread use for platinum agents than taxanes. Different practices exist around the use of skin testing, drug challenge, and choice of desensitization protocol. Here, we review the epidemiology, mechanism, and clinical presentation of HSRs to platinum and taxane agents, as well as key controversies in their evaluation and management.

Monomeric IgE and mast cell development, survival and function.

Mast cells play a major role in allergy and anaphylaxis, as well as a protective role in immunity against bacteria and venoms (innate immunity) and T-cell activation (acquired immunity).1,2 It was long thought that two steps are essential to mast cell activation. The first step (sensitization) occurs when antigen-specific IgE binds to its high-affinity IgE receptor (FcεRI) expressed on the surface of mast cells. The second step occurs when antigen (Ag) or anti-IgE binds antigen-specific IgE antibodies bound to FcεRI present on the mast cell surface (this mode of stimulation hereafter referred to as IgE+Ag or IgE+anti-IgE stimulation, respectively).Conventional wisdom has been that monomeric IgE plays only an initial, passive role in mast cell activation. However, recent findings have shown that IgE binding to its receptor FcεRI can mediate mast cell activation events even in the absence of antigen (this mode of stimulation hereafter referred to as IgE(-Ag) stimulation). Different subtypes of monomeric IgEs act via IgE(-Ag) stimulation to elicit varied effects on mast cells function, survival and differentiation. This chapter will describe the role of monomeric IgE molecules in allergic reaction, the various effects and mechanisms of action of IgE(-Ag) stimulation on mast cells and what possible developments may arise from this knowledge in the future. Since mast cells are involved in a variety of pathologic and protective responses, understanding the role that monomeric IgE plays in mast cell function, survival and differentiation will hopefully lead to better understanding and treatment of asthma and other allergic diseases, as well as improved understanding of host response to infections.