A US-Based Multicenter Retrospective Report of Perioperative Anaphylaxis, 2010-2021.

BACKGROUND: US-based perioperative anaphylaxis (POA) studies are limited to single-center experiences. A recent report found that a serum acute tryptase (sAT) >9.8 ng/mL or mast cell activation (MCA) can predict POA causal agent identification. Urinary mast cell mediator metabolites (uMC) have not been studied in POA. OBJECTIVE: To analyze the epidemiologic data of POA, to determine if sAT or MCA can predict suspected causal agent identification, and to evaluate uMC utility in POA. METHODS: This study is a retrospective multicenter review of POA cases that were subcategorized by suspected causal agent identification status. sAT, MCA (defined as sAT >2 + 1.2 × serum baseline tryptase), and uMC (N-methylhistamine [N-MH], 11ß-prostaglandin-F2α [11ß-PGF2α], leukotriene E4 [LTE4]) were recorded. RESULTS: Of 100 patients (mean age 52 [standard deviation 17] years, 94% adult, 50% female, 90% White, and 2% Hispanic) with POA, 73% had an sAT available, 41% had MCA, 16% had uMC available, and 50% had an identifiable suspected cause. POA cases with an identifiable suspected cause had a positive MCA status (100% vs 78%; P = .01) compared with POA with an unidentifiable cause. An elevated median sAT did not predict causal agent identification. Positive uMC were not associated with suspected causal agent identification during POA. Patients with positive uMC had a higher median sAT (30 vs 6.45 ng/mL; P = .001) and MCA status (96% vs 12%; P = .001) compared with negative uMC patients. Patients with POA had an elevated acute/baseline uMC ratios: 11ß-PGF2α ratio > 1.6, N-MH ratio >1.7, and LTE4 ratio >1.8. CONCLUSIONS: The presence of MCA in POA is associated with suspected causal agent identification. Positive uMC possibly correlate with a higher sAT level and MCA status but require further study. The authors suggest applying an acute/baseline uMC ratio (11ß-PGF2α ratio >1.6, N-MH ratio >1.7, and LTE4 ratio >1.87) in patients with POA for MCA when a tryptase level is inconclusive during POA evaluations.

Predicting Penicillin Allergy: A United States Multicenter Retrospective Study.

BACKGROUND: Using the reaction history in logistic regression and machine learning (ML) models to predict penicillin allergy has been reported based on non-US data. OBJECTIVE: We developed ML positive penicillin allergy testing prediction models from multisite US data. METHODS: Retrospective data from 4 US-based hospitals were grouped into 4 datasets: enriched training (1:3 case-control matched cohort), enriched testing, nonenriched internal testing, and nonenriched external testing. ML algorithms were used for model development. We determined area under the curve (AUC) and applied the Shapley Additive exPlanations (SHAP) framework to interpret risk drivers. RESULTS: Of 4777 patients (mean age 60 [standard deviation: 17] years; 68% women, 91% White, and 86% non-Hispanic) evaluated for penicillin allergy labels, 513 (11%) had positive penicillin allergy testing. Model input variables were frequently missing: immediate or delayed onset (71%), signs or symptoms (13%), and treatment (31%). The gradient-boosted model was the strongest model with an AUC of 0.67 (95% confidence interval [CI]: 0.57-0.77), which improved to 0.87 (95% CI: 0.73-1) when only cases with complete data were used. Top SHAP drivers for positive testing were reactions within the last year and reactions requiring medical attention; female sex and reaction of hives/urticaria were also positive drivers. CONCLUSIONS: An ML prediction model for positive penicillin allergy skin testing using US-based retrospective data did not achieve performance strong enough for acceptance and adoption. The optimal ML prediction model for positive penicillin allergy testing was driven by time since reaction, seek medical attention, female sex, and hives/urticaria.

The Nonirritating Concentrations of Neuromuscular Blocking Agents and Related Compounds.

BACKGROUND: Skin testing (ST) concentrations of neuromuscular blocking agents (NMBAs), NMBA-reversal agents, and the sugammadex-rocuronium inclusion complex (S-R-Cx) vary widely among reports. OBJECTIVE: To determine maximal ST nonirritant concentrations (NICs) of NMBAs (cisatracurium, rocuronium, succinylcholine, and vecuronium), NMBA-reversal agents (neostigmine and sugammadex), and S-R-Cx in NMBA-tolerant and NMBA-naïve participants. METHODS: A single-center, prospective study between October 2019 and November 2021 of adult participants with or without a planned surgical procedure. The reference standard was tolerance of medication tested during a procedure (NMBA-tolerant group) before ST. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at 5-7 increasing concentrations of 1 or more medications. All medications were reconstituted according to package insert instructions and diluted with 0.9% saline. A concentration was considered irritant when more than 5% of participants had a positive test per ST positivity criteria (wheal ≥3 mm than initial wheal and associated erythema of the same size or greater than wheal). We also compared our results with current guidelines. RESULTS: A total of 187 participants (78% NMBA-tolerant) underwent 7812 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT NICs (mg/mL): cisatracurium (0.02), rocuronium (0.05), succinylcholine (0.8), vecuronium (0.01), neostigmine (0.2), sugammadex (50), and S-R-Cx (sugammadex 7.14 + rocuronium 2). CONCLUSION: Our results suggest that SPT may be performed with undiluted stock concentrations. We confirm maximal IDT NICs for cisatracurium and rocuronium. We also propose that currently recommended maximal IDT NICs of succinylcholine, neostigmine, sugammadex, and S-R-Cx could be increased, whereas the maximal IDT NIC of vecuronium could be decreased compared with current guidelines and prior reports.

Bosutinib-Induced Stevens-Johnson Syndrome and Evidence of Tolerance to a Structurally Dissimilar Tyrosine Kinase Inhibitor.

Bosutinib is a breakpoint cluster region-Abelson gene (BCR-ABL) tyrosine kinase inhibitor (TKI) used for the treatment of chronic myeloid leukemia (CML). Patients on TKIs may develop severe cutaneous adverse reactions (SCARs). A 73-year-old female with CML treated with a second-generation TKI (bosutinib) was evaluated after developing fever and a maculopapular exanthema with skin-peeling affecting her lips, oral mucosa, and genitals 10 days after starting the medication. She required hospitalization, bosutinib discontinuation, and management with intravenous corticosteroids and antibiotics. Patch testing was contraindicated due to the severity of the reaction. The patient was subsequently challenged with first-generation TKI along with careful observation without any adverse reactions. She has not reported any adverse reactions while on therapy in the last two years. In patients who have suffered from SCARs, the suspected triggers must be avoided in all instances. In some cases, the underlying condition limits the use of alternative agents, but low-concentration patch testing may help guide alternative therapies within the same medication group. There appears to be a low cross-reactivity among generational TKIs, and our patient benefited from treatment with a structurally dissimilar alternative TKI for her CML.

State-of-the-art beta-adrenoreceptor agonists for the treatment of asthma.

INTRODUCTION: Asthma, a heterogeneous disease, is characterized by chronic airway inflammation and hyperreactivity. ß2-adrenoreceptor agonists (ß2-agonists) remain pivotal for asthma management. Short-acting ß2-agonists (SABAs) result in rapid symptomatic alleviation and bronchospasm prevention. Patients experience significant clinical benefits from therapy with long-acting ß2-agonists (LABAs) with efficacy to bronchodilate, and prolonged lung function betterment. Recently discovered ß2-agonists with longer half-lives offer once-daily dosing. AREAS COVERED: The authors provide a thorough review of the pharmacokinetics, pharmacodynamics, efficacy, tolerability, classification, and safety of ß2-agonists through an in-depth review of current literature using these databases: U.S. National Institutes of Health's National Library of Medicine (NIH/NLM), PubMed Central, and NLM clinical trials. EXPERT OPINION: ß2- agonists act primarily on airway smooth muscle cells and are quintessential for adequate asthma management. Given their pharmacodynamic and pharmacokinetic properties, SABAs are used as rescue medication. Notably, the current Global Initiative for Asthma (GINA) strategy document recommends using LABA/inhaled corticosteroid combinations both as a daily controller and as a rescue medication. Clinicians should assess this new treatment plan on a per-case basis, making sure to evaluate inhaler adherence and treat modifiable risk factors. The development of next-generation ß2- agonists is an exciting research area that could significantly improve patients' adherence to treatment regimens and, consequently, asthma control and quality of life.

IgE-Mediated Reaction to Levamisole: Evaluation of a Patient With Severe Anaphylaxis.

Levamisole has been used as adjuvant immunomodulatory therapy for certain conditions such as amyotrophic lateral sclerosis (ALS). We present a case of a 70-year-old man with ALS who was started on levamisole with adequate response. Within 10 days of treatment, he developed a maculopapular non-pruritic rash on his extremities, and the medication was discontinued. However, two days later, he developed angioedema of the face and hands, urticaria in the extremities and torso, and throat closing sensation that was successfully treated in the emergency department with epinephrine, systemic corticosteroids, and antihistamines. Eight hours later, he presented with recurrent facial angioedema. He was transferred to the ICU and received two more doses of epinephrine and intravenous methylprednisolone. The patient fully recovered within 72 hours and was discharged with the indication to avoid levamisole. One month after the reaction, skin tests (prick and intradermal) with 10-fold dilutions of 550 mg/mL levamisole were positive at a concentration of 55 mg/mL (1:10 dilution). Since the patient developed anaphylaxis and tested positive for levamisole on intradermal testing, and after discussing the options with him, we decided to advise against using this medication since the benefits did not outweigh the risks of administration. This case highlights that IgE-mediated reactions to levamisole, while rare, can occur and be life-threatening. Shared decision-making should be done between patients and physicians after open, evidence-based discussions.

Perioperative Resumption of Direct Oral Anticoagulants: Review of the Mayo Clinic Experience.

OBJECTIVE: We aimed to review recommendations for the postoperative resumption of direct oral anticoagulants (DOACs) and report complications 30 days postoperatively. METHODS: We retrospectively reviewed patients receiving DOAC therapy who underwent preoperative evaluations from January 1, 2015 through May 30, 2018. We noted days that DOAC therapy was withheld, postoperative time until resumption of the DOAC, and complications within 30 postoperative days. RESULTS: A total of 317 patients were included. Ten had complications. Complication rates among patients stratified by time to resumption were not significantly different, except for the deep vein thrombosis rate when DOACs were resumed after 72 hours (n = 2 [4.17%]; P = 0.02). The total time without DOACs did not affect the complication rates. CONCLUSIONS: We suggest withholding DOACs for 48 to 72 hours before surgery and resuming them 48 to 72 hours after surgery, if safe. The interruption of therapy was not associated with an increase in thrombotic events for patients who resumed DOACs within 72 hours postoperatively. Patients who resumed DOACs after 72 hours postoperatively had a low rate of thrombotic complications.

Incidence and risk factors for near-fatal and fatal outcomes after perioperative and periprocedural anaphylaxis in the USA, 2005-2014.

BACKGROUND: The incidence of fatal and near-fatal outcomes after perioperative anaphylaxis is unknown in the USA. Previously identified risk factors of neuromuscular-blocker-induced fatal perioperative anaphylaxis include male sex, obesity, and use of beta blockers. We examined the incidence of fatal and near-fatal outcomes after perioperative anaphylaxis in the USA and the underlying risk factors using a large national database. METHODS: Using the Nationwide Inpatient Sample from 2005 to 2014, we identified cases of fatal and near-fatal perioperative anaphylaxis, defined as perioperative anaphylaxis cases complicated by respiratory or cardiac arrest, using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. RESULTS: Amongst 5223 perioperative anaphylaxis cases, the proportion of near-fatal or fatal cases attributable to perioperative anaphylaxis was 7.0% (95% confidence interval [CI]: 6.2-7.7), with near-fatal perioperative anaphylaxis cases accounting for 5.0% (95% CI: 4.4-5.6%) and fatal cases accounting for 2.0% (95% CI: 1.5-2.5%) of cases overall. Thus, the incidence of fatal or near-fatal perioperative anaphylaxis is 1.26 in 100 000 procedures. Risk factors for fatal or near-fatal perioperative anaphylaxis include age (≥65 yr); undergoing a cardiac procedure; and comorbid conditions of weight loss, non-metastatic solid tumours, metastatic cancer, paralysis, coagulopathy, renal failure, congestive heart failure, fluid and electrolyte disorder, and neurological disorders. Individuals with near-fatal or fatal perioperative anaphylaxis reactions had increased lengths of stay and hospital costs compared with controls. CONCLUSIONS: The incidence of fatal or near-fatal perioperative anaphylaxis in the USA was 1.26 in 100 000 procedures. Risk factors for fatal or near-fatal outcomes include older age, cardiac procedures, and specific comorbidities.

Incidence of and risk factors for perioperative or periprocedural anaphylaxis in the United States from 2005 to 2014.

BACKGROUND: The estimated worldwide incidence of perioperative or periprocedural anaphylaxis (PA) is between 1 in 1250 and 1 in 20,000 procedures. OBJECTIVE: To evaluate the incidence of PA in the United States and compare patient characteristics and underlying risk factors using a large national database. METHODS: Using deidentified data from the nationwide inpatient sample from 2005 to 2014, we identified cases of PA through the International Classification of Diseases, Ninth Revision, Clinical Modification codes and conducted a retrospective analysis. RESULTS: Among 35,647,347 surgeries and procedures, there were 5458 (0.015%) PA cases identified. The incidence of PA was 15.3 cases per 100,000 procedures. When compared with controls, PA cases had an increased mortality (3.4% vs 1.4%; P < .001), median length of stay (5 vs 3 days; P < .001), and median hospital cost ($45,155 vs $24,734; P < .001). The age group between 18 and 34 years (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.13-1.58; P < .001) and female sex (OR, 1.40; 95% CI, 1.31-1.49; P < .001) were associated with increased odds of PA. Transplant (OR, 3.35; 95% CI, 2.59-4.34; P < .001), hematologic (OR, 1.63; 95% CI, 1.30-2.05; P < .001), vascular (OR, 1.49; 95% CI, 1.30-1.67; P < .001), and cardiac (OR, 1.47; 95% CI, 1.30-1.67; P < .001) procedures were at increased risk for PA. Several comorbidities were associated with PA including chronic pulmonary disease (OR, 1.41; 95% CI, 1.31-1.51; P < .001). CONCLUSION: The incidence of PA is 1 in 6531 procedures, with a mortality of 1 in 191,652 procedures. PA has worsening outcomes compared with controls. The risk factors of PA include age, sex, procedure type, and comorbidities.

Self-injectable epinephrine: doctors' attitude and patients' adherence in real-life.

PURPOSE OF REVIEW: Epinephrine is the only life-saving treatment of anaphylaxis. Prescription and administration rates of self-injectable epinephrine are generally low. It is unclear whether this is because of availability, low prescription rates, fear of using epinephrine, or a combination of these issues. RECENT FINDINGS: This review focuses on what self-injectable epinephrine devices (SIED), such as auto-injectors and prefilled syringes, are preferred by patients and healthcare professionals (HCP). Our findings suggest that a device's ease to use, proper and frequent training on its operability, and availability have an impact on preferences and adherence to treatment with SIEDs. After prescribing a patient with a SIED, clinicians should emphasize its use in anaphylaxis, educate patients/caregivers to identify anaphylaxis and on how to use the SIED, and encourage constant practicing with training devices. SUMMARY: Epinephrine is the sole recommended anaphylaxis treatment and SIEDs are of critical usefulness in the community setting. Further studying of these devices is needed to optimize education for HCPs and patients and their accessibility to SIEDs.

Increasing Allergy-Related Emergency Department Visits in the United States, 2007 to 2015.

BACKGROUND: Allergic reactions, angioedema, and anaphylaxis are commonly treated in the emergency department (ED). Contemporary evidence suggests that these conditions may be increasing in the United States. OBJECTIVE: To evaluate the contemporary epidemiology and trends of ED visits for allergic reactions, angioedema, and anaphylaxis in the United States from 2007 to 2015. METHODS: Using de-identified data from the National Hospital Ambulatory Medical Care Survey from 2007 to 2015, we identified cases of acute allergic reactions, angioedema, and anaphylaxis through International Classification of Diseases, 9th Revision, Clinical Modification codes and conducted a retrospective analysis of rates and trends of these allergy-related ED visits. RESULTS: There was a 14% overall increase in allergy-related ED visits between 2007 and 2015. Approximately 10 million ED visits in this time frame were associated with allergy-related conditions accounting for 0.85% (95% CI, 0.79-0.90) of all ED visits in the United States. Almost 3% of allergy-related ED visits were coded as anaphylaxis of which 46.1% (95% CI, 27.5-64.6) received epinephrine. Patients younger than 10 years had a higher relative risk (1.3; 95% CI, 1.0-1.6; P = .027) of allergy-related ED visits per 1000 ED visits than patients 65 years and older, and women also had a higher relative risk (1.4; 95% CI, 1.2-1.5; P < .001) than men. CONCLUSIONS: Allergy-related ED visits increased 14% from 2007 to 2015, with the highest relative risk occurring in patients younger than 10 years. These data provide further evidence of increasing allergic conditions in the United States.

Self-Reported Allergy to Thyroid Replacement Therapy: A Multicenter Retrospective Chart Review.

OBJECTIVE: To determine patterns of adverse drug reactions (ADRs), including immediate drug hypersensitivity reactions (DHRs) and predictable ADRs, to thyroid replacement therapy (TRT). TRT is the treatment of choice for hypothyroidism. Levothyroxine (LT4) is among the most commonly prescribed medications in the United States, with over 70 million prescriptions annually. Documented immediate DHRs to TRT are rare, with only a few case reports. METHODS: An 11-year (2008-2018) retrospective medical chart review of identified patients with self-reported allergy to TRT. ADRs to TRT were divided into immediate DHRs and predictable ADRs. RESULTS: A total of 466 patients were included in our study. We found an overall incidence of ADRs to TRT of 0.3%. Median age was 61.2 years; 85.8% were women, and 94.4% were Caucasian. The principal indication for TRT was autoimmune hypothyroidism (73.6%), followed by postsurgical hypothyroidism (17.4%) and subclinical hypothyroidism (6.7%). Predictable ADR manifestations to TRT were reported more commonly than DHR manifestations (57.5% vs. 42.5%, respectively). The most frequently reported of the former were palpitations (16.4%), nausea/vomiting (9.3%), and tremor (6.3%), while rash (23.8%), hives (9.5%), and pruritus (7.1%) were the most common regarding the latter. Fifty-six percent of the patients with an ADR to TRT tolerated an alternative TRT presentation. CONCLUSION: In our cohort, the majority of self-reported allergies to TRT were due to predictable ADRs rather than an immediate DHR. ABBREVIATIONS: ADR = adverse drug reaction; DHR = drug hypersensitivity reaction; FDA = Food and Drug Administration; LT3 = liothyronine; LT4 = levothyroxine; SCAR = severe cutaneous adverse drug reaction; TRT = thyroid replacement therapy.